Gene Discoveries Among Top 10 Research Advances In Heart Disease And Stroke For 1999

Other top 10 advances include the first growth of a complete heart valve in the laboratory, robotic bypass surgery, a new use for an old drug, new drugs to help treat stroke and the recognition of diabetes as a major risk for heart disease and stroke.

First created in 1996, the annual list highlights the achievements in basic and clinical research that may have the greatest impact on improving the prevention and treatment of cardiovascular disease, the nation's No. 1 killer.

1. Advancing the quest for a high blood pressure gene

High blood pressure affects some 50 million Americans and increases their risks of heart attack and stroke. Discovery of a gene that makes a protein called mineralocorticoid receptor has helped researchers understand the cause of an inherited form of high blood pressure in children. This finding was reported at the American Heart Association's 53rd High Blood Pressure Research Conference.

Researchers discovered a mutation in a 15-year-old patient with severe high blood pressure. They examined 19 close relatives, eight of whom had been diagnosed with high blood pressure before the age of 20. The eight with early onset high blood pressure all carried the mutation; the other 11 did not.

The protein is a master regulator of the body's handling of salt. The mutation leaves the receptor stuck in the "on" position. This causes the kidney to retain too much salt, ultimately leading to high blood pressure. This discovery extends the list of genes that cause either high or low blood pressure.

2. Tracking down genes that break babies' hearts

Congenital heart defects, often the result of mutated or missing genes, remain the leading cause of death for infants in the Western World during the first year of life. Researchers have now identified a gene that likely contributes to the congenital heart defects associated with DiGeorge syndrome, a common disorder marked by heart and face defects (Science, Feb. 19, 1999).

Researchers tested 182 DiGeorge syndrome patients and found that all of them lacked a gene called UFD1. When the team tested 100 healthy individuals who were unrelated to the patients, all of them had the gene.

The discovery of UFD1 followed the identification of other genes, including some involved in forming a normal heart (Science, July 3, 1998). These findings -- coupled with future discoveries of other genes responsible for malformed hearts -- offer the promise of developing interventions that could prevent many deaths.

3. Fast answers to hard questions about faulty genes

Understanding how a faulty gene causes disease is the key to prevention and treatment. Microarrays, microchips that contain thousands of pieces of DNA, can rapidly probe genes in individuals with inherited diseases. In a process called hybridization, researchers combine the microarrayed DNA with patient DNA that has been labeled with radioactive or fluorescent tags (probes) to reveal missing or mutated genes. With this knowledge, scientists can devise new diagnostic tests and drugs. At the American Heart Association's 72nd Scientific Sessions, researchers reported using microarray analysis to detect a gene defect responsible for Tangier disease -- a discovery with implications far beyond the uncommon disorder. Tangier patients have dangerously low levels of HDL, the "good" cholesterol, and a high risk of heart attack. Their blood vessel walls fail to pump out excess cholesterol for removal by the body.

After analyzing 60,000 genes from Tangier patients, scientists linked the disease to a gene called ABC1. When they added the protein that the gene makes to cells grown in the laboratory, the cells ejected significantly more cholesterol. This finding could lead to drugs to treat not only Tangier patients, but also millions of others with dangerously low levels of HDL (Journal of Clinical Investigation, 104: R25-R-31, 1999).

4. A "stunning" discovery for heart patients

Myocardial "stunning" -- severely weakened contractions of the heart that limit the amount of blood pumped through the body -- can strike people who suffer a heart attack or undergo heart surgery. Innovative animal research has confirmed earlier speculation that myocardial stunning is the result of a specific molecular alteration.

At the 72nd Scientific Sessions, researchers reported that myocardial stunning results from an abnormality in troponin I, a protein vital to ensuring that the heart muscle contracts properly. Scientists demonstrated a link between stunning and a partial breakdown in troponin I by breeding a line of animals that have had a malfunctioning troponin I gene inserted into their own gene. The mice with the altered gene developed myocardial stunning.

The discovery may eventually lead to new drugs that can prevent or reverse myocardial stunning.

5. Growing replacement parts for damaged hearts

It may sound like something from "Star Wars" or "Star Trek," but it's science. Researchers have begun growing heart valves in the laboratory.

Heart valves regulate the flow of blood from the heart's pumping chambers. Malfunctioning valves can cause serious disability or death. Surgeons have replaced damaged valves with either mechanical devices or specially treated and preserved pig valves, both of which have potential drawbacks.

Using a technology called tissue engineering, a team of researchers reported at the 72nd Scientific Sessions that it had grown the first complete in-vitro heart valves and implanted them in sheep, with promising early results. The team used autologous cells, which are cells derived from the blood vessel walls of the recipient sheep, to grow trileaflet pulmonary valves in a device with a chamber that simulates the flow of blood in the body. The trileaflet valve governs blood flow between the heart's right ventricle and the blood vessels leading to the lungs. Six of the valves were implanted in sheep and had functioned well for five months at the time of the report.

