Duke researchers reverse damage of heart failure with gene therapy

March 04, 2001

DURHAM, N.C. -- After previously demonstrating that they could use gene therapy to prevent heart damage in rabbits with congestive heart failure, Duke University Medical Center researchers have now gone one step further to use gene therapy to actually reverse the damage already done to the rabbits' heart tissue.

Also for the first time, the researchers reported they employed minimally invasive techniques to deliver the gene therapy, giving them hope that in the near future, the same approach could be viable in treating humans with heart failure, one of the most difficult groups of heart patients to treat.

The Duke team, led by Walter Koch, associate professor of experimental surgery, reported the latest advances in the March 6 issue of the journal Circulation.

"We inserted a gene for a protein that inhibits the action of a particular cardiac enzyme into a modified form of a common virus and delivered it directly into the heart of a rabbit with heart failure through its coronary circulation," Koch said. "One week after the therapy, the damage suffered by the heart cells was reversing.

"If our work continues to progress as it has, we anticipate being able to possibly test this approach in a certain group of patients within three years," Koch said. "We would likely try it first on severe heart failure patients in the hospital awaiting a heart transplant to see if we could reverse the dysfunctioning part of the heart -- sort of like a molecular assist device."

Heart failure is a debilitating and ultimately deadly heart condition characterized by the heart muscle's inability to stretch and contract properly, meaning that oxygen-rich blood is not sufficiently delivered throughout the body. It usually occurs as a result of coronary artery disease or a heart attack. Patients experience fatigue, weakness, and often cannot conduct everyday activities. To date, physicians can only treat symptoms.

The Duke researchers wanted to find a way to boost the ability of the heart to pump blood and in a series of experiments conducted throughout the 1990s, they identified two key molecules responsible for regulating the heart's pumping action.

As a natural response to a diseased heart, the body releases the hormone norepinephrine, also known as the "fight-or-flight" hormone, directly into the heart, causing it to beat up to five times faster than normal. While in the short-term, this improves the heart's pumping action, in the long run it leads to heart failure. Norepinephrine works by binding to molecules called beta adrenergic receptors (BARs) located on the surface of heart cells.

Over time, these over-excited receptors become desensitized to the effects of norepinephrine, largely due to the effects of a second molecule, beta-adrenergic receptor kinase (BARK), which in healthy hearts helps restore heart contractions to normal after norepinephrine stimulation. Higher than normal amounts of BARK are found in failing heart tissue in humans. The investigators attached the gene that produces a peptide (BARKct) that blocks the actions of BARK onto a modified adenovirus, the virus that causes the common cold. The adenovirus acts as the "transport vehicle" which "infects" heart cells, and in the process, drops off the new gene. Once in heart cells, the gene directs the production of BARKct. In the experiments, the virus did not cause inflammation or provoke an immune response, the researchers said.

"Last year, we demonstrated that if we delivered this gene at the same time as producing a heart attack, we could prevent and delay the heart from being damaged," Koch said. "In our latestseries of experiments, we delivered the BARKct gene three weeks after a heart attack, and one week later, the damaged heart cells were returning to normal function. We began to reverse the heart damage in rabbits."

For Koch, the ability to deliver the gene therapy noninvasively is as significant as the effectiveness of the delivered gene, known as a transgene. The experiments used a catheter-based system, much like that used routinely on humans. Currently, the only clinical trials using gene therapy for heart diseases involves the use of growth factors that stimulate the creation of new blood vessels. However, this therapy is delivered directly to the heart muscle during open heart surgery, such as coronary bypass surgery.

"In the case of patients with heart failure, most are too sick to be able to withstand the rigors of a major surgery," Koch explained. "We already know that even very sick patients can safely undergo catheter-based procedures, so it would be an effective and safe way to deliver the therapy."

For their experiments, the researchers delivered the BARKct transgene through a catheter positioned in the coronary artery that supplies blood to the left ventricle, the heart chamber responsible for pumping newly oxygenated blood throughout the body. The right ventricle did not receive the gene therapy, in effect acting as a control. After one week, the researchers performed detailed analysis of the two chambers and found that the treated chamber had enhanced function towards normal levels, while the right ventricle continued to be in a state of failure.

The current adenovirus vector remained viable in the rabbit for about three to four weeks, Koch said, adding that an important area of continued research is the development of vectors that will permit longer expression of the gene. However, at least initially in those severely ill patients, a month or two of "molecular" support could keep heart failure patients alive long enough to receive a human transplant.

The choice of possible viral vectors for heart failure, however, is limited, mainly because heart cells, also known as myocytes, do not divide. In some gene therapy experiments for cancer, for example, researchers use retrovirus vectors, which allows the therapeutic genetic material to be inserted into the target cell, and then all subsequent generations of that cell will carry the new gene. Since myocytes do not divide, the researchers must "infect" as many myocytes as possible to achieve a therapeutic effect.

Now that the researchers have proven the principle of gene therapy for heart failure in such animal models as mice, rats and rabbits, they are now testing their approach in porcine models before moving on to human trials.

These findings also open the possibility of delivering transgenes to different target cells in the heart to treat other heart ailments, such as those that regulate calcium and potassium channels. "Levels of BARK are elevated in patients with many forms of heart disease, so our hypothesis is that it is a critical molecule in heart dysfunction," Koch said. "That makes not only an exciting target for gene therapy, but also a potential target for a pharmaceutical-based approach."
Members of the Duke research team included Dr. Ashish Shah, Dr. David White, Dr.Sitaram Emani, Dr. Alan Kypson, Dr. R. Eric Lilly, Katrina Wilson, Dr. Donald Glower and Dr. Robert Lefkowitz, a Howard Hughes Medical Institute investigator.

The Duke investigators are supported by grants from the National Heart, Lung, Blood Institute, part of the federal National Institutes of Health, and the American Heart Association.

You may contact the Duke University Medical Center News Office during the day at 919-684-4148 or after hours and weekends at 919 970-3671. Also, visit its Web site at http://www.news.mc.duke.edu for news releases and a comprehensive list of Duke medical experts who can assist you, as well as other resources.

Hold for release:
Contact: Richard Merritt
4 p.m., Monday, March 5, 2001

Note to editors: Walter Koch, Ph.D., is available at 919-684-3007, koch0002@mc.duke.edu

A color image is available as WalterKoch.1.jpg in http://photo1.dukenews.duke.edu/pages/Duke_News_Service

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.