Top

Published in:

01-10-2019 | Fetal Alcohol Spectrum Disorder

Prenatal Alcohol Exposure Causes Adverse Cardiac Extracellular Matrix Changes and Dysfunction in Neonatal Mice

Authors: Van K. Ninh, Elia C. El Hajj, Alan J. Mouton, Jason D. Gardner

Published in: Cardiovascular Toxicology | Issue 5/2019

Abstract

Fetal alcohol syndrome (FAS) is the most severe condition of fetal alcohol spectrum disorders (FASD) and is associated with congenital heart defects. However, more subtle defects such as ventricular wall thinning and cardiac compliance may be overlooked in FASD. Our studies focus on the role of cardiac fibroblasts in the neonatal heart, and how they are affected by prenatal alcohol exposure (PAE). We hypothesize that PAE affects fibroblast function contributing to dysregulated collagen synthesis, which leads to cardiac dysfunction. To investigate these effects, pregnant C57/BL6 mice were intraperitoneally injected with 2.9 g EtOH/kg dose to achieve a blood alcohol content of approximately 0.35 on gestation days 6.75 and 7.25. Pups were sacrificed on neonatal day 5 following echocardiography measurements of left ventricular (LV) chamber dimension and function. Hearts were used for primary cardiac fibroblast isolation or protein expression analysis. PAE animals had thinner ventricular walls than saline exposed animals, which was associated with increased LV wall stress and decreased ejection fraction. In isolated fibroblasts, PAE decreased collagen I/III ratio and increased gene expression of profibrotic markers, including α-smooth muscle actin and lysyl oxidase. Notch1 signaling was assessed as a possible mechanism for fibroblast activation, and indicated that gene expression of Notch1 receptor and downstream Hey1 transcription factor were increased. Cardiac tissue analysis revealed decreased collagen I/III ratio and increased protein expression of α-smooth muscle actin and lysyl oxidase. However, Notch1 signaling components decreased in whole heart tissue. Our study demonstrates that PAE caused adverse changes in the cardiac collagen profile and a decline in cardiac function in the neonatal heart.

Jones, K. L. (2011). The effects of alcohol on fetal development. Birth Defects Research Part C: Embryo Today, 93(1), 3–11. https://doi.org/10.1002/bdrc.20200.CrossRefPubMed

Floyd, R. L., & Sidhu, J. S. (2004). Monitoring prenatal alcohol exposure. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 127C(1), 3–9. https://doi.org/10.1002/ajmg.c.30010.CrossRef

Karunamuni, G., Gu, S., Doughman, Y. Q., Peterson, L. M., Mai, K., McHale, Q., et al. (2014). Ethanol exposure alters early cardiac function in the looping heart: A mechanism for congenital heart defects? American Journal of Physiology-Heart and Circulatory Physiology, 306(3), H414–H421. https://doi.org/10.1152/ajpheart.00600.2013.CrossRefPubMed

Tan, C. H., Denny, C. H., Cheal, N. E., Sniezek, J. E., & Kanny, D. (2015). Alcohol use and binge drinking among women of childbearing age—United States, 2011–2013. MMWR Morbidity and Mortality Weekly Report, 64(37), 1042–1046. https://doi.org/10.15585/mmwr.mm6437a3.CrossRefPubMed

Finer, L. B., & Henshaw, S. K. (2006). Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspectives on Sexual and Reproductive Health, 38(2), 90–96. https://doi.org/10.1363/psrh.38.090.06.CrossRefPubMed

Trussell, J., Lalla, A. M., Doan, Q. V., Reyes, E., Pinto, L., & Gricar, J. (2009). Cost effectiveness of contraceptives in the United States. Contraception, 79(1), 5–14. https://doi.org/10.1016/j.contraception.2008.08.003.CrossRefPubMed

Naimi, T. S., Lipscomb, L. E., Brewer, R. D., & Gilbert, B. C. (2003). Binge drinking in the preconception period and the risk of unintended pregnancy: Implications for women and their children. Pediatrics, 111(5 Pt 2), 1136–1141.PubMed

