The new Op-Ed feature started last month with a piece by Joe Alcock, “Disabling the smoke detector in sepsis.” Our hope was that this feature would spark interest and contributions by more authors and so far we are off to a great start. Veterinary pathologist Edmund LeGrand has volunteered the following piece which examines, from an adaptationist viewpoint, the intriguing question as to why the human heart has such limited powers of post-infarction regeneration. We’d like to thank both Ed and Joe for their contributions and remind readers that we are open to contributions from anyone. We also want to encourage commentary on all of our Op-Ed pieces; please feel free to submit contributions and comments for approval to [email protected].
Regeneration and the Heart of the Adaptationist Approach
Edmund K. LeGrand, DVM, PhD, DACVP
The ability to regrow an arm, a leg, or another large portion of the body that has been amputated is a more widespread trait than you might think. Invertebrates like sea stars and flatworms can replace most of their body parts after removal, but even some vertebrates have impressive regenerative abilities. Lizards regenerate their tails, newts can regrow limbs and repair parts of the eye, and zebrafish can regrow fins and repair other tissues like the heart. Mammals, however, are pretty limited in this realm of regrowth. Humans can regrow muscle and liver tissue, but regenerative repair of other organs, including the heart, is extremely limited. Why might this be? Two recent papers are notable in addressing the question (1, 2).
The review paper “Evolution, comparative biology and ontogeny of vertebrate heart regeneration” (1) provides an in-depth comparative analysis of factors correlated with heart regeneration. Either phylogenetically or developmentally, myocardial regeneration seems to be associated with “a low metabolic state, low heart pressure, immature cardiomyocyte structure, hypoxia, an immature immune system and the inability to regulate body temperature.” It was considered that there may be limiting trade-offs involving some of these factors.
Trade-offs may be the second favorite word, after selection, of those who take the adaptationist approach of asking “why” or “why not” questions. Given that stem cells can replenish most tissues (there are even small numbers of myocardial stem cells in adult humans (3)) and that ancestral organisms and embryos have myocardial regeneration, the question seems to go beyond “Why can’t the adult human heart repair itself?” Rather, we might ask “Why doesn’t the heart repair itself?” and “What problems might arise were regeneration to occur?”
Sometimes finding a possible answer requires looking at a problem from a new vantage point. A number of years ago while addressing the apoptotic propensity of various cell types, it struck me that neurons and cardiomyocytes, with low replacement rates and hence a disinclination to undergo apoptosis, have life-long interactions with neighboring cells (4). As with a world-class sports team or symphony involving high levels of skill and precise interactions, each team member adapts to the others’ strengths and compensates for their weaknesses through long-term association. For the brain and heart, an important question becomes “Under what conditions should dead cells be replaced or not?” Each neuron is highly specialized; the same can’t be said for cardiomyocytes, which have two main roles requiring precision: to contract and to conduct the electrical rhythm to neighboring cells. I suggested that “perhaps in the short period of time when a newly created replacement cell is establishing contacts (gap junctions) with its new neighbors, there might be enough disruption of electrical impulse conduction to start an arrhythmia.”
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n the October 20, 2016 issue of Nature, Shiba et al (2) advanced the long-sought goal of injecting myocardial stem cells into heart tissue to help repair infarcts in monkeys. Notably, four of five monkeys with an infarct treated with injected myocardial stem cells developed sustained ventricular tachycardia (though the monkeys were asymptomatic) versus none of the five placebo-treated controls. Thus, it is possible, though not confirmed, this could be a trade-off that reduces the benefit of heart regeneration. While the authors emphasized the success of injected stem cells in integrating and coupling with surviving cardiomyocytes, they concluded by saying that “further research to control post-transplant arrhythmias is necessary.”
