DALLAS (American Heart Association) -- New treatments for
heart failure - implantable heart devices and cell-grown tissues
- are among the top 10 research advances in heart disease
and stroke for 2001, says David Faxon, M.D., president of the
American Heart Association.
Other major milestones include drug-eluting stents and the use
of stem cell transplants to repair stroke-damaged brains.
Created in 1996, the "Top 10" list highlights major gains in
heart disease and stroke research.
1. Drug-eluting stents to prevent reblockage of coronary
arteries. In what could become one of the biggest
breakthroughs in treating cardiovascular disease, scientists
used drug-coated stents to prevent the reblockage of the
stented section of a coronary artery. Reblockage occurs in
about 15 percent to 30 percent of angioplasty patients who
receive stents. Researchers involved in several clinical trials
have found that stents coated with a drug prevent the
overgrowth of cells that typically causes the stented artery to
The RAVEL study of 238 patients at 19 centers across Europe
and Latin America compared patients who received a standard
stent to those who received one coated with Sirolimus, an
antibiotic that inhibits the overgrowth of cells. The results were
presented at September's European Society of Cardiology
meeting in Stockholm. No patients who received the
drug-eluting stent had restenosis (reblockage) at the
seven-month follow-up, but 26 percent of those who received
conventional stents had reblockage. Patients who received the
drug-eluting stent also had a significant reduction in major
cardiac events such as heart attack or death during the
follow-up period (3.3 percent vs. 27.1 percent).
Results from ELUTES (European Evaluation of Paclitaxel Eluting
Stent) were presented at the American Heart Association's
2001 Scientific Sessions in Anaheim, Calif., in November. The
192 patients in ELUTES were divided into five groups. Four
groups received a stent coated with varying doses of the
cancer drug. Patients in the fifth group were used as controls.
At six-months follow-up, the group that received the stent with
the highest dose had a 3.1 percent restenosis rate compared
with a 20.6 percent reblockage rate in the control group. A
number of other drug-eluting stent trials are under way.
2. Implantable left ventricular assist devices serve as
"replacement therapy" for end-stage heart failure. Heart failure
patients treated with a left ventricular assist device (LVAD)
lived longer and better than patients who did not receive the
device. In a study called REMATCH, 68 patients received the
LVAD and 61 patients were treated with drugs and medical
Surgeons implanted the pump, which is the size of a compact
disc player, into the upper part of the abdominal wall or in the
peritoneal lining. A tube on the device enters the left ventricle
and drains blood from the ventricle into the device. The pump
sends the blood to the aorta. Another tube attached to the
pump extends outside the body and is attached to a
videotape-sized battery pack, which is worn on a shoulder
holster. Patients wear a beeper-sized control system on a belt.
The device assists the heart's left ventricle, which becomes
weakened in heart failure. The LVAD lets blood pass from the
left ventricle to the aorta, which supplies oxygen-rich blood to
the brain and the rest of the body.
In early human trials, researchers tested the LVAD as a
"bridge-to-transplant device." This paved the way for its
ultimate use - a long-term heart replacement therapy for
patients not eligible for heart transplants. An estimated 50,000
to 100,000 people with end-stage heart failure could benefit
from this type of therapy.
3. Implantable heart showing promise. On July 2, 2001,
59-year-old Robert Tools became the first person to receive the
AbioCor implantable heart. He lived for 151 days. Cause of
death was severe abdominal bleeding according to his
physician Robert D. Dowling, M.D., of Jewish Hospital in
Louisville, Ky., who performed the procedure. Jewish Hospital is
one of five sites participating in the AbioCor artificial heart
Tools, like other patients in the trial, had severe heart failure
and was too ill for a heart transplant. The trial determined
whether the implantable heart can extend life with acceptable
quality for patients with less than 30 days' life expectancy, and
for whom no other therapeutic alternative exists. To be
accepted, patients must have severe heart failure affecting
both the left and right ventricles of the heart and have a life
expectancy of no more than 30 days.
The heart is implanted in the chest and mimics the function of
the human heart by circulating blood through the body. It is
battery-operated and weighs only about 2 pounds.
The heart may eventually be an alternative for patients who
are candidates for heart transplants but for whom no donor
human heart is available. An estimated 4.7 million Americans
have congestive heart failure. Many of them would be
candidates for a heart transplant, but only about 2,000 donor
hearts are available each year in the United States.
4. Tissue engineering with bone marrow and cord blood grows
heart parts. Cardiovascular surgery requires replacement parts
such as heart valves, blood vessels and vascular patches, but
their function may be complicated by blood clots, tissue
overgrowth, limited durability, infection and the inability to
grow. The body can reject donor tissue. Tissue engineering
using a patient's own blood or cells offers an alternative
source. It holds particular promise in pediatric surgery where a
graft with growth potential is important.
