385Acta Med Indones - Indones J Intern Med • Vol 53 • Number 4 • October 2021 ORIGINAL ARTICLE ABSTRACT Aim: To summarize the prognosis of Corona Virus Disease 2019 (COVID-19) patients with elevated troponin and N-terminal pro brain natriuretic peptide (NT-proBNP) levels and demonstrate the involvement of myocardial injury as a complication in COVID-19. Methods: A systematic literature search was performed using several databases (PubMed, MEDLINE, PROQUEST and SCOPUS ) for studies published up to August 2020. Observational studies about the mortality outcome of COVID-19 patients who experienced cardiac injury, as defined by the elevation of serum levels of troponin, brain natriuretic peptide (BNP), with NT-proBNP or only BNP or only NT-proBNP, were included. In addition, a critical appraisal was conducted for all included studies using the Critical Appraisal for Prognostic Studies checklist published by the Centre for Evidence-Based Medicine by the University of Oxford. Results: Seven retrospective observational studies fulfilled the inclusion criteria. This study found that there is a higher risk of death in COVID 19 patients with higher levels of troponin and NT-proBNP, indicating the importance of these biomarkers as determinant factors to predict in-hospital deaths. Conclusion: Based on the analysis, elevation of troponin and NT-proBNP levels plays an essential role in determining the patient prognosis because it is shown to be associated with in-hospital mortality. This also supports the involvement of myocardial injury as a prominent fatal complication in COVID-19. Keywords: COVID-19, myocardial injury, troponin, BNP, NT-proBNP, prognostic factors. Elevation of Cardiac Biomarkers in COVID-19 As a Major Determinant for Mortality: A Systematic Review Tracy Anabella Hermansyah1, Eka Ginanjar2*, Valerie Hirsy Putri3 1 Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. 2 Division of Cardiovascular, Department of Internal Medicine Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia. 3 Bunda General Hospital, Jakarta, Indonesia. *Corresponding Author: Eka Ginanjar, MD. Department of Internal Medicine, Faculty of Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71, Jakarta 10430, Indonesia, Email: ekaginanjar.MD@gmail.com. INTRODUCTION In early 2020, a pandemic state was reported in relation to the coronavirus disease-2019 (COVID-19), a novel strand of severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2). 1,2 By August 21, 2020, the global number of confirmed cases had reached more than 4 million, with over 780,000 deaths having occurred in 213 different countries.3 Although the major complication of COVID-19 infection is respiratory failure, there have been reports of myocardial injury defined by elevated biomarker values in patients, with troponin I as the main biomarker used.1,4- 8 The use of troponin I is based on its unique regulatory protein encoded by a specific gene that is only found in the myocardium, making it a fundamental aspect to clinically define the diagnosis of myocardial injury.9-10 Other biomarkers, such as troponin T (TnT), brain natriuretic peptide (BNP), and N-terminal brain natriuretic peptide (NT-proBNP), are also used to further support the determination of any myocardial damage.11 Tracy Anabella Hermansyah Acta Med Indones-Indones J Intern Med 386 To date, the most plausible cause of the myocardial injury found in COVID-19 is the presence of