BOOST study published: An "important first" for stem-cell research and the heart

July 08, 2004

Thu, 08 Jul 2004 22:30:00

Hanover, Germany - The first randomized trial of stem-cell transfer in the heart, showing an improvement in left-ventricular function in MI patients undergoing the procedure, has been published in the July 10, 2004 issue of the Lancet, most of which is dedicated to the subject of stem-cell research.

The BOOST trial, by a team led by Dr Kai Wollert (Hanover Medical School, Germany), was first presented at the American Heart Association meeting last November, as reported by heartwire .

An accompanying commentary describes the study as an "important first" but adds that more basic studies must now be done to identify the mechanism by which the benefit was produced, especially in light of the fact that other stem-cell-transfer studies have shown potentially harmful results.

In another article, two experts say autologous stem-cell transfer could be a simple, cheap, and widely applicable treatment for MI patients but question who will pay for its development. And an editorial says it is now time for scientists to make the case for stem-cell research.

BOOST shows 6.7% increase in LVEF

In the BOOST paper, the investigators note that previous clinical studies have shown that infusion of autologous bone-marrow cells into the infarct-related coronary artery is feasible after MI, but because these studies were not randomized, the efficacy of this procedure has remained uncertain. They therefore conducted a randomized trial in which 60 patients, having undergone successful percutaneous coronary intervention for acute ST-segment elevation MI, received either optimum postinfarction medical treatment (controls) or optimum medical treatment and intracoronary transfer of autologous bone-marrow cells a mean of 4.8 days after PCI.

The primary end point was global left-ventricular ejection fraction (LVEF) change from baseline to six-month follow-up, as determined by cardiac MRI. This increased by 0.7% in the control group and 6.7% in the bone-marrow-cell group (p=0.0026).

Transfer of bone-marrow cells enhanced left-ventricular systolic function primarily in myocardial segments adjacent to the infarcted area. But left-ventricular end diastolic volumes did not decrease, indicating that transfer of bone-marrow cells did not improve left-ventricular remodeling at six months. Cell transfer did not increase the risk of adverse clinical events, in-stent restenosis, or proarrhythmic effects.

Wollert et al say that the effects of cell transfer in this study were over and above benefits associated with established strategies to promote functional recovery after acute MI, such as PCI with stent implantation, and postinfarction pharmacotherapy with ACE inhibitors, angiotensin-receptor blockers, and beta blockers.

Mechanism promoting paracrine effects?

They point out that this study was not designed to assess the mechanisms of action but that it is unlikely that transdifferentiation of bone-marrow-derived hemopoietic stem cells to cardiomyocytes could account for the beneficial effects seen. Rather, they suggest that the bone-marrow cells promote paracrine effects (eg, secretion of angiogenic factors) and that paracrine signaling promotes functional recovery.

Noting that intracoronary injection of bone-marrow-derived mesenchymal stromal cells has been shown to cause microinfarctions in dogs, Wollert et al point out that the nucleated bone-marrow cells as used in the BOOST study are significantly smaller than expanded mesenchymal stromal cells, which may explain why they did not observe infarctions.

The researchers conclude: "Our results lend support to the concept that autologous bone-marrow cells can be used to enhance left-ventricular functional recovery in patients after acute myocardial infarction." But they add that larger trials are needed to address the effect of bone-marrow-cell transfer on clinical end points such as the incidence of heart failure and survival.

Further basic research needed to establish mechanism

In the accompanying commentary, Drs Jürgen Hescheler, A Welz, and Bernd K Fleischmann (University of Bonn, Germany) note that studies in mice have not been able to reproduce initial results suggesting prominent transdifferentiation of hemopoietic stem cells into heart-muscle cells, which raises doubts that such differentiation could account for the benefit seen in the BOOST study. They say the mechanism might involve improved angiogenesis or vasculogenesis, better survival of hibernating myocardium, paracrine effects of injected cells, or modulation of the wound tissue.

They stress that further basic research must now be done to find out more about the mechanism of benefit. "Medicine profits from the fact that clinicians often provide a first impulse and then basic scientists take over the background research into mechanisms. After these mechanisms have been elucidated, we might even be able to replace the injection of cells by an appropriate drug," they conclude.

Simple, cheap, and widely applicable, but who will pay for its development?

In a "seminar" on stem cells and repair of the heart, Drs Anthony Mathur (Queen Mary University of London, UK) and John Martin (University College London, UK) say that the use of autologous bone-marrow cells for the treatment of ischemic heart disease would seem "simple, cheap, and widely applicable" if efficacy in further randomized, controlled, and, if possible, masked clinical trials can be demonstrated.

But they warn that funding of larger-scale trials could be a problem, given that autologous bone-marrow cells themselves have no value as intellectual property. Commercial sources are unlikely to fund clinical trials unless the treatment process is combined with a patentable preparation or delivery system, and further trials will need to be funded by the governments, charities, or philanthropy, they comment.

Noting that there is a tendency for academic physicians to compete with each other, Mathur and Martin emphasize that open collaboration among basic scientists and clinicians around the world is crucial for further progress in this field to be made.

Scientists must make the case for stem-cell research

A further editorial, signed by the Lancet, says that scientists must now make the case for stem-cell research. But it notes that convincing critics of the value of embryonic stem cells poses especially difficult problems. "Few other scientific advances have challenged such fundamental human values or posed such ethical dilemmas. The field is also unique in that the science has caught the public's imagination at a much earlier stage than previous developments, due in part to overly optimistic reporting of preliminary findings. Stem-cell researchers and other proponents are faced with a challenge: how to win back support for this important work with only promises to bargain with," it comments.

Related links

1. [HeartWire > News; Nov 10, 2003]

2. [HeartWire > News; Oct 27, 2003]

3. [HeartWire > News; Oct 13, 2003]

4. [HeartWire > News; Apr 1, 2003]

5. [HeartWire > News; Sep 9, 2002]

6. [HeartWire > News; Aug 28, 2003]

7. [HeartWire > News; Jan 3, 2003]


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