Correlation between structural heart disease and cardiac SARS-CoV-2 manifestations
Felix Nägele, Michael Graber, Jakob Hirsch, Leo Pölzl, Sabina Sahanic, Manuel Fiegl, Dominik Hau, Clemens Engler, Sophia Lechner, Anna Katharina Stalder, Kirsten D Mertz, Jasmin D Haslbauer, Alexandar Tzankov, Michael Grimm, Ivan Tancevski, Johannes Holfeld, Can Gollmann-Tepeköylü, Felix Nägele, Michael Graber, Jakob Hirsch, Leo Pölzl, Sabina Sahanic, Manuel Fiegl, Dominik Hau, Clemens Engler, Sophia Lechner, Anna Katharina Stalder, Kirsten D Mertz, Jasmin D Haslbauer, Alexandar Tzankov, Michael Grimm, Ivan Tancevski, Johannes Holfeld, Can Gollmann-Tepeköylü
Abstract
Background: The prognosis of COVID-19 patients with cardiac involvement is unfavorable and it remains unknown which patients are at risk. The virus enters cells via its receptor angiotensin-converting enzyme 2 (ACE2). Myocardial ACE2 expression is increased in structural heart disease (SHD). We, therefore, aimed to analyze correlations between structural heart disease and cardiac SARS-CoV-2 manifestation.
Methods: The clinical course of COVID-19 in patients with structural heart disease was assessed in a prospective cohort of 152 patients. The primary endpoints consisted of hospitalization and survival. Cardiac tissue of 23 autopsy cases with lethal COVID-19 course was obtained and analyzed for (a) the presence of SHD, (b) myocardial presence of SARS-CoV-2 via RT,-PCR, and (c) levels of ACE2 expression using immunofluorescence staining.
Results: Structural heart disease is found in 67 patients, of whom 56 (83.60%) are hospitalized. The myocardium is positive for SARS-CoV-2 in 15 patients (65%) in 23 autopsy cases of lethal COVID-19. Moreover, most hearts with evidence of myocardial SARS-CoV-2 have structural heart disease [11 (91,67%) vs. 1 (8,33%), p = 0.029]. Myocardial presence of SARS-CoV-2 is correlated with a significant downregulation of ACE2 compared to negative control hearts (6.545 ± 1.1818 A.U. vs. 7.764 ± 2.411 A.U., p = 0.003). The clinical course of patients with cardiac SARS-CoV-2 manifestation is unfavorable, resulting in impaired survival (median, 12 days and 4.5 days, respectively, HR 0.30, 95% CI, 0.13 to 0.73, p = 0.0005) CONCLUSIONS: We provide evidence for a correlation between SHD, altered ACE2 receptor expression, and cardiac SARS-CoV-2 manifestation. Consequently, structural heart disease may be considered a distinct risk factor for a severe clinical course after infection with SARS-CoV-2.
Registration number local irb: Ethics Committee of Northwestern and Central Switzerland ID 2020-00629; Ethics Committee of the Medical University Innsbruck EK Nr: 1103/2020.
Gov number: NCT04416100.
Conflict of interest statement
The authors declare no competing interests.
© 2022. The Author(s).
Figures
References
- Camerer CF, et al. Evaluating the replicability of social science experiments in Nature and Science between 2010 and 2015. Nat. Hum. Behav. 2018;2:637–644. doi: 10.1038/s41562-018-0399-z.
- Driggin E, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J. Am. Coll. Cardiol. 2020;75:2352–2371. doi: 10.1016/j.jacc.2020.03.031.
- Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 2020;17:259–260. doi: 10.1038/s41569-020-0360-5.
- Thum T. SARS-CoV-2 receptor ACE2 expression in the human heart: Cause of a post-pandemic wave of heart failure? Eur. Heart. J. 2020;41:1807–1809. doi: 10.1093/eurheartj/ehaa410.
- Nicin L, et al. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur. Heart J. 2020;41:1804–1806. doi: 10.1093/eurheartj/ehaa311.
- Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46:586–590. doi: 10.1007/s00134-020-05985-9.
- Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: From basic mechanisms to clinical perspectives. Nat. Rev. Cardiol. 2020;17:543–558. doi: 10.1038/s41569-020-0413-9.
- Menter T, Cueni N, Gebhard EC, Tzankov A. Case report: Co-occurrence of myocarditis and thrombotic microangiopathy limited to the heart in a COVID-19 patient. Front. Cardiovasc. Med. 2021;8:809. doi: 10.3389/fcvm.2021.695010.
- Amendola, A. et al. Human cardiosphere-derived stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression. (2021).
- Guzik TJ, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc. Res. 2020;116:1666–1687. doi: 10.1093/cvr/cvaa106.
- Sahanic, S. et al. The role of innate immunity and bioactive lipid mediators in COVID-19 and influenza. Front. Physiol. 12, 688946 (2021).
- Sonnweber, T. et al. Cardiopulmonary recovery after COVID-19: An observational prospective multicentre trial. Eur. Respir. J.57, 2003481 (2021).
- Galderisi M, et al. Standardization of adult transthoracic echocardiography reporting in agreement with recent chamber quantification, diastolic function, and heart valve disease recommendations: An expert consensus document of the European Association of Cardiovascular Imag. Eur. Heart J. Cardiovasc. Imaging. 2017;18:1301–1310. doi: 10.1093/ehjci/jex244.
- Haslbauer JD, et al. Characterisation of cardiac pathology in 23 autopsies of lethal COVID-19. J. Pathol. Clin. Res. 2021;7:326–337. doi: 10.1002/cjp2.212.
- Khokhar SK, Mitui M, Leos NK, Rogers BB, Park JY. Evaluation of Maxwell® 16 for automated DNA extraction from whole blood and formalin-fixed paraffin embedded (FFPE) tissue. Clin. Chem. Lab. Med. 2012;50:267–272. doi: 10.1515/cclm.2011.763.
- Gilda JE, et al. A semiautomated measurement of muscle fiber size using the Imaris software. Am. J. Physiol. Physiol. 2021;321:C615–C631. doi: 10.1152/ajpcell.00206.2021.
- Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5.
- Hu, B., Guo, H., Zhou, P. & Shi, Z.-L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol.19, 141–154 (2021).
- Shi S, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5:802–810. doi: 10.1001/jamacardio.2020.0950.
- Wang Q, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181:894–904.e9. doi: 10.1016/j.cell.2020.03.045.
- Crackower MA, Sarao R, Oliveira-dos-Santos AJ, Da Costa J, Zhang L. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–828. doi: 10.1038/nature00786.
- Clerkin KJ, et al. COVID-19 and cardiovascular disease. Circulation. 2020;141:1648–1655. doi: 10.1161/CIRCULATIONAHA.120.046941.
- Chung CJ, et al. Restructuring structural heart disease practice during the COVID-19 pandemic: JACC review topic of the week. J. Am. Coll. Cardiol. 2020;75:2974–2983. doi: 10.1016/j.jacc.2020.04.009.
- Chung MK, et al. SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy. EBioMedicine. 2020;58:102907. doi: 10.1016/j.ebiom.2020.102907.
- Fernández-Ruiz I. RAAS inhibitors do not increase the risk of COVID-19. Nat. Rev. Cardiol. 2020;17:383. doi: 10.1038/s41569-020-0401-0.
- Glasbey JC, et al. Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic. Br. J. Surg. 2021;108:88–96. doi: 10.1093/bjs/znaa051.
- Oudit GY, et al. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice. Cardiovasc. Res. 2007;75:29–39. doi: 10.1016/j.cardiores.2007.04.007.
- Imai Y, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116. doi: 10.1038/nature03712.
- Topol EJ. COVID-19 can affect the heart. Science. 2020;370:408–409. doi: 10.1126/science.abe2813.
- Li W, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450–454. doi: 10.1038/nature02145.
Source: PubMed