Feb. 22, 00 - Researchers from the Massachusetts General Hospital (MGH) have shown that it is possible to improve cardiac function in aging rats by delivering extra copies of a key gene to the heart muscle via gene therapy techniques. In the Feb. 22 issue of Circulation the team reports that transferring additional copies of the gene SERCA2a directly into the hearts of aging rats alleviated a typical functional abnormality of aging hearts called diastolic dysfunction, an inability of the heart muscle to relax normally. Previous research in animals and in human heart muscle cells has shown that increasing SERCA2a could improve the function in actual heart failure, but this study is the first to show that altering gene expression could improve the more common heart abnormalities associated with normal aging.

"As our population continues to age in the coming years, we know we're going to be seeing more and more people with heart failure, which already is the most frequent cause of hospitalization in people over 65 in this country," says Roger Hajjar, MD, of the MGH Cardiovascular Research Center (CVRC), the paper's senior author. "The knowledge that increasing SERCA2a gene expression might improve function of the aging heart gives us a target for therapies that might prevent people from progressing to heart failure."

Hajjar adds that such therapies could be based on new medications that might impact the process controlled by SERCA2a or could utilize new gene therapy approaches with delivery vectors, some currently in development, that promise to be more effective and safer than the adenovirus-based system used in this study. He also stresses that it is by no means certain that these animal results will carry over to human patients and that additional research is required to verify and follow up the current findings.

In congestive heart failure the heart muscle is weakened and cannot pump effectively, allowing fluids to back up in the circulatory system and sometimes 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.

With true heart failure, the weakened heart muscle functions poorly throughout the entire heartbeat cycle - both in the contraction (systolic) phase and in the relaxation (diastolic) phase. However, in a significant number of older people (40 percent of those over 60), the heart contracts normally but the relaxation phase is abnormal, a problem called diastolic dysfunction. These patients exhibit some symptoms of congestive heart failure and many proceed to the complete syndrome.

It is well known that failing hearts do not properly handle calcium, a mineral that plays a key role in the contraction of any muscle cell. Inside the cell, calcium is stored in a structure called the sarcoplasmic reticulum (SR); when it is released in response to the appropriate signals, calcium causes muscle cells to contract. After contraction, calcium returns to the SR via a molecular calcium pump, the SERCA2a protein. Earlier research at the MGH and elsewhere strongly suggested that decreased function of the SERCA2a pump was linked to heart failure and to diastolic dysfunction. While recent studies support the hypothesis that increasing expression of the SERCA2a gene could improve the function of a failing heart, whether the same strategy could alleviate diastolic dysfunction had not yet been tested.

In the current study, additional copies of the SERCA2a gene inserted into a standard experimental viral vector were delivered directly into the hearts of aged rats (26 months old) via a surgically implanted catheter. Three other groups of rats were used for comparison purposes: aged rats that underwent a similar operation without receiving a vector; aged rats that received the vector without the SERCA2a gene, and adult rats (6 months old) that had surgery but received no vector.

Two days after the procedures, measurements were taken of the levels and activity of the SERCA2a protein and of a variety of cardiac functions. Both groups of aged rats that did not receive the SERCA2a gene showed the typical impairments in relaxation, compared with the adult rats, but no abnormalities in systolic function. In those aged rats that did receive the SERCA2a gene, diastolic function improved significantly, although some measurements did not return to the levels seen in adult rats.

"Currently treatment options for diastolic dysfunction are very limited," Hajjar says. "These results suggest possible avenues for treating this very significant problem that results from the aging process itself, rather than from a specific disease."

Hajjar's co-authors are Ulrich Schmidt, MD, PhD, first author; Federica del Monte, MD, PhD; Michael Miyamoto, MD; Takashi Matsui, MD, PhD, and Anthony Rosenzweig, MD, all of the MGH CVRC; and Judith Gwathmey, VMD, PhD, of Boston University Medical Center. The work was supported by grants from the National Institutes of Health, the Doris Duke Charitable Foundation and the American Federation of Aging Research.