Tips from the American Heart Association’s Scientific Sessions

Newswise — Described below are several key advances from researchers affiliated with Johns Hopkins to be presented at the AHA's Scientific Sessions 2004.

"PAINTING" TECHNIQUE SUCCESSFULLY TRANSFERS GENE THERAPY TO HEART

(Embargoed for release at 9:30 a.m. CT/10:30 a.m. ET, Sunday, Nov. 7; Abstract Poster Number #47/B36, Hall I-2, Ernest N. Morial Convention Center.)

In experiments with pigs, scientists at Johns Hopkins have successfully used a technique called "gene painting" to target gene therapy to a specific region of the heart and change the heart's rhythm.

"Getting the genes where we want them has been a key limiting factor in the successful development of gene therapies for heart conditions," said cardiac electrophysiologist Kevin Donahue, M.D., an associate professor at The Johns Hopkins University School of Medicine and its Heart Institute. "This new technique brings us one step closer to making gene therapies that can be tested on specific heart problems."

The technique, if future studies in pigs and in humans are promising, could help in the development and delivery of future gene therapies for atrial fibrillation, a common ailment in which the electrical signaling that triggers the heartbeat goes awry.

Donahue led a controlled study that evaluated whether a gene therapy, using a gene called HERG-G628S that helps regulate the heartbeat, could effectively alter the heartbeat in 20 pigs with an irregular heart rhythm. The gene therapy was contained in a plastic, gel-like substance that was "painted" onto the surface of the right atrium of the heart. The gel also contained a dye so that its spread could be tracked inside the organ. After three weeks, the heartbeat had returned to normal, and the dye had penetrated only the atria.

Targeted Modification of Atrial Electrophysiology by Homogeneous Transmural Atrial Gene Transfer. Kan Kikuchi, Tetsuo Sasano, Amy McDonald, Kevin Mills and Kevin Donahue.

****

TRADITIONAL RISK FACTORS FAIL TO IDENTIFY WOMEN AT HIGH RISK OF HEART DISEASE (Embargoed for release at 2:45 p.m. CT/ 3:45 p.m. ET, Monday, Nov. 8; Abstract Oral Sessions #3657, Room 352, Ernest N. Morial Convention Center.)

Traditional risk factor scoring fails to identify most women at high risk of coronary artery disease, according to an analysis by Johns Hopkins researchers. However, more women die of heart disease than do men, but women develop it on average 10 years later.

"A key tool in preventing heart disease is to first identify those who are most likely to develop the condition, many years before symptoms start," said the study's senior author, cardiologist Roger Blumenthal, M.D., an associate professor and the director of the Ciccarone Preventive Cardiology Center at The Johns Hopkins University School of Medicine and its Heart Institute. Blumenthal is also a spokesman for the American Heart Association. "What we now know is that you can identify more women at risk of heart disease when you add measures of lifestyle factors, such as physical activity, habits and body weight, to traditional risk factor assessments, including age, blood pressure, smoking and high blood cholesterol levels."

Drs. Khurram Nasir, Erin Michos and Blumenthal led a study that evaluated the risk of heart disease in 2,447 women with no early signs of heart disease. All the women were older than 45, the age at which most women develop coronary artery disease. When the researchers used traditional risk factor scoring with the Framingham Risk Estimate (FRE), 90 percent of the women tested were classified as very low risk (defined an FRE of less than 10 percent risk of heart attack within the next 10 years). Current guidelines suggest no need for aspirin or cholesterol-lowering therapy for such a low FRE, while also recommending no further cardiac risk assessment for five years. The remaining 10 percent qualified for some kind of therapy. However, subsequent assessment of coronary artery calcification, using electron beam CT scans, showed that twice as many women, 20 percent, actually had advanced atherosclerosis. In these cases, the heart's arteries have become hardened and narrowed due to the buildup of fat and calcium deposits, and treatment should include aspirin and therapies to lower cholesterol levels. The FRE score only captured 16 percent of these cases and erroneously classified 84 percent as being at very low risk of developing heart disease over the next 10 years.

Traditional Rick Factor Assessment Markedly Underestimates Subclinical Atherosclerosis Risk in Asymptomatic Women. Khurram Nasir, Joel Braunstein, John Rumberger, Matthew Budoff, Erin Michos and Roger Blumenthal.