ACE2 receptors in the myocardium; these receptors allow the binding of SARS- Cov2 structural protein, leading to a direct viral infection of the heart. Furthermore, infection- mediated vasculitis by COVID-19 may also contribute to causing direct myocardial injury because of the ACE2 receptor expressions in the arterial and venous endothelial cells. Both events may lead to an indirect immunological response resulting in a hypersensitivity reaction, which manifests as the myocardial injury and dysfunction seen in COVID-19. Such occurrences often lead to a fatal outcome.1 Many studies have found that intensive care unit (ICU) admissions and in-hospital mortality may also be associated with elevated biomarkers, further supporting the essential determinant factor of patients’ prognosis in clinical settings.12 Thus, many clinicians have drawn their attention to the role of troponin and NT-proBNP elevation in determining the prognosis of patients with COVID-19. METHODS As a foundation for performing an extensive literature search, this study chose a relevant clinical question using a patients/intervention/ comparison/outcome (PICO) model to define suitable terms for use in the search. The chosen terms derived from the following question: Could the elevation of troponin and BNP/NT-proBNP determine the prognosis of patients with COVID-19 myocardial injury? The selected keywords comprised of P (patients), I (intervention) and O (outcome), whereas C (comparison) was not considered as the main focus and therefore, excluded (Table 1). We used the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for this review. A literature search was performed using four databases (PubMed, MEDLINE, PROQUEST and SCOPUS) from April 24 to August 26, 2020, using a combination of Medical Subject Headings (MeSH) terms based on the PICO keywords derived from the clinical question (Table 2). Only longitudinal cohort studies or randomized controlled trials that observed death as the main outcome for COVID-19 patients with elevated NT-proBNP and/or troponin were included in this study. Table 1. PICO. Patient (P) Intervention (I) Comparison (C) Outcome (O) COVID-19 Myocardial Injury Patients Elevation of Troponin and BNP/NTpro-BNP - Mortality/Death Case BNP/NTproBNP, Brain Natriuretic Protein/N-terminal pro brain natriuretic peptide ;COVID-19, Coronavirus Disease 2019; Table 2. Literature search strategy. Database Search Terms Hits PubMed ((((("COVID-19"[Title/Abstract]) OR (CORONAVIRUS[Title/Abstract])) AND (MYOCARDIAL INJURY [Title/Abstract]) AND ((TROPONIN[Title/Abstract]) OR (BNP [Title/Abstract]) OR (NT-PROBNP[Title/Abstract])) AND (MORTALITY [Title/Abstract]) 178 PROQUEST ((COVID-19) OR (CORONAVIRUS)) AND (MYOCARDIAL INJURY) AND ((TROPONIN)) OR (BNP) OR (NT-PROBNP)) AND (MORTALITY) 45 SCOPUS ((COVID-19) OR (CORONAVIRUS)) AND (MYOCARDIAL INJURY) AND ((TROPONIN)) OR (BNP) OR (NT-PROBNP)) AND (MORTALITY) 17 Medline ((COVID-19) OR (CORONAVIRUS)) AND (MYOCARDIAL INJURY) AND ((TROPONIN)) OR (BNP) OR (NT-PROBNP)) AND (MORTALITY) 215 Total 455 Vol 53 • Number 4 • October 2021 Elevation of Cardiac Biomarkers in COVID-19 387 Critical Appraisal A critical appraisal was conducted thoroughly by the author for all included studies using the Critical Appraisal for Prognostic Studies checklist published by the University of Oxford (www. cebm.net). Any uncertainties for inappropriate topics was then consulted to the second reviewer. Study