6. Diabetes recognized as a major risk factor for heart disease and stroke

The American Heart Association has moved diabetes up to the status of cigarette smoking, high blood pressure, high cholesterol, obesity and a lack of exercise as a major modifiable risk factor for heart disease and stroke.

Diabetes affects about 10.3 million Americans, 90 to 95 percent of whom have Type II diabetes. Another 5.4 million are estimated to have undiagnosed diabetes. A scientific statement published in the September 7, 1999 issue of Circulation: Journal of the American Heart Association, noted that the incidence of Type II diabetes continues to grow. The Type II form is linked to obesity, physical inactivity and genes.

People with diabetes, compared to those without diabetes, have a threefold or greater risk of dying from a heart attack, stroke, heart failure or kidney disease. The statement urged Americans to cut their risk of developing diabetes by exercising regularly and controlling weight.

7. New HOPE for an old drug

The HOPE (Heart Outcomes Prevention Evaluation) trial offered hope to physicians seeking more effective ways to reduce the risk of cardiovascular deaths.

In an international study of 9,541 heart and diabetes patients, researchers discovered that ramipril, a drug that has long been used to lower high blood pressure, can also cut the risk of heart attacks, strokes and other cardiovascular deaths in people at high risk of these events -- even if they have normal blood pressure. The finding was reported at the 72nd Scientific Sessions.

Ramipril belongs to a family of drugs called ACE inhibitors. Although initially developed as a blood pressure lowering drug, ACE inhibitors have multiple protective effects, which include protection of the vessel wall and anti-inflammatory properties. These findings open new avenues for prevention of atherosclerosis.

HOPE researchers also compared vitamin E, an antioxidant, against a placebo to see if it was more effective in preventing cardiovascular problems. It wasn't.

8. Innovative clot-busters help stroke victims

Three hours is considered "the golden window," the time limit for effective results from clot-busters in stroke patients. But a trial (PROACT II ) of recombinant prourokinase, another experimental clot-dissolver, found that the drug could help patients with severe strokes caused by blockages of the middle cerebral artery -- even when given six hours after symptom onset. In another study, researchers testing a clot-dissolving drug derived from the venom of a pit viper snake found it improved stroke patients' chances of regaining the physical and mental abilities they had prior to their stroke. In a 500-person trial, 42 percent of patients given the drug Ancrod within three hours after their first stroke symptoms recovered completely. By comparison, only 34 percent of patients given an inactive substance attained full recovery. The Ancrod patients, however, had a greater risk of bleeding in the brain, 5 percent versus 2 percent of the placebo group.

While the U.S. Food and Drug Administration has not approved the drugs, the two advances spark hope for new acute stroke treatments. Both studies were reported at the American Heart Association's 24th International Conference on Stroke and Cerebral Circulation.

9. New aids for detecting coronary disease

Angiography remains the "gold standard" for definitively diagnosing coronary heart disease. In this procedure, a catheter is inserted into an artery, pushed up to the heart, and a dye injected. X-ray "movies" of the flowing dye reveal artery narrowings that could trigger a heart attack. Although of great benefit, the procedure requires a hospital stay and can cause discomfort and some risk for patients.

Two new imaging procedures, called ultrafast CT and MRA (three-dimensional coronary magnetic resonance angiography) provide noninvasive ways to spot blocked arteries. The ultrafast CT takes fast pictures, producing a very accurate depiction of the amount of calcium in the coronary arteries. Calcium collects in the plaques, which are fatty deposits that may impede coronary blood flow, thus causing angina or triggering a heart attack or stroke. Studies show that the technique is a good measurement of the amount of coronary disease and may help physicians better tailor their treatments. The U.S. Food and Drug Administration approved clinical use of ultrafast CT angiography for the first time in November 1999.

MRA, a second noninvasive imaging test, uses a powerful magnet and radio waves to provide detailed images of the coronary arteries. A study reported in the June 22 issue of Circulation: Journal of the American Heart Association showed that coronary MRA results were similar to X-ray angiography. The test takes less than one hour. Another advantage of MRA is that it also can be used to evaluate cardiac anatomy and other heart functions, thereby providing a comprehensive, noninvasive, cardiac examination.

10. Robotic surgery lends a helping hand to heart surgeons

Bypass surgery has proved to be a lifesaving but invasive procedure. It requires splitting open the chest and usually stopping the heart to sew blood vessels in place that can carry blood around one or more blocked heart arteries.

Early results from a robotic experiment indicate that bypass surgery one day may be done on the beating heart through tiny holes. U.S. researchers who have tested the computer-assisted procedure reported at the 72nd Scientific Sessions that the first 15 patients treated suffered no complications related to the procedure and their grafted veins remained open.

Three holes in the chest allow the insertion of a light/camera unit and two instruments, each held by separate robotic arms. Sitting at a console, the surgeon maneuvers handles shaped like microsurgical instruments that are connected to a computer. The computer controls the robotic-held instruments, which duplicate the surgeon's motions. A major advantage is that the computer can eliminate any quivering of the surgeon's hands, perhaps making the technique useful for microsurgery operations that are currently impossible.