****

ULTRASOUND OF CAROTID ARTERY IN NECK DETECTS EARLY SIGNS OF HEART FAILURE(Embargoed for release at 9:30 a.m. CT/10:30 a.m. ET, Tuesday, Nov. 9; Abstract Poster Number #2771, C104, Hall B1, Ernest N. Morial Convention Center.)

Ultrasound examination of the carotid artery of the neck, plus an MRI to test heart function, can improve identification of individuals most at risk of developing heart failure, according to early study findings by researchers at Johns Hopkins.

"Ultrasound is very effective at identifying early signs of atherosclerosis, the hardening and narrowing of the arteries such as the carotid artery, which is a good tool for identifying people at risk of developing heart failure early on," said the study's lead author, Verônica Fernandes, M.D., a cardiology research fellow at the The Johns Hopkins University School of Medicine and its Heart Institute. "The sooner we know there is a problem, the sooner we can take corrective action, including drug therapy and lifestyle risk factor modification, such as reducing blood pressure, exercising more and adjusting diet to change cholesterol levels.

"While it is too early to suggest that the link between artery thickness and changes in heart function predict the development of heart failure, we can say that the connection does improve our ability to detect the disease in people who do not show any symptoms."

As part of a larger study, the Hopkins team used ultrasound to measure the thickness of the carotid artery wall in 500 men and women between the ages of 45 and 84, with no previous symptoms of heart disease. The researchers found a direct link between increased wall thickness and reduced, or weakened, heart function, which could represent an early indication of heart failure. Indeed, when the researchers measured with MRI the strength of heart contraction, known as the strain and strain rate, they found that people with a carotid wall thickness of less than 0.76 millimeters had better heart function than people with a wall thickness greater than 0.93 mm, who had weaker heart function.

The results were early findings from the Multi-Ethnic Study of Atherosclerosis (MESA), a 10-year study that started in 2000, which is following the heart health of nearly 7,000 men and women to see if they develop atherosclerosis.

Increased Carotid Intima-Media Thickness Is Associated with Regional Myocardial Dysfunction Detected by Tagged MRI in Asymptomatic Individuals: the Multi-Ethnic Study of Atherosclerosis. Verônica Fernandes, Thor Edvardsen, Benilton Carvalho, David Bluemke, Khurram Nasir and João Lima, Johns Hopkins; Joseph Polak and Daniel O'Leary, Tufts-New England Medical Center, Boston, Mass.

****

"WALLFLOWER" BIOCHEMICAL PATHWAY HAS PROTECTIVE ROLE IN HEART FAILURE(Embargoed for release at 3 p.m. CT/4 p.m. ET, Wednesday, Nov. 10; Abstract Oral Sessions #1603, Room 398-399, Ernest N. Morial Convention Center.)

For more than a decade, nitric oxide-making enzymes have been recognized as key players in protecting the heart from further damage after a heart attack, but new research from Johns Hopkins reveals that the least well-studied of the three enzymes could be the most important in the heart.

Most research has focused on the first two versions of the enzyme found in the heart: inducible and endothelial nitric oxide synthase. Now, in animal studies, researchers at Johns Hopkins have confirmed a greater protective role for the last enzyme found, constitutive nitric oxide synthase, also known as myocyte neuronal nitric oxide synthase (NOS1) because of its consistent presence in heart and brain cells.

"Nitric oxide plays a critical role in recovery from a heart attack: It can dilate, or expand, the coronary arteries, and help regulate the strength of the heart's contraction," said cardiologist Roberto Saraiva, M.D., a research fellow at The Johns Hopkins University School of Medicine and its Heart Institute. "Now we know that myocyte neuronal nitric oxide synthase, specifically, increases survival rates and heart function in mice after heart attack. Next, we have to figure out why and, possibly, attempt to harness these benefits as a future therapy."

Mice without the NOS1 gene were 2.5 times more likely to die within 60 days after a heart attack compared to mice with the gene. Indeed, cardiac function was 20 percent worse in the mice without the NOS1 than in the control group.

Neuronal Nitric Oxide Synthase Deficient Mice Have Increased Mortality and Depressed Cardiac Performance Following Myocardial Infarction. Roberto Saraiva, Cheuk Sun, Khalid Minhas, Daniel Durand, Koenraad Vandegaer, Lili Barouch and Joshua Hare.