design, patient demographics, value changes in troponin and BNP and/or NT-proBNP value, mortality rate, risk ratio/odd ratio, hazard ratios and other outcomes from adjusted statistical (if stated) were extracted from the included studies for further analysis. RESULTS Search Selection A total of 455 papers were identified from the four databases. After the deduplication process, 450 different papers were screened based on their titles and abstracts (Figure 1). As a result, 216 articles were excluded from the initial screening, leaving 234 articles to undergo a full review and further selection process. Seven articles were selected as the final sample for this study. A summary of the selection process according to the PRISMA statement can be seen in the PRISMA diagram on Figure 1.13 The characteristics of the baseline study can be seen in Table 3. All chosen studies varied from a single-center or multicenter observational cohort and observed the relationship between the elevation of myocardial biomarkers of COVID-19 patients and the mortality outcome. Zhou et al14., Chen et al.15, and Stefanini et al.16 focused on the association of patients’ clinical outcomes with troponin and NT-proBNP as myocardial markers. Guo et al.17, Gao et al.18, Zhang et al.19, and Shi et al.20 included other myocardial injury biomarkers, such as Creatinine Kinase Myocardial Band (CKMB), myohemoglobin, or myoglobin. These studies underwent critical appraisal as presented in Table 4. Id e n ti fi c a ti o n In c lu d e d lig ib ili ty S c re e n in g (n=7) Figure 1. Prisma Flow Diagram of search and selection process Tracy Anabella Hermansyah Acta Med Indones-Indones J Intern Med 388 Ta bl e 3. C ha ra ct er is tic o f i nc lu de d st ud ie s A ut ho r In st itu tio n/ C ou nt ry S tu dy C on du ct ed D es ig n In cl us io n C ri te ri a E xc lu si on C ri te ri a P ar tic ip an ts M yo ca rd ia l bi om ar ke r te st ed O th er b io m ar ke r te st ed P ri m ar y en dp oi nt s S ec on da ry en dp oi nt (s ) R es ul ts Zh ou e t a l Ji ny in ta n H os pi ta l an d W uh an P ul m on ar y H os pi ta l (W uh an , C hi na R et ro sp ec tiv e C oh or t S tu dy C on fir m ed C O V ID -1 9 in pa tie nt s w ho d ie d or di sc ha rg ed be tw ee n 29 th D ec 2 01 9 an d 31 st J an 2 02 0 N on C O V ID -1 9 In pa tie nt s, P at ie nt s w ith ou t ac ce ss ib le m ed ic al re co rd s 19 1 P at ie nt s H s- cT nI W hi te b lo od c el l, Ly m ph oc yt e co un t, H ae m og lo bi n, P la te le t co un t, A lb um in , A LT , C re at in in e, L ac ta te de hy dr og en as e, C re at in in e ki na se , se ru m fe rr iti n, Il - 6, P ro ca lc ito ni n, , P ro th ro m bi n tim e, d- di m er D ea th , D is ch ar ge d N /a H s- cT nI : 3. 0 pg /m l s ur vi vo r (5 4/ 19 1) v s 22 .2 pg /m l no n su rv iv or (1 37 /1 91 ) O R H s- cT nI 8 0. 07 (C I 10 .3 4 – 62 0. 36 ) G uo e t a l S ev en th H os pi ta l o f W uh an C ity , C hi na R et ro sp ec tiv e C oh or t S tu dy C on fir m ed C O V ID -1 9 in pa tie nt s w ho d ie d or di sc ha rg ed be tw ee n 23 rd Ja n 20 20 a nd 23 rd F eb 2 02 0 C O V ID -1 9 in pa tie nt s w ith ou t a co m pl et e m ed ic al re co rd 18 7 P at ie nt s Tr op on in T , C K M B fr ac tio n, M yo gl ob in , N T- pr oB N P W hi te b lo od c el l, Ly m ph oc yt e co un t, N eu tro ph il, A lb um in , A LT , C re at in in e, A m in ot ra ns fe ra se (a la ni ne , a sp ar ta te ), hs C R P, G lo bu lin , P ro ca lc ito ni n, P ro th ro m bi n tim e, d- di m er , A P TT , C ho le st er ol (t ot al , tri gl yc er id e, H D L, L D L) , S er um p ot as si um , S er um C al ci um D ea th , D is ch ar ge d N /a M or ta lit y in N or m al T nT (1 2[ 8. 