Heart disease is the leading cause of death in the United States for both men and women, but in women in particular the disease often goes undetected. Finding ways to detect symptoms of heart disease in women can help us detect signs and risk factors early and help prevent deaths and increase the quality and length of life.
Heart disease takes many forms, the most common being that of coronary artery disease, which comes with the classic pictures of plaque buildup in the arteries that we are used to. But other signs of heart disease can include something called pathological cardiac hypertrophy. Cardiac hypertrophy refers to enlargement of the heart muscle (cardiac = heart, hyper = super or above, trophy = growth), and it usually refers to the lower ventricles of the heart. growth), and it usually refers to the lower ventricles of the heart. Cardiac hypertrophy is a protective mechanism in response to physiologic stressors, like high blood pressure. However, the heart cannot maintain a hypertrophied state indefinitely. If hypertrophy is not resolved, the heart will develop fibrosis (proliferation of fibroblasts), leading to a stiffening of the heart muscle, which can produce debilitating symptoms (you know, like death).
But how do you study cardiac hypertrophy and find ways to REVERSE it? Well…you have to look at pregnancy.
Holden, McCarty, and Waikel. “Characterization of cardiac remodeling during pregnancy in rats”. Eastern Kentucky University, presented at Experimental Biology, 2011.
Why pregnancy? During pregnancy, large changes have to occur in the female body as it adapts to carrying, growing, and feeding a fetus. One of those adaptations is a natural cardiac hypertrophy, as the heart muscle grows and strengthens to accommodate the extra blood flow needed for the fetus. But the interesting thing about cardiac hypertrophy during pregnancy is that it isn’t PERMANENT. Instead (except for rare pathological conditions), it reverses dramatically, going back to a normal size. The authors of this study hope that by studying the way the heart enlarges and then retracts in pregnancy, they can differentiate between the healthy and pathological markers of hypertrophy, perhaps developing some markers than can be used to detect heart disease in women.
In this case, they took pregnant rats, non-pregnant rats, and rats that had given birth only 24 hours before, and looked at their hearts. They found that, not surprisingly, the weight of the heart increased in the pregnant rats by about 10{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3}. This was due entirely to the increase in cardiomyocyte (heart cell) size, as the cells got bigger to accommodate a larger blood volume from the pregnant rat.
But this increase in heart size was short lived. 24 hours after giving birth, the heart sizes were already on the way back down to normal, though they have not yet determined when the heart will be entirely back to normal size.
While this change in size is interesting, what they were really interested in looking at was the gene expression, particularly of the proteins MHC alpha, GPER, and ANP. MHC alpha stands for myosin heavy chain alpha, where myosin is an extremely important motor protein. Other studies have shown that activation of MHC alpha may help to prevent heart failure. Holden et al found in this study that MHC alpha is increased during pregnancy as well as right after pregnancy, and this may suggest a protective role in the pregnant heart.
GPER stands for G Protein-Coupled Estrogen Receptor, a membrane bound receptor which binds estrogen, and which is expressed in the heart. Estrogen is known to be protective against heart disease in women (this is why women develop heart disease later in men, and why heart disease risk in women increases rapidly following menopause), and GPER increased during pregnancy in the heart, and then decreased to normal levels 24 hours post-partum. While this might help as a protective measure in the pregnant heart, it could also indicate that the heart is responding to the changes in estrogen levels that occur during pregnancy.
ANP stands for atrial naturetic peptide, and is a marker of the pathologic kind of cardiac hypertrophy. They did not see any alteration in this one during pregnancy.
The authors of this study also chose to look at micro RNAs. Micro RNAs are a relatively new discovery, tiny (on average only 22 nucleotides long!) segments of RNA which don’t code for proteins like mRNA does. Instead, they bind to the mRNA itself, and help to regulate how much of the mRNA gets made into protein. Changes in these micro RNAs not only could be used to characterize cardiac hypertrophy during pregnancy, they could potentially be used as biomarkers for pathological cardiac hypertrophy (or so we hope). Holden et al found changes in microRNA195 and microRNA21, both of which increased during pregnancy and decreased post-partum. MicroRNA195 has been known to increase in pathologic cardiac hypertrophy, and so this came as no surprise. The authors also found that microRNA21 had a big increase during pregnancy and then a quick decrease afterward. microRNA21 interacts with estrogens, and can decrease the expression of receptors that control the increase of pro-fibrotic proteins. This could mean that the increase in microRNA21 was protective against cardiac fibrosis in the pregnant rats.
The work isn’t done. By further characterizing the differences between normal cardiac hypertrophy due to conditions like pregnancy, and comparing it to pathologic cardiac hypertrophy, Holden et al hope to come up with new biomarkers to allow for early detection of hypertrophy, potentially saving and extending the lives of women with heart disease.
References:
van Rooij et al “A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure.”Proc Natl Acad Sci U S A. 2006
Bhupathy P, Haines CD, Leinwand LA. “Influence of sex hormones and phytoestrogens on heart disease in men and women.” Womens Health (Lond Engl). 2010
Malik et al. “Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure” Science 18 March 2011
van Rooij, E., Sutherland, L., Liu, N., Williams, A., McAnally, J., Gerard, R., Richardson, J., & Olson, E. (2006). A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure Proceedings of the National Academy of Sciences, 103 (48), 18255-18260 DOI: 10.1073/pnas.0608791103
Bhupathy, P., Haines, C., & Leinwand, L. (2010). Influence of sex hormones and phytoestrogens on heart disease in men and women Women’s Health, 6 (1), 77-95 DOI: 10.2217/whe.09.80
Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard M, Godinez G, Kawas R, Kraynack E, Lenzi D, Lu PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii M, Suehiro I, Sylvester S, Tochimoto T, Valdez C, Wang W, Katori T, Kass DA, Shen YT, Vatner SF, & Morgans DJ (2011). Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science (New York, N.Y.), 331 (6023), 1439-43 PMID: 21415352
