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This is the second part of an interview on the latest developments
in cardiology. Sean Henahan interviewed Dr. Rose Marie Robertson,
outgoing president of the American Heart Association and director
for the Women's Heart Health Institute at Vanderbilt University
Medical Center.
(click here to return to Part 1 of the interview)
Q: What are we learning about individual differences in response
to a given treatment? We hear more and more about the concept of
'tailoring' treatment based on a genetic profile.
A: We are talking about a new way to design and prescribe drugs.
Traditionally we have used a very primitive approach- we find a
plant that is said to have some medicinal property. Reaching blindly
into the closet that mother nature prepares, we pull out compounds
and test effects. If it seems to have a profile of useful effects
in human disease, we pursue that. We might then make versions with
fewer side effects or more convenient dosing, variations on a theme.
Now we can do some different things. We can characterize the place
on a cell where the drug has an effect. We can now understand the
molecular structure and the actual physical chemical structure of
that receptor and can predict what will interact with it. In some
cases we can actually design a drug to react with a specific receptor.
Or we can predict what compound made by the body would interact
with it. One aspect of molecular biology and physical chemistry
has been to help us design drugs better.
When we give drugs, not everyone responds the same. There are many
reasons for that. Sometimes there are differences in how people
break a drug down. The drug might stay in the blood stream of one
person much longer than another person. One person may simply not
respond to a drug at all while the next individual does. There are
variations in all of us in a number of important enzyme systems.
The cytochrome
P450 system would be a good example. There are genetic polymorphisms
between individuals , making different forms of the same enzyme.
Depending which one you make, your response to a drug can be quite
different. The way we know that is to give the drug to someone and
see how they respond. This involves a careful process of testing
and titrating, keeping in mind that some people will have a stronger
response.
If you could predict that a patient might not handle a drug well,
you could alter the way you deliver that drug or select a different
drug. It also may effect how a drug would interact with other drugs
in an individual. The electrical systems of some individuals hearts
have a difference in repolarization, that is, how the heart muscle
handles ions. That changes the electrical activity of the cell.
If someone is susceptible to certain drugs those drugs could cause
serious or fatal heart rhythm problems. Other people could take
those drugs with impunity. We are finally beginning to sort this
out.
Q: Hypertension, or elevated blood
pressure, has long been recognized as a risk factor for heart
disease. Since the 1960s there has been a campaign to increase public
awareness and encourage treatment. How successful has the effort
been?
A: I can hardly say it has been a success. Objectively, we have
to say, given all the information we have, we have really failed
to deliver this information to the public in a way that is effective.
Less than 27% of the public with recognized hypertension have the
hypertension controlled to goal levels.
We do know that in both young and old, bringing the blood pressure
down to goal levels enormously reduces the risk of stroke, heart
failure and death. We have a whole panoply of drugs that are highly
effective, we can almost always find a combination of lifestyle
changes and a drug or combination of drugs that can control blood
pressure without undue side effects.
Despite all this information, we are not doing it. It is really
hard to explain why. There are many barriers to people getting appropriate
care. Some people don't know they have hypertension. Others know
they have hypertension but either don't have access to medical system
because of socioeconomic status or where they live. Still others
don't access the system even though they could, because health is
just not high enough on their radar screens.
We also know that a high proportion of prescriptions for anti-hypertension
medications that are written are not even filled. Some are filled
but not taken for very long. Some of the fault clearly lies with
the medical profession. We don't communicate well enough with our
patients. We may prescribe a medication, the patient takes pill
and notices something and stops taking it. It might or might not
be related to the treatment, but we don't get out the message that
if they have a problem they should call us right away. They shouldn't
wait until the next office visit, missing all that time in between
when we could have been making things better.
I think the public is becoming more empowered and becoming more
insistent, wanting their blood pressure numbers to be made normal.
I see patients saying 'I'm on treatment for my high blood pressure,
but I still have high blood pressure, shouldn't it be lower?' The
answer is yes. Patient-physician partnership is essential.
We have learned a lot about the underlying biology of blood pressure.
