MGH research shows gene therapy may be able to reverse heart failure

December 06, 1999

Researchers from the Massachusetts General Hospital (MGH) have for the first time shown that gene therapy may be able to reverse heart failure, one of the major causes of death and disability in North America and Europe. In their study appearing in the December 7 issue of Circulation, the team from the MGH Cardiovascular Research Center (CVRC), along with collaborators from Boston University Medical Center and Imperial College in London, report delivering additional copies of a gene called SERCA2a to muscle cells from failing human hearts. Cells that incorporated the gene and produced elevated levels of its protein began to function in a normal fashion, contracting more quickly and more powerfully.

"This ability to modify the contraction of failing human cardiac cells represents an important step toward gene therapy for heart failure," says Roger Hajjar, MD, of the MGH CVRC, who led the study. "And by confirming the role the SERCA2a protein plays in heart failure, we now have a molecular target for other therapeutic approaches."

In heart failure the heart muscle is weakened and cannot pump effectively, allowing fluids to back up in the circulatory system and sometime into the lungs. Heart failure is a growing health problem in the developed world, with more than 400,000 people being diagnosed in the U.S. each year. While deaths from coronary heart disease have decreased in recent years, heart failure deaths are on the rise - more than doubling from 1979 to 1995.

Current treatments - primarily medications such as ACE inhibitors and beta blockers - can slow the progression of heart failure but not stop the condition. The only current cure, for which most patients are ineligible, is a heart transplant. Almost half of those diagnosed with heart failure will not survive five years after their diagnosis. It has been known for 15 years that failing hearts do not handle calcium properly. The contraction of heart muscle cells - like all muscle cells - is controlled by cycling levels of calcium, which is stored in a cellular structure called the sarcoplasmic reticulum (SR). In response to the electrical impulses that control heartbeat, calcium is released from the SR into the main body of the cell (the cytosol), stimulating the cell to contract.

After contraction, calcium moves back from the cytosol into the SR via a molecular calcium pump, the SERCA2a protein. In heart failure, the return of calcium into the SR is diminished. With this disruption to the normal cycling of calcium, the muscle cells cannot respond appropriately to the heartbeat impulses. They contract weakly and the heart's pumping activity decreases. Previous research linked these abnormalities to decreased function of the SERCA2a calcium pump, but it was unclear whether protein levels actually were reduced in failing hearts. Animal studies also had shown that increasing production of SERCA2a improved heart function, both in individual cells and in living animals. But it was not yet clear that gene transfer techniques also would work in human heart cells.

In the current study, the researchers isolated muscle cells from 10 failed hearts that had been removed for transplantation. Using a standard virus vector employed in gene therapy studies, they delivered additional copies of the SERCA2a gene to these heart muscle cells. Within 24 hours of receiving the gene, which induced overproduction of the SERCA2a protein, the cells from failed heart began beating and contracting at levels very similar to those seen in cells from normal hearts. The cycling of calcium also appeared normal in cells incorporating the additional gene copies.

"These results in isolated cardiac cells need to be validated in the whole human heart, but we're optimistic that this goal will be accomplished," Hajjar says. He adds that, while current gene therapy trials for a variety of conditions have had disappointing results, new vector systems currently under development may be more successful in producing long-lasting results.

The study's co-authors are Federica Del Monte, MD, PhD, first author; Ulrich Schmidt, MD, PhD; Takashi Matsui, MD, PhD; Zhao Bin Kang, MD; William Dec, MD; and Anthony Rosenzweig, MD, of the MGH; Sian Harding, PhD, of Imperial College; and Judith Gwathmey, VMD, PhD, of Boston University Medical Center. The study was supported by grants from the National Institutes of Health, the Doris Duke Charitable Foundation and the British Heart Foundation.

Massachusetts General Hospital

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 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