The maternal-age-associated risk of congenital heart disease is modifiable

Schulkey, Claire E.; Regmi, Suk D.; Magnan, Rachel A.; Danzo, Megan T; Luther, Herman; Hutchinson, Alayna K; Panzer, Adam A; Grady, Mary M.; Wilson, David B.; Jay, Patrick Y.

doi:10.1038/nature14361

Cited by 73 publications

(68 citation statements)

References 27 publications

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“…Second, the mice in our study voluntarily exercised, likely at lower levels than those in the forced-exercise study. Although we did not control for the exact amounts of exercise each female received, our experimental design was based off of a study that showed moderate voluntary exercise in HFD females was beneficial in the reversal of congenital heart disease in their offspring (Schulkey et al, 2015). Finally, a weak relationship between exercise and weight loss has also been reported in humans (Swift et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The effects of voluntary exercise on oocyte quality in a diet-induced obese murine model

Boudoures¹,

Chi²,

Thompson³

et al. 2016

Reproduction

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Obesity negatively affects many aspects of the human body, including reproductive function. In females, the root of the decline in fertility is linked to problems in the oocyte. Problems seen in oocytes that positively correlate with increasing BMI include changes to the metabolism, lipid accumulation, meiosis, and metaphase II (MII) spindle structure. Studies in mice indicate dietary interventions fail to reverse these problems [4]. How exercise affects the oocytes has not been addressed. Therefore, we hypothesized an exercise intervention would improve oocyte quality. Here we show in a mouse model of an exercise intervention can improve lipid metabolism in germinal vesicle (GV) stage oocytes. Oocytes significantly increased activity and transcription of the β-oxidation enzyme Hadha (Hydroxyacyl-CoA-dehydrogenase) in response to exercise training only if the mice had been fed a high fat diet (HFD). An exercise intervention also reversed the lipid accumulation seen in GV stage oocytes of HFD females. However, delays in meiosis and disorganized MII spindles remained present. Therefore, exercise is able to improve, but not reverse, damage imparted on oocytes as a result of a high fat diet and obesity. By utilizing an exercise intervention on a HFD, we determined only lipid content and lipid metabolism is changed in GV oocytes. Moving forward, interventions to improve oocyte quality may need to be more targeted to the oocyte specifically. Because of the HFD induced deficiency in β-oxidation, dietary supplementation with substrates to improve lipid utilization may be more beneficial.

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Section: Discussionmentioning

confidence: 99%

The effects of voluntary exercise on oocyte quality in a diet-induced obese murine model

Boudoures¹,

Chi²,

Thompson³

et al. 2016

Reproduction

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“…This was also the most common diagnosis among the extended pedigrees. We also observed incomplete penetrance, the cause for which is poorly understood but may relate to maternal factors [17]. …”

Section: Discussionmentioning

confidence: 99%

Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families

et al. 2016

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BackgroundThe genetic basis for dilated cardiomyopathy (DCM) can be difficult to determine, particularly in familial cases with complex phenotypes. Next generation sequencing may be useful in the management of such cases. MethodsWe report two large families with pleiotropic inherited cardiomyopathy. In addition to DCM, the phenotypes included atrial and ventricular septal defects, cardiac arrhythmia and sudden death. Probands underwent whole exome sequencing to identify potentially causative variants.ResultsEach whole exome sequence yielded over 18,000 variants. We identified distinct mutations affecting a common amino acid in NKX2.5. Segregation analysis of the families support the pathogenic role of these variants.ConclusionOur study emphasizes the utility of next generation sequencing in identifying causative mutations in complex inherited cardiac disease. We also report a novel pathogenic NKX2.5 mutation.

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“…To our surprise, the incidence of heart defects in the resulting Nkx2-5 +/− offspring matched that expected for a maternal basis. The offspring of young mothers who ovulated from old ovaries had a low incidence, whereas the offspring of old mothers and young ovaries had a high incidence (Schulkey et al, 2015). An oocyte-based mechanism may contribute to the maternal-age effect in humans, but there is no evidence for one in our mouse model.…”

Section: The Maternal-age Associated Risk Of Congenital Heart Diseasementioning

confidence: 99%

“…The diet had no effect on the incidence of heart defects among the offspring of young mothers, who were markedly hyperglycemic and glucose intolerant. Older mothers developed severe obesity, yet the maternal-age associated risk remained the same (Schulkey et al, 2015). The negative results strongly suggest that the investigation of specific mechanisms one at a time would be risky and inefficient.…”

Section: The Maternal-age Associated Risk Of Congenital Heart Diseasementioning

confidence: 99%

“…Clearly, maternal-fetal interactions, aging and exercise involve myriad pathways. At least one that is common to all three processes mediates the maternal-age associated risk, but the investigation of any one of them would probably be fruitless, as the high-fat diet experiment described above attests (Schulkey et al, 2015). An unbiased genetic approach to discover the relevant genes and pathway would probably be more efficient than focusing upon a specific hypothesis or mechanism.…”

Section: An Unbiased Genetic Approach To the Maternal Effects On Omentioning

confidence: 99%

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Transgenerational cardiology: One way to a baby's heart is through the mother

Jay

Akhirome

Magnan

et al. 2016

Molecular and Cellular Endocrinology

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Despite decades of progress, congenital heart disease remains a major cause of mortality and suffering in children and young adults. Prevention would be ideal, but formidable biological and technical hurdles face any intervention that seeks to target the main causes, genetic mutations in the embryo. Other factors, however, significantly modify the total risk in individuals who carry mutations. Investigation of these factors could lead to an alternative approach to prevention. To define the risk modifiers, our group has taken an “experimental epidemiologic” approach via inbred mouse strain crosses. The original intent was to map genes that modify an individual’s risk of heart defects caused by an Nkx2-5 mutation. During the analysis of >2000 Nkx2-5+/− offspring from one cross we serendipitously discovered a maternal-age associated risk, which also exists in humans. Reciprocal ovarian transplants between young and old mothers indicate that the incidence of heart defects correlates with the age of the mother and not the oocyte, which implicates a maternal pathway as the basis of the risk. The quantitative risk varies between strain backgrounds, so maternal genetic polymorphisms determine the activity of a factor or factors in the pathway. Most strikingly, voluntary exercise by the mother mitigates the risk. Therefore, congenital heart disease can in principle be prevented by targeting a maternal pathway even if the embryo carries a causative mutation. Further mechanistic insight is necessary to develop an intervention that could be implemented on a broad scale, but the physiology of maternal-fetal interactions, aging, and exercise are notoriously complex and undefined. This suggests that an unbiased genetic approach would most efficiently lead to the relevant pathway. A genetic foundation would lay the groundwork for human studies and clinical trials.

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The maternal-age-associated risk of congenital heart disease is modifiable

Cited by 73 publications

References 27 publications

The effects of voluntary exercise on oocyte quality in a diet-induced obese murine model

The effects of voluntary exercise on oocyte quality in a diet-induced obese murine model

Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families

Transgenerational cardiology: One way to a baby's heart is through the mother

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