With modern, guideline-directed therapy,¹ which includes angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-receptor blockers, mineralocorticoid receptor blockers, and angiotensin receptor neprilysin inhibitors, up to 40% of patients with dilated cardiomyopathy (heart failure with reduced ejection fraction) may experience a return of left ventricular ejection fraction (LVEF) and ventricular geometry to normal.² This encouraging result follows a progressive series of important advances in research on heart failure therapies having diverse mechanisms of action. Until recently, however, it was uncertain if such patients had actually recovered from heart failure with reduced ejection fraction or if they had only entered a state of remission.

The TRED-HF trial has brought clarity to this important question.³ In this study, patients with heart failure with reduced ejection fraction and complete reversal of left ventricular dysfunction were randomized to have their heart failure medications withdrawn or maintained. Within just 8 weeks, 44% of the patients in the medication withdrawal group relapsed, as reflected by a reduction in LVEF, an increase in left ventricular end-diastolic volume, and an increase in cardiac biomarkers. These results clearly indicated that even after years of productive research on the development of advanced medical therapies, it is not yet possible to reverse the underlying pathological process.

Consequently, there is an important need for therapies to durably restore ventricular function, and one approach has focused on stem cell–based therapies.⁴ Stem cells, which are derived from the bone marrow or umbilical cord blood, have been infused into the coronary arteries or injected directly into the myocardium. The original hypothesis was that stem cells would engraft in the myocardium and replace damaged cardiomyocytes. Subsequent research has suggested that stem cells probably do not differentiate into functional cardiomyocytes, but as an alternative hypothesis, it was hoped that they might have paracrine effects that would benefit myocardial function.

However, the weight of the evidence to date indicates that any clinical benefit resulting from stem cell therapy for heart failure with reduced ejection fraction has been small and inconsistent. The study by Yau et al⁵ in this issue of JAMA is yet another example of a negative study in a largely disappointing body of cell-based research. The investigators injected bone marrow–derived mesenchymal precursor cells into the myocardium of patients who were receiving LVAD support for advanced heart failure—106 patients received mesenchymal stem cells and 53 received sham injections—and found no benefit on the ability to wean the patients from LVAD support at 6 months. This study is important because it provides further evidence that mesenchymal precursor cells injected into the myocardium may not be the answer to the challenging problem of advanced heart failure due to dilated cardiomyopathy.

Given the generally negative results of cell-based studies to date, a European Society of Cardiology Working Group concluded that the promise of cell therapy has not yet been fulfilled.⁶ The recent disclosure that the research of one of the pioneers of cell-based therapy, Piero Anversa, was largely fraudulent, has tainted this field of investigation.⁷

Astonishingly, despite the lack of an evidence base, a recent survey concluded that there are at least 570 businesses in the United States that offer stem cell therapy, at least 61 of which market to patients with heart failure. Since stem cell therapy for heart failure is not approved by the US Food and Drug Administration, it appears that further regulatory action needs to be directed to these unauthorized activities.

To what extent should funding bodies continue to invest research dollars in stem cell therapy for heart failure? Although a note of optimism was recently offered,⁴ based on the unimpressive results to date, it will be even more important to be parsimonious about investments in stem cell therapy for heart failure unless new ideas and novel approaches open fresh avenues for potential success.