Researchers at the University Hospital Zurich in Switzerland
used human bone marrow cells as a new cell type to engineer
heart valves in the laboratory. The cells were seeded on heart
valve scaffolds made from bioabsorbable materials and grown
in a pulse duplicator bioreactor system that mimics the blood
circulation of humans.
Heart valves open and close to let blood flow in only one
direction as it is pumped through the heart's chambers. Each
valve has several flap-like structures, called leaflets or cusps.
The engineered human valves opened and closed
synchronously in the pulse duplicator system. Microscopic
examination showed an even cell growth and mechanical
function was comparable to natural human heart valves.
In 1999, this group was the first to grow a complete heart
valve in the laboratory in a study that used cells from sheep
blood vessel walls. The valves showed excellent functional
performance in blood circulation and strongly resembled natural
heart valves. Another group used early-stage endothelial cells,
called endothelial progenitor cells (EPCs), from human umbilical
cord blood to create endothelial layers for cardiovascular tissue
engineering. EPCs came from cord blood obtained after a
C-section and were culture-grown.
The new cells were seeded onto a bioabsorbable polymer
scaffold to make tissue strips with the potential to be molded
into any form (valve, vessel, patch, etc.). The cells were treated
with vascular endothelial growth factor (VEGF) and fibroblast
growth factor (bFGF) to stimulate cell growth. The treated cells
were grown in a pulse duplicator system for two weeks. The
cells formed capillary-like tubes, indicating the start of blood
The researchers concluded that human umbilical cord blood is
valuable source of EPCs, providing novel cells for tissue
engineering. The exciting possibilities for this cell source include
"banking" the cells for future use. Cord blood cells could
potentially be used to create a tissue-engineered structure
needed to correct a cardiac birth defect diagnosed prenatally.
The new tissue could be ready to use when the baby is born -
or even before birth for potential prenatal/fetal surgical repair.
In other cell transplant experiments, adult human cardiac
myocytes (heart muscle cells) regenerated after heart attack.
This means the heart may be able to replace damaged tissue
by producing new functional cells. A subpopulation of myocytes
that is not "terminally differentiated" re-entered the cell cycle
and divided after the infarction. In similar research, adult stem
cells derived from bone marrow regenerated, forming new
functional heart cells when injected around the site of the heart
5. Gene therapy shown to reduce angina. Experimental
treatments using genes for vascular endothelial growth factor
(VEGF) are not new. But in 2001 researchers brought a new
twist to this pioneering treatment for coronary artery disease.
For the first time, researchers have data from a randomized,
blinded, placebo-controlled trial indicating that blood flow to the
heart improves after VEGF2 treatment. Patients treated with
the VEGF2 gene had less angina, increased their ability to
exercise and had improved myocardial perfusion. Placebo
treated patients had none of these changes.
VEGF is a naturally occurring protein that stimulates the
proliferation and migration of endothelial cells and endothelial
progenitor cells, leading to formation of new blood vessels. The
theory is that injecting the gene into the heart triggers the
growth of new blood vessels in the oxygen-starved heart
Previous trials suggested that gene transfer of VEGF diminished
chest pain and increased blood flow to the heart. However,
those studies used a surgical approach to directly inject the
gene into the heart. Thus, it wasn't possible to have a
placebo-controlled trial, a major limitation of the trials.
In the study, 19 patients with class III or IV angina - the most
severe chest pain associated with heart disease - received six
injections in their left ventricle of either a placebo solution
(saline) or a VEGF2 gene therapy solution. The injections were
made using a special catheter that can identify areas of the
heart muscle that lack an adequate blood supply. The patients
all tolerated the gene delivery procedure without complications.
Angina improved by two to three classes in eight of 12 patients
who received the VEGF2 gene. One person reported that
VEGF2 gene therapy completely eliminated chest pain. None of
the six placebo patients experienced a significant reduction in
angina class. The difference in outcome between the VEGF2-
and placebo-treated patients was statistically significant, a
surprising fact in this relatively small pilot study. A large,
randomized trial is being planned.
6. Cholesterol-lowering drugs bring benefits to high-risk
populations, even when LDL is normal. The MRC/BHF Heart
Protection Study (HPS) is the world's largest randomized trial of
cholesterol-lowering drugs and of antioxidant vitamins in
people at increased risk of coronary heart disease (CHD). Even
though they have been used for decades, statin drugs'
usefulness in particular populations is unknown. The study is
one of the first to include substantial numbers of people in
categories that were excluded from other studies of this kind.