9% ]) vs E le va te d Tn T (3 1[ 59 .6 % ]) [p <0 .0 01 ] B ot h Tn T an d N T- pr oB N P le ve ls in cr ea se d si gn ifi ca nt ly d ur in g th e co ur se o f h is pi ta liz at io n in th os e w ho u lti m at el y di ed [p <0 .0 01 ], bu t n o su ch d yg na m ic c ha ng es in th os e bi om ar ke rs w er e ev id en t i n su rv iv or s S hi e t a l R en m in H os pi ta l of W uh an U ni ve rs it R et ro sp ec tiv e C oh or t S tu dy C on fir m ed C O V ID -1 9 in pa tie nt s be tw ee n 20 th Ja n 20 20 a nd 10 th F eb 2 02 0 C O V ID -1 9 in pa tie nt s w ith ou t ca rd ia c bi om ar ke rs da ta 41 6 P at ie nt s H s- cT nI , N T- pr oB N P, C K M B , N T pr o- B N P, M yo he m og lo bi n Le uk oc yt e, Ly m ph oc yt e, P la te le t, E ry th ro cy te , H ae m og lo bi n, C -r ea ct iv e pr ot ei n, P ro ca lc ito ni n, C re at in in e, A m in ot ra ns fe ra se (a la ni ne , a sp ar ta te ), S er um p ot as si um , S er um C al ci um D ea th , di sc ha rg ed , re m ai ne d in ho sp ita l N /a H s- cT nI : ca rd ia c in ju ry (0 .1 9[ 0. 08 -1 .1 2] p< 0. 00 1) v s w ith ou t (< 0. 00 6) [< 0. 00 6- 0. 00 9] p< 0. 00 1] D ea th o f P at ie nt w ith ca rd ia c in ju ry (4 2/ 82 ) vs w ith ou t ( 15 /3 34 ) [p <0 .0 01 ] Vol 53 • Number 4 • October 2021 Elevation of Cardiac Biomarkers in COVID-19 389 D is ch ar ge d pa tie nt s w ith c ar di ac in ju ry (2 /8 2) vs w ith ou t ( 38 /3 34 ) [p <0 .0 01 ] P at ie nt re m ai ne d in th e ho sp ita l w ith c ar di ac in ju ry (3 8/ 82 ) v s w ith ou t (2 81 /3 34 ) [ p< 0. 00 1] C he n et a l To ng ji H os pi ta l, W uh an , C hi na R et ro sp ec tiv e C oh or t S tu dy C on fir m ed C O V ID -1 9 cr iti ca lly il l in pa tie nt s be tw ee n 13 th Ja n 20 20 a nd 28 th F eb 2 02 0 N ot sp ec ifi ed 27 4 P at ie nt s H s- Tn I, N T- pr oB N P W hi te b lo od c el l co un t, N eu tro ph il, Ly m ph oc yt e, M on oc yt e, P la te le t, H ae m og lo bi n, C -r ea ct iv e pr ot ei n, P ro ca lc ito ni n, C re at in in e, A m in ot ra ns fe ra se (A la ni ne , A sp ar ta te ), To ta l B ili ru bi n, A lk al in e ph os ph at as e, ga m m a gl ut am yl tra ns pe pt id as e, Tr ig ly ce rid es , S er um po ta ss iu m , S er um C al ci um , B lo od U re a N itr og en , C re at in e K in as e, L ac ta te de hy dr og en as e, P ro th ro m bi n tim e, ac tiv at ed p ar tia l th ro m bo pl as tin e tim e, D -d im er , f er rit in , er yt hr oc yt e, th yr oi d st im ul at in g ho rm on e, fre e tri io do th yr ox in e, fre e th yr ox in , Im m un og lo bu lin (A ,G ,M ), C 3, C 4, Il -1 B , IL -1 re ce pt or , I l-6 , I l-8 , Il- 10 , T um or n ec ro si s fa ct or a lp ha , U rin ar y pr ot ei n, U rin ar y O cc ul t bl oo d D ea th , R ec ov er ed N /a E le va te d H s- Tn I i n de ce as ed p at ie nt s (6 8/ 94 [7 2% ]) vs re co ve re d pa tie nt s 15 /1 09 [1 4% ] E le va te d N T- pr oB N P in de ce as ed p at ie nt s( 68 /8 0 [8 5% ]) vs re co ve re d pa tie nt s (1 7/ 93 [1 8% ]) Tracy Anabella Hermansyah Acta Med Indones-Indones J Intern Med 390 G ao e t a l H ub ei G en er al H os pi ta l, C hi na R et ro sp ec tiv e O bs er va tio na l S tu dy C O V ID -1 9 pa tie nt s w ith s ev er e co nd iti on s (r es pi ra to