Stemcell Therapy: From Translational Hurdles to New Frontiers

Thomas F. Lüscher, MD, FESC

Disclosures

Eur Heart J. 2017;38(39):2915-2918. 

It is an old human dream to regrow lost parts of the body much like certain fish and amphibians can. Regenerative medicine has revived this dream and has made impressive progress on the experimental level.[1] In rodents, dead tissue as it develops in acute myocardial infarction can be replaced with a variety of progenitor cells, while most patients—unless they are revascularized in a timely fashion—end up with a large scar, remodelling, and eventually heart failure and death. Unfortunately, clinical trials with different progenitor cells have, in contrast to experimental findings, yielded disappointing results thus far,[2–7] possibly because of ageing and dysfunction of these cells.[8]

This Issue is addressed in a Current Opinion entitled 'The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of Acute Myocardial Infarction and Heart Failure-update 2016' by the European Society of Cardiology Task Force for Stem Cells in Cardiovascular Disease.[9] The Task Force issued its first consensus document in 2006. Since then there has been great progress in the field, although the indications and future direction of cell therapy in cardiovascular disease remain unclear. In their paper, the group presents their current thinking on what has been learned in the past 10 years and what recommendations can be drawn for the future.

Intracoronary infusion of autologous nucleated bone marrow cells enhanced the recovery of left ventricular ejection fraction after ST-segment elevation myocardial infarction in the randomized controlled, open-label BOOST trial.[10] Kai C. Wollert and colleagues from the Hannover Medical School in Germany reassessed the therapeutic potential of nucleated bone marrow cells in their article 'Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST-2randomizedplacebo-controlled clinical trial'.[11] The randomized placebo-controlled, double-blind BOOST-2 trial was conducted in 10 centres in Germany and Norway in 153 patients with large ST-segment elevation myocardial infarction using a multiple arm design investigating the dose–response relationship and exploring whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on bone marrow cell efficacy. Patients were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose or low-dose bone marrow cells, or irradiated high-dose or low-dose bone marrow cells. Overall, baseline left ventricular ejection fraction as determined by magnetic resonance imaging (MRI) was 45%. At 6 months, left ventricular ejection fraction increased by 3.3% in the control group and 4.3% in the high-dose cell group. The estimated treatment effect was 1.0%, while that of low-dose bone marrow cells was 0.5%. Likewise, irradiated bone marrow cells did not have significant treatment effects. Thus, the BOOST-2 trial does not support the use of nucleated bone marrow cells in patients with ST-segment elevation myocardial infarction, and moderately reduced left ventricular ejection fraction. These results are further discussed in a thought-provoking Editorial by Jozef Bartunek from the O.L.V. Ziekenhuis, Cardiovascular Center in Aalst, Belgium.[12]

Another approach of regenerative therapy is the use of cardiosphere-derived cells[13] which have exhibited several favourable effects on heart structure and function in pre-clinical models; however, the effects of cardiosphere-derived cells on ageing have not been evaluated. Diastolic dysfunction is characteristic of aged hearts. In a Basic Science paper entitled 'Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats', Eduardo Marban and colleagues from the Cedars-Sinai Medical Center in Los Angeles, California (USA) assessed the effects of cardiosphere-derived cells on heart structure, function, gene expression, and systemic parameters in aged rats.[14] They compared intracardiac injections of neonatal rat cardiosphere-derived cells with vehicle in 22-month-old or 4-months-old rats. Transcriptomic analysis revealed that cardiosphere-derived cells recapitulated a youthful pattern of gene expression in the hearts of old animals, with 86% of the genes being differentially expressed. Of note, in rats receiving cardiosphere-derived cells, telomeres were longer in cardiac cells. Furthermore, cardiosphere-derived cells attenuated hypertrophy by echo and decreased cardiomyocyte area and myocardial fibrosis at histology. Cardiosphere-derived cell injection also improved diastolic dysfunction and lowered serum brain natriuretic peptide (Figure 1). In old rats transplanted with cardiosphere-derived cells, exercise capacity increased by ~20%, body weight decreased by ~30%, and hair regrowth after shaving was more robust. Serum biomarkers of inflammation such as interleukin-10, interleukin-1βb, and interleukin-6 improved in the cardiosphere-derived cells group. In culture, young cardiosphere-derived cells secreted exosomes which increased telomerase activity, elongates telomere length, and reduces the number of senescent human heart cells. Thus, it appears that young cardiosphere-derived cells rejuvenate old animals as gauged by cardiac gene expression, heart function, exercise capacity, and systemic biomarkers. These promising findings are put into context in an Editorial by Francisco Fernandez-Aviles from the Hospital General Universitario Gregorio Marañón in Madrid, Spain.[15]

Figure 1.

Echocardiographic and haemodynamic changes in diastolic function. (A) Representative images of echo-Doppler transmitral flow and of tissue Doppler in a rat from the phosphate-buffered saline (PBS-control) and in a rat from the cardiosphere-derived cell (CDC) transplanted groups. (B) E/A and E/E' ratios are decreased in CDC-treated rats after 1 month. (C) Representative images of left ventricular (LV) pressure–volume loops (PVLs) in a rat from PBS-control and CDC-treated groups. (D) LV end-diastolic pressure–volume relationship (EDPVR) slopes are decreased in the old CDC-treated group after 1 month, and the time constant of relaxation, Tau is significantly lower in this group vs. PBS-control. Number of animals: CDC-treated (n = 11) or PBS-injected (n = 11). P-values: all significant values are shown. Blue values (CDC group) represent the significance of the difference between baseline and the endpoint within the group. Black values represent the significance between the groups (from Grigorian-Shamagian L, Liu W, Fereydooni S, Middleton RC, Valle J, Cho JH, Marbán E. Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats. See pages 2957–2967).

A completely novel concept of atherogenesis is the microbiome and its product that influence cardiovascular structure and function.[16] In stable coronary artery disease as well as in acute coronary syndromes,[17] the microbiome product trimethyl-N-oxide or TMAO and others[18,19] turned out to be prognostic beyond that of classical risk factors. In a Meta-Analysis article entitled 'Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose–response meta-analysis', Cinzia Perrino and colleagues from the University of Naples Federico II in Italy noted that the gut microbiota-derived metabolite TMAO is emerging as a new potentially important cause of increased cardiovascular risk.[20] The purpose of this meta-analysis was systematically to estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardiovascular and cerebrovascular events. MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. A total of 17 clinical studies that enrolled 26 167 individuals were included in the analytic synthesis. High TMAO plasma levels were associated with increased incidence of all-cause mortality with a hazard ratio of 1.91, and major adverse cardiovascular and cerebrovascular events with a hazard ratio of 1.67 (Figure 2). Dose–response meta-analysis revealed that the relative risk for all-cause mortality increased by 7.6% for each 10 μmol/L increment of TMAO. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. Thus, this is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

Figure 2.

Impact of trimethylamine-N-oxide (TMAO) plasma levels on all-cause mortality: random effects hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality in the overall population (from Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, Trimarco B, Esposito G, Perrino C. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. See pages 2948–2956).

The editors hope that this issue of the European Heart Journal will be of interest to its readers.

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