Patients aged 40-80 with a history of occlusive vascular
disease or diabetes were eligible, provided their doctors did
not consider statin therapy a clear choice. Between July 1994
and May 1997, 20,536 patients were recruited in 69 United
Kingdom hospitals. Previous heart attack was reported by
8,510 (most of whom were elderly, female or had "low" total
cholesterol levels). They also had other forms of cardiovascular
disease such as previous stroke or TIA, peripheral artery
disease, diabetes (with overlap between these categories).
Participants were randomly allocated 40 mg of simvastatin daily
or matching placebo for 5 ½ years. Vitamins were given to half
of each treatment group (600 mg vitamin E, 250 mg vitamin C,
20 mg beta-carotene daily). The other half received a placebo.
The vitamins had no effect on vascular or related death or
Cholesterol-lowering therapy reduced total and vascular
mortality, total CHD, stroke, and revascularization procedures.
After making allowance for non-compliance (including non-study
statin use), simvastatin given at 40 mg daily reduced "major
vascular events" by at least one-third among patients (women,
people over 70 years old, those with LDL below 3.0 mmol/l [116
mg/dL] and those with diabetes or non-coronary occlusive
disease without pre-existing CHD).
Further development in treating lipid disorders came from
recommendations from the National Cholesterol Education
Panel (NCEP). They suggest a new approach to treat adults
with elevated blood cholesterol. The recommendations, the
NCEP Adult Treatment Panel III (ATP III), call for physicians to
use "the basic principle" to match the intensity of the therapy
to the person's risk. A table that estimates a person's 10-year
risk is used as a guide for treatment goals. Risk is calculated by
adding points based on the presence of risk factors such as
elevated cholesterol, smoking status, blood pressure, HDL and
age. Individuals with two or more risk factors should be treated
Other new features of ATP III focus on treating diabetes,
multiple metabolic syndrome and other risks factors. The panel
supports a complete lipoprotein profile: total, LDL and HDL
cholesterol and triglyercerides, rather than screening for total
cholesterol or HDL alone. It presents strategies for promoting
lifestyle changes to reduce risk and drug therapies. The report
recommends new targets for optimal LDL levels. Optimal levels
of LDL are 100 mg/dL or less; and low HDL optimal levels
should be from 35 to 40 mg/dL. The triglycerides classification
cut point has been lowered.
Primary prevention of cardiovascular disease should begin with
reducing intakes of saturated fat, increased physical activity
and weight control. Secondary prevention should include
reducing LDL cholesterol below 100 mg/dL by lifestyle changes
and drug therapy.
7. New genetic predictors of cardiovascular disease. In one of
the largest genetic studies of its kind, researchers discovered
three genetic variants that may explain why some families are
prone to premature heart disease. Investigators at 15
institutions used "high throughput" microarray genotyping to
sift through 62 genes of 352 people with coronary artery
disease and 418 individuals without. The culprit genes regulate
thrombospondins (TSP), a family of matrix proteins that helps
blood clot and repair arteries.
The investigators discovered distinctive variations in the genes
of families with coronary artery disease, including a protective
one. Changes known as single-nucleotide polymorphisms (SNP)
were observed in genes that encode the different
thrombospondin proteins. These proteins govern new blood
vessel growth, blood clotting and the blood vessel response to
oxidized low-density lipoprotein cholesterol (LDL).
In the families with coronary artery disease, at least two
members had a heart attack or coronary revascularization at a
young age - before age 45 in men and age 50 in women. The
variant identified as thrombospondin-1 (TSP-1) was associated
with a nine-fold risk of premature heart attack. Those with the
TSP-4 variant had an 89 percent greater risk of heart attack.
The TSP-2 variant was linked to a 69 percent lower heart attack
Individuals with two copies of one of the variants, called the
missense variant in thrombospondin-1, had a higher risk of
early heart disease and the lowest levels of thrombospondin-1
in blood tests. Individuals with variants of the TSP gene tended
to have low levels of thrombospondin. The study, the largest
genotyping of cardiovascular risk to date, may help unravel the
major causes of death and disability.
Mutations in another gene called LMNA cause a disease called
Dunnigan-type familial lipodystropy, in which carriers have a
six-fold increased risk of coronary artery disease. In particular,
women with this gene mutation were found to have a markedly
high rate of coronary artery bypass surgery before the age of
55. Because the mutant gene was also linked with insulin
resistance, type 2 diabetes, lipid problems and hypertension,
this research may help improve the understanding of major
coronary heart disease risk factors.
A third gene for Familial Wolff-Parkinson-White Syndrome was
identified by researchers who conducted genetic studies on 70
members of a family with the syndrome. The syndrome is the
second most common cause of paroxysmal supraventricular
tachycardia (irregular heartbeat). Understanding the genetic
defects may lead to more specific treatments for the disease.
