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Thyroid problems linked to worsening heart failure
Evidence for hormonal control of heart regenerative capacity during endothermy acquisition
Cardiovascular Research Institute and Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA.
2Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA.
3Department of Medicine, Division of Cardiology, University of California San Francisco, San Francisco, CA 94158, USA.
4Department of Internal Medicine, IGFL, INRA, Univ. Lyon 1, CNRS, ENS Lyon, 69 007 France.
5Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, RTP, NC 27709, USA.
6Calico Life Sciences, 1170 Veterans Blvd, South San Francisco, CA 94080, USA.
7School of Biological Sciences, The University of Adelaide, South Australia, Adelaide, Australia.
8Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA 94708, USA.
9Helen Wills Neuroscience Institute and Department of Bioengineering, UC Berkeley, Berkeley, CA 94708, USA.
10Department of Biology, Bucknell University, Lewisburg, PA 17837, USA.
11Department of Biology and UF Genetics Institute, University of Florida, Gainesville, FL, USA.
12Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Tissue regenerative potential displays striking divergence across phylogeny and ontogeny, but the underlying mechanisms remain enigmatic.
Loss of mammalian cardiac regenerative potential correlates with cardiomyocyte cell-cycle arrest and polyploidization, as well as the development of postnatal endothermy.
We reveal that diploid cardiomyocyte abundance across 41 species conforms to Kleiber’s law−the ¾-power law scaling of metabolism with bodyweight−and inversely correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays cell-cycle exit, and retains cardiac regenerative potential in adults.
Conversely, exogenous thyroid hormones inhibit zebrafish heart regeneration. Thus, our findings suggest that loss of heart regenerative capacity in adult mammals is triggered by increasing thyroid hormones and may be a tradeoff for the acquisition of endothermy.
http://science.sciencemag.org/content/e ... ticle-info
Uitleg in dit artikel (Engels):Thyroid hormone helped our ancestors survive but left us susceptible
Although most victims survive the 735,000 heart attacks that occur annually in the U.S., their heart tissue is often irreparably damaged—unlike many other cells in the body, once injured, heart cells cannot regenerate.
According to a new UC San Francisco study, the issue may date back to our earliest mammalian ancestors, which may have lost the ability to regenerate heart tissue in exchange for endothermy—or as it's known colloquially, "warm-bloodedness"—a Faustian evolutionary bargain that ushered in the age of mammals but left modern humans vulnerable to irreparable tissue damage after heart attack.
Early mammals were small, rodent-like creatures that emerged in a world dominated by cold-blooded animals. Rather than compete directly, early mammals evolved a novel strategy that enabled them to occupy new niches: endothermy. While cold-blooded animals, unable to regulate their own body temperature, were hostage to ever-changing weather conditions and relegated to temperate climates, warm-blooded mammals were able to spread to colder climes and to thrive nocturnally. But, as the new study shows, this came at a steep cost.
"Many of the lower vertebrates can regenerate body parts and organs, including the heart, but most mammals cannot. This feature was lost somewhere in the ectotherm-to-endotherm transition," said Guo Huang, Ph.D., investigator at UCSF's Cardiovascular Research Institute, assistant professor of physiology and senior author of the new study, published March 7 in the journal Science.
At first glance, there's no obvious connection between a mammal's ability to regulate its body temperature and its inability to repair heart damage. But the new study reveals that these seemingly disparate biological traits are inextricably linked—by thyroid hormones.
Thyroid Hormones Halt Heart Cell Regeneration
The thyroid gland produces a pair of well-studied hormones that are known to regulate body temperature, metabolic rate and normal heart function. Because of their critical role in promoting heat generation to maintain body temperature, these hormones have been posited to be the driving force behind the evolutionary transition from cold- to warm-bloodedness.
But Huang's study revealed that these hormones are also responsible for shutting off cardiac cell division, thus preventing heart tissue from repairing itself after an injury. This discovery represents the first demonstrated connection between thyroid hormones, cardiac development and repair, and the evolution of endothermy.
Before our study, scientists knew that thyroid hormones were important for controlling heart rate and heart contractility. But the link with heart regenerative potential had never been shown before," Huang said.
Huang's team took a multi-species approach, comparing heart cell "ploidy"—the number of copies of each chromosome pair in a cell—across 41 different vertebrate species. Ploidy is closely linked to a cell's ability to divide and replicate. Virtually all actively dividing animal cells are diploid, containing only one pair of each chromosome, a copy inherited from mothers and another from fathers. By contrast, polyploid cells contain multiple copies of each pair and generally can't divide.
This comparative approach revealed a clear connection between ploidy and body temperature. Cold-blooded animals—fish, amphibians and reptiles—had heart cells that were largely diploid and responded to cardiac injury by ramping up cell division. Warm-blooded mammals had heart cells that were overwhelmingly polyploid, and lab experiments confirmed that these cells rarely divide in response to cardiac damage.
"This led us to hypothesize that the same thyroid hormones responsible for regulating body temperature might also be responsible for the diploid-to-polyploid transition and the arrest of cardiac cell division," Huang said.