Linask, K. K., & Han, M. (2016). Acute alcohol exposure during mouse gastrulation alters lipid metabolism in placental and heart development: Folate prevention. Birth Defects Research Part A: Clinical and Molecular Teratology, 106(9), 749–760. https://doi.org/10.1002/bdra.23526.CrossRefPubMed

Iveli, M. F., Morales, S., Rebolledo, A., Savietto, V., Salemme, S., Apezteguia, M., et al. (2007). Effects of light ethanol consumption during pregnancy: Increased frequency of minor anomalies in the newborn and altered contractility of umbilical cord artery. Pediatric Research, 61(4), 456–461. https://doi.org/10.1203/pdr.0b013e3180332c59.CrossRefPubMed

10.

Loser, H., & Majewski, F. (1977). Type and frequency of cardiac defects in embryofetal alcohol syndrome. Report of 16 cases. British Heart Journal, 39(12), 1374–1379.CrossRefPubMedPubMedCentral

11.

Burd, L., Deal, E., Rios, R., Adickes, E., Wynne, J., & Klug, M. G. (2007). Congenital heart defects and fetal alcohol spectrum disorders. Congenital Heart Disease, 2(4), 250–255. https://doi.org/10.1111/j.1747-0803.2007.00105.x.CrossRefPubMed

12.

Serrano, M., Han, M., Brinez, P., & Linask, K. K. (2010). Fetal alcohol syndrome: Cardiac birth defects in mice and prevention with folate. American Journal of Obstetrics and Gynecology, 203(1), 75-e7. https://doi.org/10.1016/j.ajog.2010.03.017.CrossRef

13.

Parkington, H. C., Coleman, H. A., Wintour, E. M., & Tare, M. (2010). Prenatal alcohol exposure: Implications for cardiovascular function in the fetus and beyond. Clinical and Experimental Pharmacology and Physiology, 37(2), e91–e98. https://doi.org/10.1111/j.1440-1681.2009.05342.x.CrossRefPubMed

14.

Gray, S. P., Denton, K. M., Cullen-McEwen, L., Bertram, J. F., & Moritz, K. M. (2010). Prenatal exposure to alcohol reduces nephron number and raises blood pressure in progeny. Journal of the American Society of Nephrology, 21(11), 1891–1902. https://doi.org/10.1681/ASN.2010040368.CrossRefPubMedPubMedCentral

15.

Turcotte, L. A., Aberle, N. S., Norby, F. L., Wang, G. J., & Ren, J. (2002). Influence of prenatal ethanol exposure on vascular contractile response in rat thoracic aorta. Alcohol, 26(2), 75–81.CrossRefPubMed

16.

Lockhart, M., Wirrig, E., Phelps, A., & Wessels, A. (2011). Extracellular matrix and heart development. Birth Defects Research Part A—Clinical and Molecular Teratology, 91(6), 535–550. https://doi.org/10.1002/bdra.20810.CrossRef

17.

Deb, A., & Ubil, E. (2014). Cardiac fibroblast in development and wound healing. Journal of Molecular and Cellular Cardiology, 70, 47–55. https://doi.org/10.1016/j.yjmcc.2014.02.017.CrossRefPubMed

18.

Souders, C. A., Bowers, S. L., & Baudino, T. A. (2009). Cardiac fibroblast: The renaissance cell. Circulation Research, 105(12), 1164–1176. https://doi.org/10.1161/CIRCRESAHA.109.209809.CrossRefPubMedPubMedCentral

19.

Gershlak, J. R., Resnikoff, J. I., Sullivan, K. E., Williams, C., Wang, R. M., & Black, L. D. 3rd (2013). Mesenchymal stem cells ability to generate traction stress in response to substrate stiffness is modulated by the changing extracellular matrix composition of the heart during development. Biochemical and Biophysical Research Communications, 439(2), 161–166. https://doi.org/10.1016/j.bbrc.2013.08.074.CrossRefPubMed

20.

