Q&A Report: Metabolic Mechanisms that Contribute to Pregnancy-Induced Cardiac Growth and its Reversal
The answers to these questions have been provided by:
Helen E. Collins, PhD, FAHA
Assistant Professor
Medicine
University of Louisville
In your Tamoxifen-inducible cardiomyocyte-specific knock-out (KO) model, what did you use and how did you induce pregnancy?
We have utilized the tamoxifen-inducible alpha-myosin heavy chain MCM-Cre to generate our tamoxifen-inducible, cardiomyocyte-specific Bdh1 KO mouse model. This is utilizing Bdh1 floxed mice obtained from the Laboratory of Dr. Daniel Kelly. We provided all mice in the studies tamoxifen chow for up to three weeks followed by a period of two weeks of washout on normal mouse chow. Following the normal chow washout period, we paired mice for timed pregnancy studies to reduce the impact of tamoxifen on estrogen signaling in early pregnancy.
The mouse hearts seem to recover pretty well after multiple pregnancies. What is the period of time between pregnancies?
In the multiple pregnancies studies, between each pregnancy-lactation cycle, we waited a period of three weeks before repairing mice for subsequent pregnancies.
What are the cardiac biomarkers that should be screened during pregnancy?
Several biomarkers do exist that are screened in instances of pregnancy-associated cardiovascular diseases. These include BNP, NT-proBNP, troponins, s-flt1, and PIGF. There is not one biomarker that is necessarily effective due to the plethora of changes that occur during pregnancies complicated with comorbidites, etc. I believe that we need to develop a panel of biomarkers to assess different groups of women with different diseases. However, to do this we also need to appreciate how some of the factors change with uncomplicated pregnancies.
It seems that it would be useful to compare healthy maternal cardiac growth to pathological maternal cardiac growth. Do you have any plans to do this with your animal model, perhaps with an exercise or dietary treatment prior to pregnancy to predispose the animals to healthy vs. unhealthy progression during pregnancy?
We have plans to compare the cardiac remodeling responses observed in normal, healthy pregnancies with those associated with co-morbidities and pregnancy associated disease conditions moving forward now that we have a solid foundation of the changes that occur. We have conducted some diet studies in conjunction with pregnancy and will be conducting studies with two physiological hypertrophic stimuli, pregnancy and exercise.
Was the heart weight in the non-pregnant (NP) before the fourth pregnancy statistically greater than NP before first pregnancy? Do you have any preliminary measures of cardiac function in those hearts?
In the multiple pregnancies studies, we do have complete gravimetric assessments, histological assessments, and some biochemical assays performed, but we are currently doing echocardiographic analyses to determine cardiac function differences. For the multiple pregnancies studies, each time-point has an age-matched control group, so the non-pregnant groups between 1 and 4 pregnancies are all different and the differences that exist would be the result of differences in age between those groups.
What is the time course for the reversal of hypertrophy after pregnancy?
We have seen that the effects of lactation subside by three weeks postpartum in postpartum dams with and without a period of lactation; however, in comparison to non-pregnant controls we have observed increased heart size until one year postpartum.
Have you looked at the impact of cardiac risk factors such as diabetes and obesity in your studies?
We first wanted to ascertain the cardiovascular adaptations in response to a normal, uncomplicated pregnancy because that has been notoriously understudied and could potentially add in additional variables to consider. However, now that we have established a foundation for the cardiac changes that occur during healthy pregnancies, we will now build on maternal co-morbidities and pregnancy-associated disease models to further understand the biological and metabolic processes impacted by disease. Following advanced maternal age, diabetes and obesity would be good cardiac risk factors to examine.
Does the hypertrophy observed correlate with the number of pups?
We have conducted correlation analyses of cardiac size versus number of pups; however, in our studies we have not observed significant correlations. This may require a larger experimental group size and we will be able to answer this with our current Bdh1 WT/KO studies which are significantly powered.