Having spent a career as a comparative pathologist in the pharmaceutical industry, I appreciated Joe Alcock’s recent op-ed in The Evolution and Medicine Review (Oct. 9, 2016) noting the repeated failures in developing treatments for sepsis. My frustrations with the absence of adaptationist thinking in drug development had previously led me to address the issue (4,5). I stated that the scientific community will soon know what each gene product does, making possible the creation of drugs that can affect each protein. But that mechanistic understanding doesn’t guarantee that the evolutionary function will be understood. Without taking the adaptationist approach, the full understanding of the phenomenon may not be achieved until problems arise in preclinical development in animal models, in clinical trials, or (more disastrously) after the product is on the market.
In approaching why myocardial regeneration is limited in mammals, it’s important that we listen for those smoke detector alarms. Luckily, the problem of arrhythmias with myocardial regeneration was discovered early in the therapeutic development process. While it wasn’t obvious what the trade-offs are in myocardial regeneration, it was certainly clear that trade-offs are involved. In many areas of medical research, a more thorough approach that emphasizes asking the whys can help us avoid unnecessary clinical missteps and can help us get to the heart of a problem.
References
- Vivien, CJ, Hudson JE, Porrello ER. 2016. Evolution, comparative biology and ontogeny of vertebrate heart regeneration. npj Regenerative Medicine 1:16012.
- Shiba Y, et al. 2016. Allogenic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538:388-391.
- Urbanek K, et al. 2005. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proceedings of the National Academy of Sciences 102: 8692-8697.
- LeGrand EK. 1997. An adaptationist view of apoptosis. Quarterly Review of Biology 72: 135-147.
- LeGrand EK. 2001. Evolutionary thinking as a tool in pharmaceutical development. Drug Development Research 52:439-445.
Image showing ventricular tachycardia via TextbookofCardiology.org, by user Drj.
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Ed LeGrand is to be congratulated for taking an adaptionist approach to the vexed question of why the regenerative potential of the human heart is so limited – resulting in a downward spiral toward heart failure after a severe myocardial infarction. He is interested in possible evolutionary trade-offs which might have limited the higher vertebrate heart’s regeneration potential and singles out research by Shiba et al, which recorded transient, asymptomatic tachycardia in monkey hearts after injection with myocardial stem cells. The implication is that cardiomyocytes in, certainly, primate hearts, experience problems successfully integrating themselves with other resident cardiomyocytes, on having recently arrived on the scene via differentiation from stem cells. Could such tachycardia exist outside the research laboratory and might it therefore be a limiting factor that had mitigated, over evolutionary time, for loss of heart regeneration?
While I applaud LeGrand’s approach I cannot help feeling that he may have backed the wrong horse in his trade-off stakes and I prefer the various plausible candidates offered by his second reference, Vivien et al. In “Body by Darwin” I argued that one important trade-off in the evolution of the four-chambered vertebrate heart and high-pressure circulatory system was the inability for the heart to feed itself by absorbing oxygen and nutrients from ventricular blood, through the wall of the chamber, to perfuse heart tissue. As hearts became more densely muscular the only way to get oxygen into them became through the evolution of a coronary artery circulation – with its attendant drawback of susceptibility to atherosclerosis, thereby precipitating a heart attack. (That coronary artery occlusion is an evolutionary-old susceptibility rather than a life-style condition in humans in modern times can be seen by the fact that it occurs in athletic fish like salmon who have muscular hearts and coronary arteries.) Vivian et al argue that, since heart cell regeneration is seen in 2, 3, and 4-chambered hearts, and in hearts without a coronary artery circulation, it means that the evolution of the 4-chambered mammalian heart, per se, does not correlate with loss of regenerative capacity. However, they do have six horses in the heart regeneration trade-off stakes, that all relate to the evolution of the vertebrate heart as a very muscular pump capable of supplying the high pressure blood circulatory systems that emerged as vertebrate life transitioned to land:
Pressure. Transition from aquatic to terrestrial life, they say, necessitated the high pressure closed circulatory system, and it is established that animals which have heart regeneration potential generally have low pressure systems. Conversely, if you reduce the ventricular loading on the heart (the pressure it must eject against) cardiomyocytes can re-enter the cell cycle. So, the structural and metabolic adaptations of cardiomyocytes may have provided a more efficient pump but have come at the expense of regeneration capacity. This links to:
Metabolism. To cope with the metabolic demands imposed by a high pressure system, cardiomyocytes transition from glycolysis to the more efficient mitochondrial oxidative phosphorylation. This releases reactive oxygen species which can lead to cardiomyocyte cell-cycle arrest.