In particular we have learned how important the renin-angiotensin
system is, even in patients who are not hypertensive. X One of the
most interesting studies over the last several years was the HOPE
(link?) study, in which patients who did not have high BP but had
other risk factors for coronary disease were treated with an ACE
inhibitor, a drug that inhibits the enzyme that converts angiotensin
1 into angiotensin 2. Preventing high levels of this enzyme has
several interesting effects. For example, there is clearly a benefit
in terms of reduced risk of heart attack, stroke and death, even
in patients who do not have hypertension. Another positive effect
with this treatment is a reduction in the incidence of diabetes.
That trial opened up a whole new set of indications for a drug that
has been around for a while. This shows the importance of continuing
to study drugs even after they are on the market for a while.
Q: One of the ironies of better treatment of cardiovascular
disease is that the incidence of heart failure is increasing as
patients live longer. What have we learned about heart failure that
might lead to better treatment of this problem?
A: This is a fascinating area. A number of years ago, people with
heart failure were all considered to have the same problem. These
patients, with shortness of breath, swollen ankles and physical
limitations were all lumped together. Over the years we have recognized
that there are many different kinds of heart failure. Some will
have heart failure because the heart muscle becomes weak and can't
pump as well. That form is often seen in association with coronary
heart disease or survival after a heart attack. In other cases,
infection of the heart or inflammation of the heart can also cause
heart muscle damage.
In another group with heart failure, the heart looks quite different.
Instead of being enlarged and not pumping very well, these people
will have hearts that are thick and muscular and look like they
are pumping very vigorously. But they are so thick and stiff that
in fact it is hard for the heart to pump, those people have heart
failure for entirely different reasons. The problem is with diastolic
function (filling the heart) rather than systolic dysfunction where
the heart can't squeeze well enough.
In recent years we have identified the genes that can cause many
cases of this form of heart failure, know as hypertrophic cardiomyopathy,
where there is more heart muscle than there ought to be. Because
we've studied families with this problem we can say that we know
specifically which gene causes a problem, and we can identify those
whose condition is associated with normal life span, and those with
different genetic problem, people may be at risk of dying suddenly
at an early age. We would obviously approach those people quite
differently. Genetics have a big difference in this area.
Q: The treatment of heart attack has changed drastically over
the years. Tell us about that.
 A:
We now have several ways to intervene when a person shows up with
a heart attack that can save lives and reduce or nearly eliminate
damage to heart tissue. Our ability to open occluded coronary arteries
with angioplasty (opening a blocked artery with an intravenously
inserted balloon or stent device) or thrombolytic (clot buster)
medicines has saved many lives.
Timing is the key. The impact of these interventions is felt fully
only when get there early. The sooner people come to the hospital
with a heart attack the better we can do. People often don't have
the right concept of what is happening when they have a heart attack.
Recent studies reveal that when people have chest discomfort they
don't realize that while they are sitting there having that discomfort,
wondering what is going on, should I got to the hospital, every
minute that they are sitting there they are losing heart muscle
cells and they are not going to get them back. There is damage occurring
minute by minute The sooner we can restore blood flow, the sooner
we can stop this damage from happening. In contrast, when patient
does recognize that something is wrong and gets to the hospital,
and we get the artery open right away, sometimes you can hardly
tell where the heart attack would have been. That is how we wish
it were all the time.
This field continues to evolve. Our ability to open arteries with
angioplasty, that is putting in a catheter with little balloon,
seems quite effective initially. In most patients we can really
improve blood flow. But we have seen problems. One problem is called
elastic recoil, when the artery recloses once you remove the balloon.
Another is that the catheter itself can rough up the lining of the
artery, which may lead to formation of blood clots. Now, with the
development of new drugs like clopidogrel and ticlopidine, and 2b3a
antagonists, were able to inhibit clotting, making these procedures
much safer.
Other times we see an an actual dissection of the artery, in which
part of the vessel would peel off and close the vessel, causing
damage to the heart. The solution has been to insert a small device
to mechanically hold that vessel open. This device, which looks
something like the spring on a ball-point pen, is called a stent.
