Author + information
- Cesare M. Terracciano, MD, PhD∗ (, )
- Manoraj Navaratnarajah, MRCS, PhD,
- Sean O.Z. Bello, MRCS and
- Michael Ibrahim, MBBS, BA, PhD
- ↵∗Imperial College London, National Heart & Lung Institute, Laboratory of Myocardial Electrophysiology, 4th floor, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom
Mechanical unloading using left ventricular assist devices (LVADs) induces reverse remodeling of the failing myocardium to levels that are possibly superior to any other strategy. However, evidence of a significant and reliable curative efficacy is scarce. This paradox is explained by insufficient and/or possibly detrimental effects of mechanical unloading, despite a regression of pathological changes from the subcellular to the multicellular level. Because a reduction of cardiomyocyte size is a universal finding after LVAD treatment, we and others have called this effect “atrophy,” which indicates a set of features that make myocyte mass and function inadequate to sustain the workload of the heart when it is reloaded. In the paper by Diakos et al. (1) published in the Journal, the effect of LVAD treatment on myocardial atrophy was specifically investigated, and it was concluded that no atrophy occurred in these patients. In this paper, atrophy was predominantly defined as the evidence of subnormal cardiomyocyte size. A set of associated parameters were also considered, and we congratulate the investigators for the substantial set of data and the effort to further characterize this interesting population of patients. However, we have some concerns on the interpretation of the data presented.
This was not the first study to investigate the effect of unloading of the failing hearts on myocardial atrophy. We and others measured myocyte size after LVAD treatment in patients and found similar results (2). We also performed several studies using the rat heterotopic abdominal heart transplantation (HAHT) model in normal and failing hearts. HAHT induces a very substantial degree of unloading, and we showed that this could reverse the hypertrophic response of an established model of murine heart failure after 1 week of unloading and also induce substantial myocyte atrophy, to subnormal levels, of normal and failing myocytes after 4 weeks of unloading (3). This suggests that the degree of atrophy depends, not surprisingly, on the degree of unloading.
More than 10 years ago, we showed that, in patients treated with combined LVAD and pharmacological therapy, including clenbuterol, the maintenance of normal cell size was not a determinant of clinical recovery. Rather, functional improvements in excitation–contraction coupling were associated with clinical recovery, which suggested that even a myocyte of normal size can be dysfunctional (2). We also showed that reductions in cell size, within certain limits from normal, did not produce dysfunction and could even be associated with functional improvement in failing myocytes after unloading (3). We termed this “physiological” hypotrophy or atrophy, suggesting again that the absolute cell size is not deterministic of cell function, and that the consequences of the reduction in cell size depend upon the pathological substrate.
Another concern regarding this study was that most of the experiments showed only values before and after LVAD, and did not compare these values with the normal myocardium. Considering that the pre-LVAD samples represent a substantially diseased tissue, the lack of improvement in ultrastructural features, for example, suggests a lack of cellular recovery. Furthermore, with the evidence that hypertrophy and atrophy share a number of signalling pathways (4), the lack of difference between pre- and post- LVAD does not rule out atrophy. In addition, with respect to t-tubules, the investigators limited their analysis to the distance of ryanodine receptors from the sarcolemma—which was used as an index of atrophy for an unclear reason—with no reference to the parameters that were associated with cellular functions, including calcium handling (density, regularity, morphology, and local excitation–contraction coupling) (5). We showed that t-tubular disruption is a feature of both overloaded and unloaded dysfunctional myocardium, and the current findings would be consistent with the dysfunction of overload (pre-LVAD) and atrophy (post-LVAD) (5). The divergence of these data might be partly ascribed to the heterogeneity of the patient population, together with differences in unloading and/or pharmacological management.
We suggest that the current data should not be used as an indication of normalization of function and lack of atrophy, but rather as further evidence that current clinical strategies of mechanical unloading are insufficient to produce meaningful recovery of the myocardium. More studies are needed to optimize these strategies and explore associated therapies.
- 2015 American College of Cardiology Foundation
- Diakos N.A.,
- Selzman C.H.,
- Sachse F.B.,
- et al.
- Terracciano C.M.,
- Hardy J.P.,
- Birks E.J.,
- Khaghani A.,
- Banner N.R.,
- Yacoub M.H.
- Ibrahim M.,
- Terracciano C.M.