Data faulted, Brigham study on heart cells is withdrawn

A Brigham and Women’s Hospital stem cell study, which raised the possibility that the human heart could repair itself, has been retracted after an internal investigation showed the researchers used compromised data.

The retraction comes just a week after a Japanese scientist was accused of fabricating data in a major stem cell paper that was led by a different Brigham scientist.

The authors of the retracted paper claimed they had found evidence that heart muscle can regenerate at a higher rate than previously thought. The work was part of a broad effort to discover the body’s natural regenerative abilities and harness them to create therapies that could repair damaged or diseased hearts.

The paper, published in 2012 in the journal Circulation, was withdrawn Tuesday by the journal’s publisher, the American Heart Association. “An ongoing institutional review by Harvard Medical School and Brigham and Women’s Hospital has determined that the data are sufficiently compromised that a retraction is warranted,” the journal said.

“This retraction is highly significant. In my 30 years in cardiovascular science I cannot recall a paper of similar prominence being retracted from Circulation,” Dr. Charles Murry, codirector of the Institute for Stem Cell and Regenerative Medicine at the University of Washington, wrote in an e-mail. “This appears to settle the controversy about the rate of cell replacement in the human heart.”

Dr. Rose Marie Robertson, chief science officer for the American Heart Association, said that the journal received the retraction request from Harvard Medical School, in a letter that described concerns about several figures in the paper. She declined to elaborate on what the specific problems were.

The journal’s retraction notice does not specify whether the data irregularities were accidental or intentional, or which researchers were at fault. The authors include several high-profile scientists, including Dr. Piero Anversa, a cardiologist whose research has often raised questions from other scientists, and Dr. Joseph Loscalzo, chief of medicine at the Brigham.

Robertson said that based on the information provided by Harvard, the Heart Association did not have concerns about the role Loscalzo played in the paper. Loscalzo is the editor of the journal Circulation and recused himself from the retraction process, she said.

The study was supported by funds from the National Institutes of Health. In 2013, Anversa’s lab received $6.9 million from the agency, according to an NIH website. The federal Office of Research Integrity, which reviews allegations of scientific misconduct on federally sponsored research, said because of privacy reasons, it could not confirm or deny an investigation.

The key authors of the paper did not respond to direct requests for comment, and a Brigham spokeswoman declined to make them available. The hospital released a statement saying, “Any questions, concerns, or allegations regarding research conducted at BWH are confidentially evaluated per the hospital’s policies and federal regulations.”

In 2009, Dr. Jonas Frisén, a professor of stem cell research at the Karolinska Institute in Sweden, published a study showing a very low rate of renewal of human heart muscle cells — around 1 percent of cells turned over per year. The finding was surprising, because the heart had long been viewed as an organ that does not have the ability to regenerate at all. That low rate has been replicated in other laboratories.

But in 2012, Anversa’s laboratory used the same technique — measuring an isotope of carbon found in the nucleus of cells — to detect a much higher rate of heart muscle cell renewal, as much as 23 percent turning over per year. The laboratory also found that the rate of renewal increased with age, contrary to what other scientists had found. Frisén said he and his colleagues read the paper extremely carefully, but could not make sense of it.

“It wasn’t possible from what they had written to understand exactly what they had done and how they had treated the data,” Frisén said.

He began corresponding with the authors and asking detailed questions. He said there were some minor mistakes that appeared accidental, such as using the wrong units, and some errors that may have stemmed from their unfamiliarity with using the technique. For example, he said the Brigham team didn’t appear to have controlled for contamination.

But there were also “cases where they had treated data in ways that were not described, or individual data points seemed to have been treated in a different way than the rest of the data. I don’t know if it was intentional or accidental,” Frisén said. “I can say that these alterations made the data look more similar to what they had proposed” as their conclusion.

Several scientists said that, given the controversy and questions that have surrounded some of Anversa’s other work, they hope the investigation will go further than this one paper.

“We need to know which parts of his work are really true for the field, because this is such an important area of science and medicine,” said Dr. Kenneth Chien, professor of cell and molecular biology at Karolinska Institute. “The last thing our field needs to lose is the trust of other scientists, of other industry leaders, and most importantly — of patients with heart disease.”

The field of cardiac stem cells has pushed hard to translate basic research findings into experimental treatments for patients, which means that questions surrounding Anversa’s findings may have repercussions beyond the laboratory.

Dr. Eduardo Marbán, director of the Cedars-Sinai Heart Institute, said that data presented at an American Heart Association meeting in November 2013 called into question some of Anversa’s earlier work, which found that cells that carried a marker called c-kit were a type of stem cell that could give rise to heart muscle cells.

The presentation by Jeffery Molkentin, a researcher supported by the Howard Hughes Medical Institute who is traveling and could not be reached, raised real doubts about that finding, Marbán said.

“It is hard to imagine stronger evidence against the idea that c-kit-positive heart cells are innate stem cells that can repopulate the injured heart,” Marbán wrote in an e-mail.

The work on c-kit-positive heart cells helped lay the groundwork for clinical trials.

In 2011, Anversa and colleagues published another controversial paper in the New England Journal of Medicine. The authors claimed to have identified a type of stem cell that could give rise to different types of cells in the lung. Other researchers were highly skeptical of the results, and the journal Nature Medicine took the unusual step of publishing three critiques of the study, despite the fact that it did not appear in that journal’s pages.

In 2001, Anversa’s laboratory published evidence that bone marrow cells could “transdifferentiate,” giving rise to cells that could repair the heart. But in 2004, two separate teams of scientists published conflicting results that suggested that transdifferentation was rare, if it was occurring at all, and offered alternative explanations.

That work helped lay the groundwork for a number of clinical trials.