This is the stent era. They have really improved outcomes. So where
we once would have had to go from angioplasty with a closed artery
to bypass surgery, now with stents, that hardly ever happens any
more. The stent supports against elastic recoil and keep vessel
wall open mechanically. The combination of stents and the new anti-clotting
medicines and has really been very effective .
A different set of problems are seen with stents. Sometimes the
vessel still wants to re-occlude, and closes up. One approach to
treat this has been to put a radioactive wire in vessel briefly
after to prevent restenosis after angioplasty. We are also now putting
in stents that are coated with drugs that help artery stay open.
Q: Haven't there been some efforts to replace dead heart tissue
with functioning muscle by transferring cells directly?
A: Yes, there are some remarkable clinical studies underway at
the moment. These involve the transfer of stem cells or myocytes
directly into the affected heart tissue in patients who have had
a heart attack.
The problem with people who have had heart attacks is that, they
have a thick fibrous scar on the heart. That scar tissue is not
beating, not functioning, not helping the heart pump blood. Until
this experimental approach we have not had any way to increase the
number of heart muscle cells after they are lost. Now we are moving
to the point where we can produce new heart muscle cells, or find
cells that might de-differentiate and become new heart muscle cells.
We have thought that in adults there are no myoblasts, that is,
cells that can become heart muscle cells. We have found recently
that there are actually cells that can differentiate into muscle
cells in adult patients. There are not many, but they can be teased
to do that.
French researchers took a piece of ordinary muscle tissue from
the leg, and found cells in that muscle that could be persuaded
to transform into cells that work like heart muscle. Remember, the
muscles in are leg are different than the ones in our heart. You
can't have muscle in leg or arm working every day, every night,
continuously without wearing out, whereas heart muscle continues
to work throughout your life.
The French researchers were able to sort out cells that could transform
and act like heart muscle cells and to grow them in tissue culture.
Then, during a bypass surgery, they injected those cells into a
scar area. Remarkably, after the procedure was complete, the researchers
could demonstrate that these cells stayed alive, and were able to
beat. They weren't perfect, but they were beating in an area where
before there was no activity. That was the first patient in the
first study of this kind, so we do have a long way to go. Nonetheless,
there is tremendous promise there.
In addition, we are also finding stem cells in our blood and bone
marrow that we used to think could only become blood cells. It looks
like we will be able to tease those stem cells into becoming new
blood vessels. This is tremendously encouraging because there are
more than 4.5 million in this country with heart failure.
Q: Another approach has been to try and encourage the growth
of new vessels to improve impaired blood supply in the heart. What
is the outlook on that front?
A: I think this is an exciting field. This could be a beneficial
approach in patients with coronary artery disease who have lost
blood supply to parts of the heart who may be having chest pain
or in those who have lost part of heart function who may not be
candidates for bypass surgery. If we could find ways to grow new
blood vessels we could supply the heart muscle with oxygen, making
it able to work better. The body has its own system for providing
new blood vessels when we need them, but doesn't always do so. We
are looking at ways to develop either genes or proteins cause new
vessels to sprout and produce functional blood flow. We are already
beginning to see evidence that providing these compounds like vascular
endothelial growth factor et al., either by putting gene in the
heart, getting it into cells and having it produce the protein,
or just getting the protein there, it appears that we can cause
new blood vessels to sprout, in areas of insufficient blood flow.
Q: What are the major challenges in the battle against heart
disease?
A: We need more people! We will need a lot of people to come into
the field to carry on the clinical work and follow up on findings
of human genome project. As more genetic information becomes available
we need more people who can look carefully at patients or do basic
work in molecular biology. Education is expensive. Many medical
students get to a point where they would consider a research career,
but have accumulated so much debt, maybe $100,000. A Bill passed
recently by the US Congress could help. It would encourage those
people to consider research careers by paying back a significant
portion of their educational debt..
It is incredibly exciting when you find an answer to even a small
part of the questions, it is a terrific feeling. You get tremendous
satisfaction when developing ways to treat or prevent diseases,
help people lead healthier lives. There is also great intellectual
excitement of being able to solve these complex problems. There
are no careers that are more satisfying or more fun than medicine
and science.
Click here to return to part 1
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