Katsumi, A., Orr, A. W., Tzima, E., & Schwartz, M. A. (2004). Integrins in mechanotransduction. Journal of Biological Chemistry, 279(13), 12001–12004. https://doi.org/10.1074/jbc.R300038200.CrossRef

21.

Baudino, T. A., Carver, W., Giles, W., & Borg, T. K. (2006). Cardiac fibroblasts: Friend or foe? American Journal of Physiology: Heart and Circulatory Physiology, 291(3), H1015–H1026. https://doi.org/10.1152/ajpheart.00023.2006.CrossRefPubMed

22.

Leask, A. (2010). Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circulation Research, 106(11), 1675–1680. https://doi.org/10.1161/CIRCRESAHA.110.217737.CrossRefPubMed

23.

El Hajj, E. C., El Hajj, M. C., Voloshenyuk, T. G., Mouton, A. J., Khoutorova, E., Molina, P. E., et al. (2014). Alcohol modulation of cardiac matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs favors collagen accumulation. Alcoholism: Clinical and Experimental Research, 38(2), 448–456. https://doi.org/10.1111/acer.12239.CrossRef

24.

Law, B. A., & Carver, W. E. (2013). Activation of cardiac fibroblasts by ethanol is blocked by TGF-beta inhibition. Alcoholism: Clinical and Experimental Research, 37(8), 1286–1294. https://doi.org/10.1111/acer.12111.CrossRef

25.

Oswald, F., Tauber, B., Dobner, T., Bourteele, S., Kostezka, U., Adler, G., et al. (2001). p300 acts as a transcriptional coactivator for mammalian Notch-1. Molecular Cell Biology, 21(22), 7761–7774. https://doi.org/10.1128/MCB.21.22.7761-7774.2001.CrossRef

26.

Dettman, R. W., Denetclaw, W. Jr., Ordahl, C. P., & Bristow, J. (1998). Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Developmental Biology, 193(2), 169–181. https://doi.org/10.1006/dbio.1997.8801.CrossRefPubMed

27.

Vrancken Peeters, M. P., Gittenberger-de Groot, A. C., Mentink, M. M., & Poelmann, R. E. (1999). Smooth muscle cells and fibroblasts of the coronary arteries derive from epithelial-mesenchymal transformation of the epicardium. Anatomy and Embryology (Berlin), 199(4), 367–378.CrossRef

28.

Grego-Bessa, J., Luna-Zurita, L., del Monte, G., Bolos, V., Melgar, P., Arandilla, A., et al. (2007). Notch signaling is essential for ventricular chamber development. Developmental Cell, 12(3), 415–429. https://doi.org/10.1016/j.devcel.2006.12.011.CrossRefPubMedPubMedCentral

29.

Xing, Y., Bai, R. Y., Yan, W. H., Han, X. F., Duan, P., Xu, Y., et al. (2007). Expression changes of Notch-related genes during the differentiation of human mesenchymal stem cells into neurons. Sheng Li Xue Bao, 59(3), 267–272.PubMed

30.

Timmerman, L. A., Grego-Bessa, J., Raya, A., Bertran, E., Perez-Pomares, J. M., Diez, J., et al. (2004). Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes & Development, 18(1), 99–115. https://doi.org/10.1101/gad.276304.CrossRef

31.

Forsyth, C. B., Shaikh, M., Bishehsari, F., Swanson, G., Voigt, R. M., Dodiya, H., et al. (2017). Alcohol feeding in mice promotes colonic hyperpermeability and changes in colonic organoid stem cell fate. Alcoholism: Clinical and Experimental Research, 41(12), 2100–2113. https://doi.org/10.1111/acer.13519.CrossRef

32.