8. Cell transplants offer promise for stroke recovery. Rat stem
cells developed into neurons and other mature brain tissue
when transplanted into normal and stroke-damaged adult rats.
This suggests the possibility that brains and spinal cords can
be repaired following trauma from stroke or other diseases.
Stem cells - which are found mainly in bone marrow in adults
in embryonic tissue - are the blueprint for development of all
the body's organs, including the brain. They have the potential
and the flexibility to grow and differentiate into many kinds of
cells. Until about 10 years ago, many scientists believed that
the ability to regenerate neurons, or nerve cells, of the brain
and spinal cord disappeared soon after birth.
Researchers from Albert Einstein College of Medicine in New
York harvested embryonic cortical cells (which come from the
cerebral cortex - the outer layer of the brain) for the
transplants. The cerebral cortex is the mantle of gray
substance covering each half of the brain. It's responsible for
higher mental functions such as thought, memory and voluntary
movement. This is the area most often damaged by strokes.
Cortical stem cells were injected into the brains of normal adult
rats and adult rats damaged by stroke. The cells were marked
with a chemical that glows when viewed under a fluorescent
microscope. The stem cells grew in the damaged area, forming
connections with neighboring cells. Blood vessels were also
seen growing to nourish the transplanted cells. At 21 to 45
days after the transplants, most stem cells grew into mature
neurons and other mature brain cells.
For his work in this area, the study's lead author, Gaurav
Gupta, M.D., received the American Stroke Association Mordecai
Y.T. Globus Young Investigator of the Year Award.
In another milestone in stroke research at the animal level,
intravenous administration of bone marrow cells reduced
stroke-induced disability. Another study showed that
with adult donor rat stromal cells (mature cells from bone
marrow) allowed the rats to return to normal or near-normal
function within 14 days of a stroke. An infusion of a stroke
patient's own stromal cells may provide benefits and is easily
given. If the treatment continues to show benefits in animals, it
may provide new treatments in the future for stroke, brain
trauma and spinal cord injury in humans. It may also be useful
in treating Parkinson's disease, multiple sclerosis, Alzheimer's
and other neurological diseases.
9. Nurture and nature associated with type 2 diabetes.
Behavior, rather than genetics, may provide the key to reducing
a woman's risk of developing type 2 diabetes. Results from the
Nurses' Health Study suggest that the majority - an estimated
nine out of 10 cases - of type 2 diabetes could be prevented by
weight loss, regular physical activity, healthy diet, abstinence
from smoking, and moderate consumption of alcohol (half to
one drink per day for women). The risk reduction was similar for
women with and without a family history of the disease.
Because diabetes is a major risk factor for cardiovascular
disease, such modifications may help prevent heart disease.
Researchers following nearly 85,000 nurses for 16 years
concluded that an estimated 91 percent of the 3,300 new
cases of type 2 diabetes diagnosed during the study could
have been prevented by lifestyle modifications.
Excess body fat was the single most important risk factor in
development of type 2 diabetes. The heavier a woman was,
the greater her risk of developing the disease, even if she was
at the high end of a normal BMI (body mass index, a measure
of body fat). An estimated 97 million Americans are overweight
Lack of physical activity was also a significant risk, independent
of body weight. Conversely, women who exercised seven or
more hours weekly cut their risk by 50 percent compared with
sedentary women. About 75 percent of the U.S. population is
considered to be minimally engaged in physical activity or daily
The women at lowest risk ate a diet high in cereal fiber and
polyunsaturated fats, and low in saturated and trans fat. They
abstained from smoking and drank moderately.
Of the 10.3 million Americans who have diabetes, about 90
percent have type 2. The number of Americans with diabetes is
expected to rise as more people become overweight or obese.
10. Passive smoking not so passive for arteries. Secondhand
smoke damages the inner layer of the blood vessels, the
endothelium, providing the first direct evidence of passive
smoking's link to heart disease. Researchers studied 30
Japanese men, average age 27, who were exposed to 30
minutes of passive smoke. A pulsed Doppler echocardiography,
a test that measures coronary artery blood flow velocity
noninvasively, provided an indication of coronary circulation,
including endothelial function.
In this test, a substance is injected to dilate the resistant
vessels in coronary circulation. Healthy blood vessels will
respond in a normal fashion to the stress; injured blood
vessels will not respond as well. Although passive smoking did
not reduce active smokers' coronary flow velocity during
hyperemia, it was reduced significantly in nonsmokers.
This finding provides evidence of a direct effect of passive
smoking on the coronary circulation in nonsmokers. And passive
smoking affects flow reserve in nonsmokers more than in active
smokers. This reduction in flow reserve indicates the presence
of endothelial dysfunction, an early process of atherosclerosis
that increases a nonsmoker's risk for heart disease.