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Halting a common virus
may help transplant patients
avoid further heart
disease.
MAYBE IT SHOULDN'T BE SURPRISING:
HEART DISEASE IS THE BIGGEST THREAT TO PEOPLE WITH HEART TRANSPLANTS
WHO HAVE SURVIVED A YEAR AFTER SURGERY.
* Worldwide, surgeons perform 2,000 heart transplants a year.
Within five years of receiving a new heart, half of all heart transplant
patients have already collected dangerous clumps that narrow the
heart's arteries, a condition known as transplant coronary artery
disease.
"Beyond the first year, this disease is the most
important predictor of death, so it's a pretty important issue in
the transplant world," says cardiovascular specialist Hannah A.
Valantine, MD, PhD, an associate professor of medicine.
But Valantine and her colleagues have encouraging
news. In the last decade, these Stanford University School of Medicine
researchers, who lead the way in understanding transplant coronary
disease, have detected substantial, albeit circumstantial, evidence
that a common, usually harmless virus is a prime culprit in the
disease. And it appears that stopping the virus can decrease transplant
coronary disease's occurrence.
The virus, called c ytomegalovirus
(CMV), infects 80 percent of the world's population and persists
for life. CMV apparently causes damage only to people with poorly
working immune systems, like transplant patients, and to the fetuses
of women who become infected during pregnancy.
The mounting evidence -- most recently published
in a paper Valantine authored in the July 6, 1999, issue of Circulation
-- has broad implications for transplant recipients and possibly
even for those in the general population who suffer from coronary
disease.
For one, the link between CMV and transplant coronary
disease overturns the long-held belief among the transplant community
that the disease results purely from a zealous immune response against
the new organ. The past 10 years of transplantation has seen powerful
drugs to suppress the immune system, yet an ongoing high rate of
transplant coronary disease.
Instead, research suggests that the disease is an
accelerated form of what people without transplants get and that
both stem from injury or inflammation in the artery walls. Many
things, including viral infections, can cause such damage. Direct
experiments on CMV indicate it expresses genes that alter its host's
immune response and induce inflammation, says CMV expert Ed Mocarski,
PhD, professor of microbiology and immunology. Virus-infected cells
in artery walls, along with responding immune cells and cholesterol
deposits can lead to narrowing of the blood vessels and clots. This
deeper understanding of CMV's role in coronary disease promises
to help prevent and treat disease in transplant recipients.
But what does it tell us about coronary disease in
the general population? "There is some evidence that CMV is important
in native, or non-transplant, coronary artery disease, which affects
one million people a year," says Valantine. She believes the disease
in transplant patients could be a helpful model
for the disease experienced in the general population because it
develops so rapidly in the former.
In July, Valantine and colleagues added more flesh
to the model when they reported in Circulation that patients
taking an anti-CMV drug immediately after transplantation had fewer
cases of the disease than a group receiving a placebo.
The study really began 10 years ago, when professor
of medicine Thomas Merigan, MD, started a randomized clinical trial
on the then-experimental anti-viral drug, ganciclovir. He found
that treating patients with ganciclovir for the first 28 days after
heart transplantation reduced CMV infection and illness in the majority
of cases. The drug is now commonly given post-operatively for this
reason.
CMV illness, the most frequent post-transplant infection,
can be deadly to newly transplanted patients and increases the risk
of organ rejection.
"We did not know at the time that CMV was also important
in transplant coronary disease," Valantine recounts.
Conveniently, transplant patients come in annually
for close examination, creating years of abundant records. So when
a possible link between CMV and coronary disease emerged, researchers
already had information available for analysis.
"This gave us the opportunity later to ask the question:
Did ganciclovir also prevent transplant coronary disease long term?"
says Valantine.
Valantine and her colleagues looked at six years
of records for 121 patients in the Merigan trial
and analyzed rates of coronary disease in the group treated with
ganciclovir versus the group given a placebo.
"It turned out there was a lower incidence in people
who received ganciclovir. The difference approached clinical significance
for the whole group. In the cohort at highest risk because they
were taking no other preventive therapies, patients treated with
ganciclovir had a highly significant reduction in coronary disease
compared with those not on ganciclovir," Valantine explains.
Overall, 43 percent of ganciclovir-treated patients
developed the disease versus 60 percent in the non-treated group.
For the subset of patients not taking calcium blockers, a preventive
therapy for coronary disease, only 32 percent getting ganciclovir
developed the disease, compared with 62 percent on placebo. The
study results point to a complex disease, hope for prevention and
"indirect evidence of an important role for CMV infection in coronary
disease," Valantine notes.
Analysis of many risk factors found that the most
significant predictors of transplant coronary disease in CMV-infected
patients were not receiving ganciclovir (almost triple the risk)
and a donor heart more than 40 years old (2.7 times the risk).
The paper states that the results are "potentially
flawed" because the original clinical trial was not designed to
study coronary disease, so the analysis lacks certainty.
To directly address the question, Valantine recommends
a larger study with the proper statistical power. She has just submitted
a grant request to the National Institutes of Health for a controlled
clinical trial of 380 patients randomized to one month or six months
on ganciclovir immediately after surgery. Researchers would use
several methods to measure coronary disease in patients once a year
for five years.
No clinical trial has directly tested whether preventing
CMV illness protects patients from developing coronary disease,
she says.
"Her research makes an interesting observation. It
really suggests larger studies should be done," says Mocarski. "The
broader literature trying to tie CMV to coronary diseases is very
mixed; some studies see an association with CMV infection, some
don't."
Paper co-author John S. Schroeder, MD, professor
of medicine, also looks forward to a definitive clinical trial but
sees immediate benefits for patients.
"Anything we can do to reduce or stop transplant
coronary disease means better survival, better use of donor organs
and a better lifestyle for patients," Schroeder says.
There is now quite a lot doctors can do. "There have
been three big advances in clinical practice in preventing transplant
coronary disease, and they are all complementary," he says.
First, Schroeder and colleagues showed in 1993 that
prescribing calcium blockers -- a common drug for people with hypertension
or chest pain -- within one week of surgery inhibits coronary disease
in transplant patients as well.
Second, research done at UCLA showed that giving
statin drugs to reduce cholesterol levels also reduced transplant
coronary disease. Third, Valantine's new study indicates that using
ganciclovir immediately after transplantation reduces coronary disease
in addition to preventing CMV illness. However, long-term therapy
with this antiviral drug is difficult because of its toxicity, Mocarski
notes.
Says Schroeder: "These advances mean more drugs but
less morbidity and mortality." SM
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