Khayrullin, A., Smith, L., Mistry, D., Dukes, A., Pan, Y. A., & Hamrick, M. W. (2016). Chronic alcohol exposure induces muscle atrophy (myopathy) in zebrafish and alters the expression of microRNAs targeting the Notch pathway in skeletal muscle. Biochemical and Biophysical Research Communications, 479(3), 590–595. https://doi.org/10.1016/j.bbrc.2016.09.117.CrossRefPubMed

33.

Ninh, V. K., El Hajj, E. C., Mouton, A. J., El Hajj, M. C., Gilpin, N. W., & Gardner, J. D. (2018). Chronic ethanol administration prevents compensatory cardiac hypertrophy in pressure overload. Alcoholism: Clinical and Experimental Research. https://doi.org/10.1111/acer.13799.CrossRef

34.

Hutchinson, K. R., Guggilam, A., Cismowski, M. J., Galantowicz, M. L., West, T. A., Stewart, J. A. Jr., et al. (2011). Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure. Journal of Applied Physiology (1985), 111(6), 1778–1788. https://doi.org/10.1152/japplphysiol.00691.2011.CrossRefPubMedCentral

35.

Hoyme, H. E., Kalberg, W. O., Elliott, A. J., Blankenship, J., Buckley, D., Marais, A. S., et al. (2016). Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders. Pediatrics, 138(2), e20154256. https://doi.org/10.1542/peds.2015-4256.CrossRefPubMedPubMedCentral

36.

Rojmahamongkol, P., Cheema-Hasan, A., & Weitzman, C. (2015). Do pediatricians recognize fetal alcohol spectrum disorders in children with developmental and behavioral problems? Journal of Developmental and Behavioral Pediatrics, 36(3), 197–202. https://doi.org/10.1097/DBP.0000000000000146.CrossRefPubMed

37.

May, P. A., Chambers, C. D., Kalberg, W. O., Zellner, J., Feldman, H., Buckley, D., et al. (2018). Prevalence of fetal alcohol spectrum disorders in 4 US Communities. JAMA, 319(5), 474–482. https://doi.org/10.1001/jama.2017.21896.CrossRefPubMedPubMedCentral

38.

Cavieres, M. F., & Smith, S. M. (2000). Genetic and developmental modulation of cardiac deficits in prenatal alcohol exposure. Alcoholism: Clinical and Experimental Research, 24(1), 102–109.CrossRef

39.

Bertrand, J., Floyd, L. L., & Weber, M. K., Fetal Alcohol Syndrome Prevention Team DoBD, Developmental Disabilities NCoBD, Developmental Disabilities CfDC, et al. (2005). Guidelines for identifying and referring persons with fetal alcohol syndrome. MMWR Recommendations and Reports, 54(RR-11), 1–14.PubMed

40.

Krishnan, A., Samtani, R., Dhanantwari, P., Lee, E., Yamada, S., Shiota, K., et al. (2014). A detailed comparison of mouse and human cardiac development. Pediatric Research, 76(6), 500–507. https://doi.org/10.1038/pr.2014.128.CrossRefPubMedPubMedCentral

41.

Buckingham, M., Meilhac, S., & Zaffran, S. (2005). Building the mammalian heart from two sources of myocardial cells. Nature Reviews Genetics, 6(11), 826–835. https://doi.org/10.1038/nrg1710.CrossRefPubMed

42.

Santini, M. P., Forte, E., Harvey, R. P., & Kovacic, J. C. (2016). Developmental origin and lineage plasticity of endogenous cardiac stem cells. Development, 143(8), 1242–1258. https://doi.org/10.1242/dev.111591.CrossRefPubMedPubMedCentral

43.

Martinsen, B. J., et al. (2005) Cardiac development. In P. A. Iaizzo (Ed.), Handbook of cardiac anatomy, physiology, and devices (pp. 15–23). New Jersey: Humana Press.CrossRef

44.

Daft, P. A., Johnston, M. C., & Sulik, K. K. (1986). Abnormal heart and great vessel development following acute ethanol exposure in mice. Teratology, 33(1), 93–104. https://doi.org/10.1002/tera.1420330112.CrossRefPubMed

45.

