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Sex differences in cardiomyopathy


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  • Testosterone and interleukin-1 beta increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Coronado, M. J., Brandt, J. E., Kim, E., Bucek, A., Bedja, D., Abston, E. D., Shin, J., Gabrielson, K. L., Mitzner, W., Fairweather, D. 2012; 302 (8): H1726-H1736


    Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than in women, but the reasons for the sex difference remain unclear. The aim of this study was to assess whether gene changes in the heart during coxsackievirus B3 (CVB3) myocarditis in male and female BALB/c mice predicted worse DCM in males. Although myocarditis (P = 4.2 10(-5)) and cardiac dilation (P = 0.008) were worse in males, there was no difference in viral replication in the heart. Fibrotic remodeling genes, such as tissue inhibitor of metalloproteinase (TIMP)-1 and serpin A 3n, were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement, we showed that testosterone increased cardiac TIMP-1 (P = 0.04), serpin A 3n (P = 0.007), and matrix metalloproteinase (MMP)-8 (P = 0.04) during myocarditis. Testosterone increased IL-1? levels in the heart (P = 0.02), a cytokine known to regulate cardiovascular remodeling, and IL-1? in turn increased cardiac serpin A 3n mRNA (P = 0.005). We found that 39 of 118 (33%) genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including serpin A 3n (3.3-fold change, P = 0.0001). Recombinant serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (P = 0.0008) while decreasing MMP-3 (P = 0.04) and MMP-9 (P = 0.03) levels in the heart. Thus, serpin A 3n was identified as a gene associated with fibrotic cardiac remodeling and progression to DCM in male myocarditis patients and mice.

    View details for DOI 10.1152/ajpheart.00783.2011

    View details for Web of Science ID 000302911500017

    View details for PubMedID 22328081

  • IL-33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function Circ Heart Fail Abston ED, Barin JG, Cihakova D, Bucek A, Coronado MJ, Bedja D, Kim JB, Georgakopoulos D< Gabrielson KL, Mitzner W, Fairweather D 2012: Accepted with rev
  • Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease CLINICAL & DEVELOPMENTAL IMMUNOLOGY Abston, E. D., Coronado, M. J., Bucek, A., Bedja, D., Shin, J., Kim, J. B., Kim, E., Gabrielson, K. L., Georgakopoulos, D., Mitzner, W., Fairweather, D. 2012


    Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

    View details for DOI 10.1155/2012/129486

    View details for Web of Science ID 000308591000001

    View details for PubMedID 22013485

  • Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis Expert Rev Clin Immunol Fairweather D, Petri MA, Coronado MJ, Cooper LT 2012; 8: In press
  • The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice Biol Sex Differ Onyimba JA*, Coronado MJ*, Garton AE, Kim JB, Bucek A, Bedja D, Gabrielson KL, Guilarte TR, Fairweather D *Both are first authors 2011; 2: 2
  • Biomarkers of heart failure in myocarditis and dilated cardiomyopathy In "Myocarditis", D. Cihakova (Ed.), InTech Fairweather D, A. C. 2011: 323-348
  • Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis BRAIN BEHAVIOR AND IMMUNITY Frisancho-Kiss, S., Coronado, M. J., Frisancho, J. A., Lau, V. M., Rose, N. R., Klein, S. L., Fairweather, D. 2009; 23 (5): 649-657


    The incidence of cardiovascular disease, including inflammatory heart diseases like myocarditis, is increased in men. Similarly, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe acute inflammation in the heart compared to females. To better understand the effect of male sex hormones on cardiac inflammation, we gonadectomized (Gdx) male BALB/c mice and examined acute CVB3-induced myocarditis compared to sham controls. Viral replication in the heart was not significantly altered between Gdx and sham mice. However, gonadectomy significantly reduced testosterone levels and inflammation in the heart. FACS analysis of cell populations isolated from the heart revealed that CD11b(+) cells were significantly reduced in Gdx males. However, a GR1(+)F4/80(+) subset of CD11b(+) cells was significantly increased. Because this subset also expressed the interleukin (IL)-4R and IL-10, we refer to these cells as "alternatively activated" or M2 macrophages. A greater percentage of M2 macrophages in Gdx males expressed the inhibitory receptor Tim-3, while fewer expressed IL-1beta and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1(-)IL-4R(lo) macrophages did not. Additionally, IL-4(+)CD4(+) Th2 cells, Foxp3(+) regulatory T (Treg) cells and Tim-3(+)CD4(+) T cells were significantly increased in the heart following Gdx. Thus, we report for the first time that the inhibitory receptor Tim-3 is expressed on M2 macrophages. Our findings show that sex hormones and/or other mediators released from the testes inhibit anti-inflammatory populations in the heart including Tim-3(+) M2, Tim-3(+)CD4(+) T cells, Th2 and Treg resulting in more severe acute cardiac inflammation in males following CVB3 infection.

    View details for DOI 10.1016/j.bbi.2008.12.002

    View details for Web of Science ID 000267274000012

    View details for PubMedID 19126426

  • Estrogenic activity and reproductive effects of the UV-filter oxybenzone (2-hydroxy-4-methoxyphenyl-methanone) in fish AQUATIC TOXICOLOGY Coronado, M., De Haro, H., Deng, X., Rempel, M. A., Lavado, R., Schlenk, D. 2008; 90 (3): 182-187


    Previous studies in extracts of sediments surrounding municipal outfalls off the coast of California, USA and effluents of New York City, NY, USA indicated the UV-filtering agent, oxybenzone (CAS# 131-57-7; benzophenone-3) as a potential estrogen. The effects of oxybenzone on estrogenic activity and reproduction were evaluated using a 14-day juvenile rainbow trout assay for plasma vitellogenin and a subsequent 21-day Japanese medaka reproduction assay. Significant induction of vitellogenin was observed in the rainbow trout at the 1000 microg/L nominal concentration (749 microg/L median measured value) of oxybenzone which was approximately 75 times greater than the concentrations observed in previous wastewater effluent. Vitellogenin induction was also observed in the 1000 microg/L nominal concentration (620 microg/L median measured) of oxybenzone in male Japanese medaka (Oryzias latipes) after 21 days of exposure. The number of eggs produced per female per day exposed to the same concentration (620 microg/L) were significantly lower after 7 days, but returned to control values after 21 days. Fertilized eggs were then monitored for 20 days to assess hatching success. The overall percentage of fertilized eggs collected during the 21-day exposure that hatched was significantly lower in the 620 microg/L oxybenzone concentration. There was also a temporal effect at this concentration as egg viability (percentage of fertilized eggs that hatched) was diminished 13-15 days after eggs were collected. All three oxybenzone concentrations (16, 132, and 620 microg/L) and the 50 ng/L estradiol positive control showed reduced hatching of eggs at day 15, and the 132 and 620 microg/L oxybenzone concentrations diminished the percentage of eggs that hatched on days 13-15. These data indicate that the UV-filter oxybenzone alters endocrine or reproduction endpoints in two fish species, but at concentrations significantly higher than those measured in the environment.

    View details for DOI 10.1016/j.aquatox.2008.08.018

    View details for Web of Science ID 000261776000003

    View details for PubMedID 18930325

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