Using pacemakers to electrically retune a heart
damaged by long bouts of a wobbling heartbeat,
where one heart muscle wall is beating sooner than the
other, leads to fast improvements in the tissue
levels of more than a dozen proteins key to the organ's
health, scientists at Johns Hopkins report in
experiments in dogs.
The team's findings, published online March 3 in the
journal Circulation, are believed to be the
first detailed chemical analysis of the pacemaker's
biological effects on the heart and could serve as
the basis for more strategic use of combined
device-plus-drug treatments for people with congestive
"Our results really help explain how pacemakers act
much like a drug, actually changing the
biology of the heart, and also explain why people can feel
so much better after just two to six months
with the device," said senior study investigator and
cardiologist David Kass, a professor at the Johns
Hopkins School of Medicine and its
Lead investigator Khalid Chakir, a postdoctoral
cardiology research fellow at Johns Hopkins,
said, "We are learning that pacemaker therapy does
profoundly more than just mechanically correct
how the heart beats; in fact, it produces major chemical
changes that benefit the muscle."
Each year, more than a half-million Americans are
diagnosed with congestive heart failure, when
the heart weakens and cannot pump enough blood to the rest
of the body. One-quarter of those men
and women affected, typically over age 50, will suffer from
a pendulating, nonuniform contraction,
requiring implantation of a pacemaker. The device
electrically stimulates both sides of the heart at
the same time, as part of so-called cardiac
resynchronization therapy to restore unison to the
Current treatments with pacemakers, scientists say,
can block the ill effects of an uneven
heartbeat, extending people's lives for months to years or
helping them return to daily activities. But
these benefits do not directly fix the cause for the
delayed conduction; they merely circumvent it.
"Now that we have found that resynchronization is
doing more fundamental things to the heart
muscle, we should be able to better combine these devices
with drugs to maximize long-term survival
and outcomes," said Kass, who is the Abraham and Virginia
Weiss Professor of Cardiology.
Chakir says previous research has shown that a year
after implantation, pacemaker
resynchronization has been effective at reducing mortality
in some heart failure patients by as much
as 36 percent, but researchers have not until now really
understood the biological effect of the
devices beyond the physical mechanics of contraction.
In the current study, the Johns Hopkins team
determined the biological effects of pacemaker
treatment on the hearts of 22 dogs with heart failure
induced by making the heart beat faster. A key
nervelike electrical pathway that normally assures the
muscle's harmonious beat was also damaged,
producing a wobbly, discoordinated contraction. In half the
dogs, the asymmetric heart-failure
condition was allowed to take its natural progressive
course; the others had cardiac resynchronization
therapy with implantation of a pacemaker.
Results from tissue analysis in these two groups were
then compared to a third group of six
dogs with healthy hearts.
In the heart failure groups, the scientists report
major ups and downs in production or activity
levels in 17 out of more than two dozen proteins known to
be involved with heart cell stress, survival
The alterations were especially notable in the group
of dogs that did not have their hearts
retuned. But tissue levels and activity of these proteins
were restored toward normal in those with
pacemakers that were tuned to re-establish an even,
coordinated contraction, with both sides beating
at the same time.
Among the stand-out proteins was one that prevents
heart muscle cells from dying, an enzyme
called phospho-BCL2 antagonist of cell death, or pBAD for
short, which was found to be five times
more active in the pacemaker-treated group than in the
A second protein, p38 MAP kinase, known to stimulate
fibrosis and cell death, was twice as
active in late-contracting parts of failing hearts in
untreated dogs than in the same heart zone of
dogs who underwent pacemaker resynchronization therapy.
Other proteins that lead to heart cell death and
worsen contraction were overexpressed in
dogs with untreated heart failure but not in the
pacemaker-treated group. These included calcium-
calmodulin-dependent kinase, which is linked to arrhythmia,
and tumor necrosis factor-alpha, which is
also tied to damaging inflammation and cell death.
The enzyme Akt, a promoter of cell survival when
turned on, was markedly less active in the
group whose hearts continued to beat out of sync.
Researchers next plan to look at how pacemakers
stimulate biological changes in the heart, with
the aim of developing treatments that bring the heart back
to a normal, healthy state.
In cardiac resynchronization therapy, both major
pumping chambers, known as the right and
left ventricles, are stimulated at the same time with a
biventricular pacemaker to optimize the
muscle's beat so that one side does not beat a short time
before the other.
The American Heart Association estimates that more
than 5 million Americans have some form
of congestive heart failure, marked by symptoms such as
shortness of breath and fatigue.
Funding for the study was provided by the National
Institutes of Health and the Peter Belfer
In addition to Kass and Chakir, researchers involved
in this study, conducted solely at Johns
Hopkins, were Samantapudi Daya, Richard Tunin, Robert Helm,
Melissa Byrne, Veronica Dimaano,
Albert C. Lardo, Theodore Abraham and Gordon Tomaselli.