Naimi, T., Brewer, B., Mokdad, A., Denny, C., Serdula, M., & Marks, J. (2003). Definitions of binge drinking. JAMA, 289(13), 1635–1636. https://doi.org/10.1001/jama.289.13.1635.CrossRef

46.

Perhonen, M. A., Franco, F., Lane, L. D., Buckey, J. C., Blomqvist, C. G., Zerwekh, J. E., et al. (2001). Cardiac atrophy after bed rest and spaceflight. Journal of Applied Physiology (1985), 91(2), 645–653. https://doi.org/10.1152/jappl.2001.91.2.645.CrossRef

47.

Razeghi, P., Baskin, K. K., Sharma, S., Young, M. E., Stepkowski, S., Essop, M. F., et al. (2006). Atrophy, hypertrophy, and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart. Biochemical and Biophysical Research Communications, 342(2), 361–364. https://doi.org/10.1016/j.bbrc.2006.01.163.CrossRefPubMed

48.

Razeghi, P., & Taegtmeyer, H. (2006). Hypertrophy and atrophy of the heart: The other side of remodeling. Proceedings of the National Academy of Sciences of the United States of America, 1080, 110–119. https://doi.org/10.1196/annals.1380.011.CrossRef

49.

Capasso, J. M., Li, P., Guideri, G., & Anversa, P. (1991). Left ventricular dysfunction induced by chronic alcohol ingestion in rats. American Journal of Physiology, 261(1 Pt 2), H212–H219. https://doi.org/10.1152/ajpheart.1991.261.1.H212.CrossRef

50.

Capasso, J. M., Li, P., Guideri, G., Malhotra, A., Cortese, R., & Anversa, P. (1992). Myocardial mechanical, biochemical, and structural alterations induced by chronic ethanol ingestion in rats. Circulation Research, 71(2), 346–356.CrossRefPubMed

51.

Drazner, M. H. (2011). The progression of hypertensive heart disease. Circulation, 123(3), 327–334. https://doi.org/10.1161/CIRCULATIONAHA.108.845792.CrossRefPubMed

52.

Lorell, B. H., & Carabello, B. A. (2000). Left ventricular hypertrophy: Pathogenesis, detection, and prognosis. Circulation, 102(4), 470–479.CrossRefPubMed

53.

Wold, L. E., Norby, F. L., Hintz, K. K., Colligan, P. B., Epstein, P. N., & Ren, J. (2001). Prenatal ethanol exposure alters ventricular myocyte contractile function in the offspring of rats: Influence of maternal Mg²⁺ supplementation. Cardiovascular Toxicology, 1(3), 215–224.CrossRefPubMed

54.

Ren, J., Wold, L. E., Natavio, M., Ren, B. H., Hannigan, J. H., & Brown, R. A. (2002). Influence of prenatal alcohol exposure on myocardial contractile function in adult rat hearts: Role of intracellular calcium and apoptosis. Alcohol Alcohol, 37(1), 30–37.CrossRefPubMed

55.

Russell, J. L., Goetsch, S. C., Gaiano, N. R., Hill, J. A., Olson, E. N., & Schneider, J. W. (2011). A dynamic notch injury response activates epicardium and contributes to fibrosis repair. Circulation Research, 108(1), 51–59. https://doi.org/10.1161/CIRCRESAHA.110.233262.CrossRefPubMed

56.

Fan, X., Yao, Y., & Zhang, Y. (2018). Calreticulin promotes proliferation and extracellular matrix expression through Notch pathway in cardiac fibroblasts. Advances in Clinical and Experimental Medicine. https://doi.org/10.17219/acem/74430.CrossRefPubMed

57.

Aoyagi-Ikeda, K., Maeno, T., Matsui, H., Ueno, M., Hara, K., Aoki, Y., et al. (2011). Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway. American Journal of Respiratory Cell and Molecular Biology, 45(1), 136–144. https://doi.org/10.1165/rcmb.2010-0140OC10.1165/rcmb.2009-0140OC.CrossRefPubMed

58.

