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Commentary: Building evidence to support empiric observations—Molecular cross talk, or simply crossed wires?

  • David S. Winlaw
    Correspondence
    Address for reprints: David S. Winlaw, MBBS, MD, FRACS, Heart Centre for Children, The Children's Hospital at Westmead and Faculty of Health and Medical Sciences, University of Sydney, Westmead 2145, Australia.
    Affiliations
    Heart Centre for Children, The Children's Hospital at Westmead and Faculty of Health and Medical Sciences, University of Sydney, Westmead, Australia
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Open ArchivePublished:February 26, 2019DOI:https://doi.org/10.1016/j.jtcvs.2019.02.054
      Although impressive clinical results have been reported with pulmonary artery banding in children with cardiomyopathy, supporting mechanisms at a cellular and molecular level remain elusive.
      See Article page 2416.
      Surgeons are reductionists; we know what works for patients, often on the basis of personal experience. We can sometimes suggest a plausible mechanism, citing basic mechanisms at work. Surgeons are also sceptics; we value clarity and simplicity and are quick to note when the “science” fails to demonstrate mechanisms supporting observations made in the clinical domain. There is a lot to be sceptical about, because so many procedures lack an evidence base or a defined mechanism of action.
      So it is when Yerebakan and colleagues
      • Yerebakan C.
      • Boltze J.
      • Elmontaser H.
      • Yoruker U.
      • Latus H.
      • Khalil M.
      • et al.
      Effects of pulmonary artery banding in doxorubicin-induced left ventricular cardiomyopathy.
      in this issue of the Journal present a series of animal experiments that seek to demonstrate cellular and molecular mechanisms underlying the apparent beneficial effects of pulmonary artery banding in children with cardiomyopathy. The Giessen group and an international collaborative
      • Schranz D.
      • Akintuerk H.
      • Bailey L.
      Pulmonary artery banding for functional regeneration of end-stage dilated cardiomyopathy in young children: world network report.
      have reported benefits of this approach in clinical practice, and there is a registered clinical trial
      Reversible pulmonary artery banding as simplified management of end-stage dilated left ventriculopathy in early life.
      underway. Septal repositioning and initiation of a regenerative response are proposed as mechanisms, drawing on experience suggested by similar approaches in l-transposition,
      • Ma K.
      • Gao H.
      • Hua Z.
      • Yang K.
      • Hu S.
      • Zhang H.
      • et al.
      Palliative pulmonary artery banding versus anatomic correction for congenitally corrected transposition of the great arteries with regressed morphologic left ventricle: long-term results from a single center.
      • Winlaw D.S.
      • McGuirk S.P.
      • Balmer C.
      • Langley S.M.
      • Griselli M.
      • Stümper O.
      • et al.
      Intention-to-treat analysis of pulmonary artery banding in conditions with a morphological right ventricle in the systemic circulation with a view to anatomic biventricular repair.
      albeit a very different clinical presentation.
      Important experimental design and methodologic issues need to be considered. First, the mortality from both initial and sham banding was substantial, and medical therapy was not used on either group. Second, the criterion standard assessment of ventricular performance with conductance catheters largely failed to demonstrate a difference between treatment and control groups, which is surprising considering the gross morphologic changes. Finally, analysis of ventricular muscle was limited to simple histologic examination, without comprehensive analysis of cell type, proportion of c-kit-positive cells, angiogenic milieu, measures of apoptosis, or gene expression data that might support the regenerative hypothesis.
      In a drug-toxicity model of ventricular failure, damage is caused primarily by oxidative stress,
      • Renu K.
      • Abilash V.G.
      • Tirupathi Pichiah P.B.
      • Arunachalam S.
      Molecular mechanism of doxorubicin-induced cardiomyopathy—an update.
      and this may not adequately mimic the pathogenesis of dilated cardiomyopathy, where disruption of the dystrophin-associated complex is a more prominent feature.
      • Jefferies J.L.
      • Towbin J.A.
      Dilated cardiomyopathy.
      Nevertheless, there were improvements in left ventricular size and ejection fraction in the treatment group, and it is suggested that in this way the model recapitulates the therapeutic effect of central pulmonary artery banding in cardiomyopathy. It is an important step toward better understanding a phenomenon that may be useful in preventing or delaying the need for mechanical support and transplantation in children. Should molecular evidence be forthcoming in future studies, it will be broadly relevant to management of corrected transposition and perhaps even in the achievement of “growth” in hypoplastic ventricles.
      For now, the big picture remains fuzzy. The reductionists amongst us still seek an understanding of the basic mechanisms. and the sceptics will prevail until molecular data support the intimation that there is regeneration and improved “cross talk” between ventricles. Could we simply be observing the superimposition of restrictive physiology on the pathology of dilated cardiomyopathy?

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