Jan. 2, 2002 DALLAS, Dec. 31 – 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 reblock. 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 monitoring.
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 clinical trial.
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 vessel formation.
The researchers concluded that human umbilical cord blood is a 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 attack.
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 muscle.
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 disease.
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 more intensely.
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 risk.
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 or 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 intravenous treatment 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 the 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 or obese.
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 exercise.
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.
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