Thousands May Be Saved by New Early-Warning of Heart
Attack Found in Five Proteins
Largest protein analysis ever finds blood test that
detects impending attack in those with reduced blood flow
Dr.
Jennifer Van Eyk explains more about protein research in videos
- click here
Nov. 10, 2008 - A far more accurate test to provide
an early warning of an impending heart attack in people with severely
reduced blood flow, or ischemia, was introduced this weekend by John
Hopkins biochemists. They identified a mixed bag of five key proteins
out of thousands secreted into blood draining from the heart's blood
vessels that may together or in certain quantities form the basis of the
test.
"Our results lay the foundation for a
first-of-a-kind, early-warning system that could save tens of thousands
of people on the brink of a heart attack," says Jennifer Van Eyk, Ph.D.,
a professor at the Johns Hopkins University School of Medicine and its
Heart and Vascular Institute.
"People experiencing chest pain too often come to
the emergency room, with subsequent electrocardiogram, also called EKG,
readings not showing any evidence that a heart attack has occurred, but
still leaving open the question of whether or not a heart attack is
imminent and about to happen or has already happened," adds Van Eyk,
senior investigator of the study and director of the Johns Hopkins NHLBI
Proteomics Group and the Proteomics Center at Johns Hopkins Bayview
Medical Center, where the protein analysis took place.
More than 8 million American men and women have
suffered at least one heart attack in their lifetime. Heart attacks
killed almost 157,000 in 2005 alone. Nearly 6 million have suffered a
stroke, which caused 150,000 deaths in 2005.
Van Eyk says people frequently have symptoms of
chest pain, shortness of breath and dizziness, with pale or clammy skin
coloring, while arterial blood is constricted but not yet closed. But
this myriad of complaints can just as easily be mistaken for the more
everyday, less-serious problems of heartburn, stomach cramps or gas.
In 2006, the U.S. Centers for Disease Control and
Prevention reported more than 12,000 visits to doctors' offices and
emergency rooms by people complaining of chest pain.
The work, involving more than a dozen scientists
and taking more than a year to perform, is believed to be the largest
protein analysis ever done at Hopkins. It was based on 76 arterial blood
samples from 19 men and women taken immediately before and after a
period of medically induced ischemia lasting as long as 45 minutes.
All had ischemia induced through accelerated pacing
of the heart's main chambers. Blood samples were provided by
cardiologists at the University of Texas Southwestern.
Key to the researchers' selection criteria for
which proteins to analyze from among tens of thousands in the blood was
what they call "a pipeline approach."
"From the start, we knew that we were looking for
rare, almost unique biomarkers that bore some direct relationship with
ischemia," says Van Eyk.
The first step, she says, was to remove from the
analysis common blood proteins, such as albumin and globulins. That left
batches of 400 proteins for in-depth measure of any changes before and
after ischemia.
Their analysis, presented yesterday at the at the
American Heart Association's (AHA) annual Scientific Sessions in New
Orleans, found that only the five proteins were present in significantly
increased amounts after ischemia occurred, with at least a doubling in
the blood concentration, compared with those recorded during healthy
blood flow.
These were -
● lumican,
● semenogelin,
● angiogenin,
● extracellular matrix protein, and
● so-called long palate, lung and nasal epithelium
carcinoma-associated protein 1.
All of the proteins are believed to originate in
the heart, but they can also be found in other tissues varying from the
corneas of the eyes (lumican) to semen.
Semenogelin, as it is known, has never before been
seen in the heart, while others, such as angiogenin, are more
predictably found in growing blood vessels and muscle tissue, and are
actively involved in tissue repair.
Little is known about the remaining two, which
ironically have the longest names: extracellular matrix protein,
secreted in a rare inflammatory disease; and long palate, lung and nasal
epithelium carcinoma-associated protein 1, thought to play a role in
innate immunity.
The Johns Hopkins biochemists say the presence of
all or even a selected set of these proteins in a simple, rapid blood
test could aid emergency paramedics and physicians during the critical
12- to 24-hour window before ischemia causes substantial heart tissue
damage or death from heart attack.
A positive reading on a blood test incorporating
these proteins, they add, could provide first responders with advance
warning to take urgent action, such as using blood thinners like aspirin
to prevent clotting, or performing cardiac catheterization to check for
any more blockages in the blood vessels feeding the heart, which may in
turn prompt more aggressive treatment.
Further actions could involve angioplasty, in which
a balloon device is threaded into the heart's surrounding blood vessels
and then expanded to widen the arteries, or even surgery.
A new test based on these five proteins, says Van
Eyk, could provide a "more definitive answer" to the question "how
serious is it?" much earlier than existing assays for heart attack, such
as tests for troponin proteins I and T.
Van Eyk says commercially available tests for
cardiac troponin, which is released into the blood in telltale patterns
for heart attack, provide results "too late to take preventive action,"
and "after some damage has already occurred."
Troponin lab tests also depend on the heart muscle
dying first, which can take hours to detect, "So a negative reading is
unreliable and can still mean that an ischemic problem is about to
happen or has already happened," she says.
In the study, the protein analysis was conducted by
mass spectrometry machines that can measure the presence of proteins in
minute amounts. The machines, operated six days a week for six months,
consumed more than 3,700 hours of spectrometric analysis.
Researchers next plan to verify the presence of the
five proteins in a larger study with at least 150 participants, and more
than 1,000 blood samples. Simultaneously, they plan further analysis of
the proteins to map their molecular structures, so that an antibody can
be identified to bind to one or several of the proteins, laying the
basis for a blood test for ischemia. And they will conduct tests to
verify that their study findings also apply to ischemia in stroke.
The technology development in the study and the
"pipeline approach" were supported by the Johns Hopkins Bayview
Proteomics Center. The Johns Hopkins NHLBI Proteomics Group is one of 10
centers funded as part of the U.S., seven-year program dedicated to the
study of proteomics and understanding the functions of proteins in the
development of cells, tissues and organisms, in both normal and disease
processes.
Van Eyk has a patent pending on the protein
analysis. Under an option agreement with The Johns Hopkins University,
Inverness Medical Innovations' Unipath Ltd., in Bedford, United Kingdom,
has the right to negotiate a license to the patent.
Other Johns Hopkins researchers who took part in
this study were Qin Fu, Ph.D.; Simon Sheng, M.Sc.; Steven Elliott,
M.Sc.; and Miroslava Stastna, Ph.D. Additional support was provided by
James de Lemos, M.D., at the University of Texas Southwestern.
(Presentation title: Translating high-throughput cardiovascular
proteomics.)
Funding support for this study was provided by
Inverness.
>> Video clips of Van Eyk commenting about
the role of proteomics in molecular medicine, plus a description of the
workings of a mass spectrometer -
click here.
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Dr.
Jennifer Van Eyk explains more about protein research in videos
- 
Nov.
10, 2008