Duke Scientist Reports Advances In Gene Therapy For Heart Failure

November 08, 1998

DALLAS -- Scientists are one step closer to making gene therapy for heart failure a reality, scientists from Duke University Medical Center reported Sunday.

Molecular biologist Walter J. Koch and his colleagues said in a report prepared for the 71st scientific sessions of the American Heart Association that they have for the first time delivered therapeutic genes throughout a rabbit's heart and have shown that the genes can increase heart function.

The animal experiments are a crucial step in developing a genetic treatment for congestive heart failure, a debilitating and deadly condition in which heart muscle loses its ability to stretch and contract, usually due to clogged arteries caused by coronary artery disease. People with congestive heart failure often experience fatigue, weakness, and an inability to carry out routine daily tasks. Right now, there is no effective means to reverse heart failure, only to treat symptoms.

According to the American Heart Association, about 400,000 new cases are recorded every year in the United States. Death rates from congestive heart failure tripled between 1974 and 1994, making it the leading cause of hospitalization among people 65 and older and costing more than $10 billion a year.

Koch, an associate professor of experimental surgery, and his colleagues have been working for several years to find ways to efficiently deliver genes to the heart to boost heart function.

Early experiments focused on identifying the molecular players that are responsible for efficient pumping action in the heart and showing which ones aren't doing their jobs in failing hearts. Using mouse models and sophisticated genetic techniques, the Duke scientists showed that two key proteins in heart cells work together to regulate heart function.

In diseased hearts, the body releases the hormone norepinephrine, the "fight-or-flight" hormone, directly into the heart, causing it to work up to five times harder than normal. Norepinephrine binds to molecules called beta adrenergic receptors (BARs) present on heart cells. This stimulation initially allows the heart to increase the power of its contractions, but in heart failure it quickly becomes self-defeating: the receptors become desensitized, meaning they no longer are able to respond to hormone stimulation. Desensitization is caused by a second molecule called B-adrenergic receptor kinase (BARK), which in healthy hearts helps restore heart contractions to normal after norepinephrine stimulation. Studies subsequently showed that BARK is elevated in failing human heart tissue.

In 1994, Duke researchers showed that mice genetically altered to produce excess beta adrenergic receptors (bARs) have supercharged hearts that beat faster and stronger than a normal mouse's heart. In 1997, the researchers inserted a gene that encodes the bAR into an adenovirus, the same virus that causes the common cold. When Koch and his colleagues allowed the virus to infect isolated failing rabbit heart cells, the bAR gene made up to 15 times the normal amount found in rabbit cells and restored normal heart signaling.

"Our studies have shown that a malfunctioning beta adrenergic receptor system leads directly to heart failure," Koch said. "By contrast, boosting levels of beta adrenergic receptors or inhibiting BARK can reverse heart failure in our mouse genetic models. Now, we are beginning to see the same result when we deliver these genes to rabbits."

The researchers used the results of the mouse studies to design their latest gene therapy experiments in rabbits. They increased the number of bARs by infusing a common cold virus genetically engineered to contain the bAR gene into a living rabbit's heart and allowing it to spread throughout the coronary arteries. Then they measured the ability of the heart to pump. Animals that received extra copies of bAR, which is equivalent to 10 times the normal number of bARs on heart cells, had significantly increased ability to pump, demonstrated by a 20 percent increase in the force of the heart's contraction.

The key to the researchers' success, Koch said, was using a new surgical method to ensure that the adenovirus spread throughout the heart. They injected the virus into the left ventricle of live rabbits while the aorta was clamped for a few seconds. This allowed the virus enough time to spread through all the coronary vessels. Clamping the aorta is sometimes used in human heart surgery, Koch said, making this gene delivery method feasible.

In previous experiments, the researchers used a catheter similar to the ones used in opening blocked arteries in people to inject the virus into the coronary arteries, the arteries that feed the heart, in live rabbits. Using this method, Koch and his colleagues demonstrated that they could get genes into heart muscle and that the heart cells made the appropriate protein product, but only in a limited area of heart muscle.

The researchers are continuing experiments with a new generation of gene transfer agents such as the cold virus. But, he said, better gene therapy vectors need to be developed before gene therapy for heart failure in people becomes a practical option.

Duke University Medical Center

Related Heart Failure Articles from Brightsurf:

Top Science Tip Sheet on heart failure, heart muscle cells, heart attack and atrial fibrillation results
Newly discovered pathway may have potential for treating heart failure - New research model helps predict heart muscle cells' impact on heart function after injury - New mass spectrometry approach generates libraries of glycans in human heart tissue - Understanding heart damage after heart attack and treatment may provide clues for prevention - Understanding atrial fibrillation's effects on heart cells may help find treatments - New research may lead to therapy for heart failure caused by ICI cancer medication

Machining the heart: New predictor for helping to beat chronic heart failure
Researchers from Kanazawa University have used machine learning to predict which classes of chronic heart failure patients are most likely to experience heart failure death, and which are most likely to develop an arrhythmic death or sudden cardiac death.

Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.

Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population

Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.

Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.

Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.

Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.

How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.

Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.

Read More: Heart Failure News and Heart Failure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.