Temperature. Heart regeneration is widespread in cold-blooded species but regeneration loss is the norm for warm-bloodedness. Given that thermoregulating animals, says Vivien, have a metabolic capacity four times as efficient as non-thermoregulating species, these metabolic adaptations may also have come at the expense of regeneration.
Hypoxia. Species that can regenerate heart cells tend to live in hypoxic environments while non-regenerative cardiomyocytes appear to be adapted to an oxygen-rich environment.
Structural organization. When zebrafish heart cells regenerate they first go through a process of de-differentiation in which the muscular internal elements of the cells – called sarcomeres – break down. It may be that adult mammalian cardiomyocytes have a sarcomere structure adapted to a very high workload that makes sarcomere disassembly more difficult.
Nucleation and ploidy. Zebrafish and newt cardiomyocytes are predominantly mono-nucleated, says Vivien. Human cardiomyocytes are binucleate and also polyploid – and both conditions are associated with cell-cycle withdrawal. It is thought that that polyploidy is an adaptation in cardiomyocytes to increase transcriptional output of genes.
Immune system. Non-mammalian vertebrates and neonatal mammals lack immunoglobulins and do not have pro-inflammatory immune systems. There seems to be an inverse relationship, therefore, between regenerative capacity and the development of a mature immune system. These evolutionary adaptations, say Vivien et al, may have resulted from pressures that permitted the development of adaptive immune system mechanisms that promoted animal survival in the face of infectious diseases but resulted in a loss of reparative potential because of excessive inflammation following tissue injury.
So. according to Vivien et al, a number of heart adaptations to allow vertebrates, and especially mammals, to pump blood at high pressure, which involve a change in respiratory metabolism, sarcomere complexity, and warm-bloodedness, could all, plausibly, involve a trade-off of an efficient pump against regenerative potential.
Vivian et al are at pains to stress the hypothetical nature of all their candidate trade-offs but their analysis is backed up by a comprehensive tour of vertebrate heart regeneration potential and their conclusion that understanding the evolutionary context for heart regeneration potential would provide stronger scientific foundations for the translation of cardiac regeneration therapies into the clinic is spot-on evolutionary medicine.
It’s always good to get a variety of views; and of course taking a broad evolutionary approach, or even a more focused adaptationist approach, doesn’t assure agreement. My take on the very limited myocardial regenerative repair in adult mammals comes from looking histologically at large fibrotic areas in hearts with infarcts. There the question is “Why doesn’t the scar get replaced by functional heart tissue?” Clearly (to me, at least), replacement of the scar is well within biological capability. Presumably, therefore, scar replacement is constantly being “explored” and rejected by natural selection. Besides the risk of arrhythmias, one might hypothesize that there may be limitations on getting enough nutrients and oxygen to the site while preserving heart wall strength (e.g., with possible limitations on vascularity in a vigorously beating heart, a fibrous scar providing strength might be less risky than trying to support functional new myocardium). My suspicion is that the role in heart regeneration of low metabolic state (including low pressure, low temperature, and hypoxia) is that it provides the conditions whereby regeneration could be explored and not rejected by selection.
In the paper by Shiba et al, the incorporation of injected myocardial stem cells in the infarcted hearts of the experimental monkeys was associated with arrhythmias that were considered asymptomatic. Presumably these caged monkeys weren’t giving their hearts the vigorous workout that might be expected of monkeys in the wild. One of the reasons some harmful effects of new drugs don’t show up in research animals or early clinical trials is because of the limited environmental conditions in the cages or among small numbers of patients (e.g., no exposure to infection or to especially hard exercise).