The researchers confirmed their hunch in a series of lab experiments involving mice, a warm-blooded mammal in which heart cells normally cannot regenerate, and zebrafish, a cold-blooded animal noted for its ability to completely repair its heart, even if large chunks—up to 20 percent—are surgically amputated.
Mammals Gain, Fish Lose Heart Healing After Thyroid Hormone Levels Altered
In the womb, mice have diploid heart cells that regularly replicate to produce new cardiac tissue. But the heart cells of newborn mice undergo rapid polyploidization and lose the ability to divide—events that coincide with a more than 50-fold increase in circulating thyroid hormones.
Experiments showed that these events were more than mere coincidence. When the researchers injected newborn mice with a drug that blocked thyroid hormone receptors and inspected their hearts two weeks later, they found four times as many dividing diploid heart muscle cells than mice that received no drug. Similar results were observed when they administered a different drug that impeded the production of thyroid hormones.
The researchers also produced genetically engineered mice whose heart cells lacked a functional receptor for thyroid hormone, which allowed their hearts to develop free from the influence of thyroid hormones. Unlike normal mice, these mutant mice were found to have significant numbers of actively dividing, diploid heart cells. Furthermore, when the scientists restricted blood flow to the heart—a condition that usually causes permanent damage to cardiac tissue—they observed a 10-fold increase in the number of dividing heart cells and 62 percent less scar tissue when compared with normal mice. Meanwhile, echocardiograms revealed an 11 percent improvement in heart function over normal mice after injury.
In stark contrast to mice and other mammals, adult zebrafish have relatively low levels of circulating thyroid hormone. This led Huang to wonder whether increasing the levels of thyroid hormone could shut off the self-repair machinery that makes zebrafish hearts uncommonly resilient.
The researchers added thyroid hormone to the water in zebrafish tanks, then surgically amputated a portion of the heart and provided the fish with ample recovery time. Normally, zebrafish would be able to completely repair this kind of damage over the course of a few weeks.
But fish that were reared in a high-hormone environment experienced a 45 percent reduction in heart cell division, a significant increase in polyploid heart cells and pronounced scarring of heart tissue after injury. Just as in mammals, thyroid hormones led to impaired cardiac regeneration in fish.
Our results demonstrate an evolutionarily conserved function for thyroid hormone in regulating heart cell proliferation and suggest that loss of regenerative potential was a trade-off that allowed mammals to become warm-blooded," Huang said.
"For early mammals, endothermy was more advantageous than retention of regenerative potential.
But now, with medical improvements allowing us to live much longer, this loss of cardiac regeneration becomes more problematic and is a fundamental cause of heart disease."
https://medicalxpress.com/news/2019-03- ... -left.html
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Thyroid problems linked to worsening heart failure
The thyroid is a tiny powerhouse. The gland, which is located at the base of the neck, releases hormones that control how the entire body uses energy and affects an array of organs throughout the body – including the heart.
Now, a new study from researchers at the University of Pennsylvania shows two thyroid disorders – subclinical hypothyroidism and low T3 syndrome – might make heart failure worse.
The findings "suggest there are groups of people who might benefit from thyroid treatment who aren't getting treated right now," said Dr. Anne Cappola, an endocrinologist at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and senior author of the study, published Friday in the American Heart Association journal Circulation: Heart Failure.
https://medicalxpress.com/news/2018-12- ... heart.html
Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes
The effects of thyroid dysfunction in patients with preexisting heart failure have not been adequately studied. We examined the prevalence of thyroid dysfunction and associations with cardiovascular outcomes in a large, prospective cohort of outpatients with preexisting heart failure.
Methods and Results:
We examined associations between thyroid dysfunction and New York Heart Association class, atrial fibrillation, and a composite end point of ventricular assist device placement, heart transplantation, or death in 1365 participants with heart failure enrolled in the Penn Heart Failure Study.
Mean age was 57 years, 35% were women, and the majority had New York Heart Association class II (45%) or III (32%) symptoms.
More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations (P<0.001 all models).
Atrial fibrillation was positively associated with higher levels of FT4 alone (P≤0.01 all models).
There were 462 composite end points over a median 4.2 years of follow-up.
In adjusted models, compared with euthyroidism, subclinical hypothyroidism (TSH 4.51–19.99 mIU/L with normal FT4) was associated with an increased risk of the composite end point overall (hazard ratio, 1.82; 95% CI, 1.27–2.61; P=0.001) and in the subgroup with TSH ≥7.00 mIU/L (hazard ratio, 3.25; 95% CI, 1.96–5.39; P<0.001), but not in the subgroup with TSH 4.51–6.99 mIU/L (hazard ratio, 1.26; 95% CI, 0.78–2.06; P=0.34). Isolated low T3 was also associated with the composite end point (hazard ratio, 2.12; 95% CI, 1.65–2.72; P<0.001).
In patients with preexisting heart failure, subclinical hypothyroidism with TSH ≥7 mIU/L and isolated low T3 levels are associated with poor prognosis.
Clinical trials are needed to explore therapeutic effects of T4 and T3 administration in heart failure.