Zeisberg, E. M., Tarnavski, O., Zeisberg, M., Dorfman, A. L., McMullen, J. R., Gustafsson, E., et al. (2007). Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine, 13(8), 952–961. https://doi.org/10.1038/nm1613.CrossRefPubMed

59.

Morrow, D., Cullen, J. P., Liu, W., Cahill, P. A., & Redmond, E. M. (2010). Alcohol inhibits smooth muscle cell proliferation via regulation of the Notch signaling pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(12), 2597–2603. https://doi.org/10.1161/ATVBAHA.110.215681.CrossRefPubMedPubMedCentral

60.

Morrow, D., Cullen, J. P., Cahill, P. A., & Redmond, E. M. (2008). Ethanol stimulates endothelial cell angiogenic activity via a Notch- and angiopoietin-1-dependent pathway. Cardiovascular Research, 79(2), 313–321. https://doi.org/10.1093/cvr/cvn108.CrossRefPubMed

61.

Sarmah, S., Muralidharan, P., & Marrs, J. A. (2016). Embryonic ethanol exposure dysregulates BMP and notch signaling, leading to persistent atrio-ventricular valve defects in Zebrafish. PLoS ONE, 11(8), e0161205. https://doi.org/10.1371/journal.pone.0161205.CrossRefPubMedPubMedCentral

62.

Bolos, V., Grego-Bessa, J., & de la Pompa, J. L. (2007). Notch signaling in development and cancer. Endocrine Reviews, 28(3), 339–363. https://doi.org/10.1210/er.2006-0046.CrossRefPubMed

63.

Boopathy, A. V., Pendergrass, K. D., Che, P. L., Yoon, Y. S., & Davis, M. E. (2013). Oxidative stress-induced Notch1 signaling promotes cardiogenic gene expression in mesenchymal stem cells. Stem Cell Research & Therapy, 4(2), 43. https://doi.org/10.1186/scrt190.CrossRef

64.

Noseda, M., Fu, Y., Niessen, K., Wong, F., Chang, L., McLean, G., et al. (2006). Smooth Muscle alpha-actin is a direct target of Notch/CSL. Circulation Research, 98(12), 1468–1470. https://doi.org/10.1161/01.RES.0000229683.81357.26.CrossRefPubMed

65.

Niessen, K., & Karsan, A. (2008). Notch signaling in cardiac development. Circulation Research, 102(10), 1169–1181. https://doi.org/10.1161/CIRCRESAHA.108.174318.CrossRefPubMed

Title: Prenatal Alcohol Exposure Causes Adverse Cardiac Extracellular Matrix Changes and Dysfunction in Neonatal Mice
Authors: Van K. Ninh
Elia C. El Hajj
Alan J. Mouton
Jason D. Gardner
Publication date: 01-10-2019
Publisher: Springer US
Keyword: Fetal Alcohol Spectrum Disorder
Published in: Cardiovascular Toxicology / Issue 5/2019
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-018-09503-8

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The STEP trials

Springer Medicine

Prenatal Alcohol Exposure Causes Adverse Cardiac Extracellular Matrix Changes and Dysfunction in Neonatal Mice

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2019

Characterization of microminipig as a laboratory animal for safety pharmacology study by analyzing fluvoxamine-induced cardiovascular and dermatological adverse reactions

Toxic Effects of Particulate Matter Derived from Dust Samples Near the Dzhidinski Ore Processing Mill, Eastern Siberia, Russia

Acute Effects of Electronic Cigarette Inhalation on the Vasculature and the Conducting Airways

Inhibitory Effect of Tricyclic Antidepressant Doxepin on Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Cardiogenic Shock Due to Aluminum Phosphide Poisoning Treated with Intra-aortic Balloon Pump: A Report of Two Cases

Carbon Monoxide Attenuates High Salt-Induced Hypertension While Reducing Pro-inflammatory Cytokines and Oxidative Stress in the Paraventricular Nucleus

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page