ry ra te ≥ 3 0/ m in o r r es t ox yh em og lo bi n sa tu ra tio n (S P O 2) ≤ 93 % or o xy ge na tio n in de x (a rte ria l ox yg en te ns io n/ in sp ire d ox yg en fra ct io n, P aO 2/ Fi O 2) ≤ 30 0 m m H g) P at ie nt s la ck in g N T- pr oB N P re su lts , P at ie nt s w ith st ro ke , ac ut e m yo ca rd ia l in fa rc tio n, m al ig na nt tu m or , a nd pr eg na nc y 54 pa rti ci pa nt s N -te rm in al pr o- B -ty pe na tri ur et ic pe pt id e (N t- pr oB N P ), H ig h se ns iti ve tro po ni n I ( H s- Tn I), C re at in in e ki na se - m yo ca rd ia l b an d (C K M B ) M yo ha em og lo bi n, U re a, C re at in in e, W hi te b lo od ce ll co un t, Ly m ph oc yt e, C R P, P ro ca lc ito ni n D ea th , su rv iv ed N /a N T- pr oB N P A re a un de r th e cu rv e (A U C ) f or in - ho sp ita l m or ta lit y w as 0 .9 09 (9 5% C I 0 .7 99 –0 .9 70 , P < 0. 00 1) . us in g th e cu t-o ff 8 8. 64 p g/ m L Zh an g et a l W uh an N o. 1 H os pi ta l, C hi na R et ro sp ec tiv e O bs er va tio na l S tu dy C on fir m ed o r S us pe ct ed C O V ID -1 9 in pa tie nt s ad m itt ed be tw ee n 25 th D ec 2 01 9 an d 15 th F eb 20 20 , w ho un de rw en t h s- cT ni te st w ith in 48 h ou rs a fte r ad m is si on N on C O V ID -1 9 In pa tie nt s, di d no t un de rg o hs -c Tn I w ith in 4 8 ho ur s af te r ad m is si on 48 p at ie nt s H ig h se ns iti ve tro po ni n I ( H s- cT nI ), C re at in in e ki na se - m yo ca rd ia l b an d (C K M B ) W hi te b lo od c el l co un t, Ly m ph oc yt e co un t, N eu tro ph il, H ae m og lo bi n, P la te le t, Th ro m bo cy te C re at in in e ki na se , A m in ot ra ns fe ra se (a la ni ne , as pr at at e) , L ac ta te de hy dr og en as e, se ru m c re at in in e, C R P, Fi br og en , d -d im er D ea th , su rv iv ed D is ch ar ge d, Tr an sf er re d M or ta lit y: p at ie nt s w ith el ev at ed h s- cT nI 7 6. 9% vs n or m al h s- cT nI 2 0% [p <0 .0 01 ] S te fa ni ni et a l H um an ita s C lin ic al a nd R es ea rc h H os pi ta l (R oz za no -M ila n, Lo m ba rd y, It al y) R et ro sp ec tiv e O bs er va tio na l S tu dy co nfi rm ed C O V ID -1 9 pa tie nt s w ith av ai la bl e da ta on c ar di ac bi om ar ke rs N o ex cl us io ns w er e ap pl ie d 39 7 pa tie nt s H ig h- se ns iti vi ty tro po ni n I ( hs - Tn I), B -ty pe na tri ur et ic pe pt id e (B N P ) D -d im er , F ib rin og en , C R P, IL -6 , F er rit in , C re at in in e, W hi te c el l co un t, N eu tro ph ils , Ly m ph oc yt es , P la te le t ba se lin e, H ae m og lo bi n ba se lin e, P ro ca lc ito ni n, A LT , A LP , T ot al b ili ru bi n ba se lin e, P T ra tio ba se lin e, P TT ra tio ba se lin e, IN R b as el in e N /a al l-c au se m or ta lit y ad m is si on in in te si ve ca re u ni t (IC U ), ac ut e re sp ira to ry di st re ss sy nd ro m e (A R D S ) an d sh oc k M or ta lit y ra te : el ev at ed hs -T nI (2 2. 5% , O R 4 .3 5 [9 5% C I 1. 72 - 11 .0 4] ) v s el ev at ed B N P (3 3. 9% , O R 7 .3 7, Vol 53 • Number 4 • October 2021 Elevation of Cardiac Biomarkers in COVID-19 391 [9 5% C I 3. 53 to 16 .7 5] ) vs b ot h (5 5. 6% , O R 1 8. 75 , [9 5% C I 9. 32 to 37 .7 1] ) v s w ith ou t el ev at ed ca rd ia c bi om ar ke rs (6 .2 5% ). A LP , A lk al in e ph os ph at as e; A LT , A la ni ne a m in ot ra ns fe ra se ; A R D S , A cu te R es pi ra to ry D is tre ss S yn dr om e; C I, C on fid en ce In te rv al ; C K M B , C re at in in e ki na se -m yo ca rd ia l b an d; C O V ID -1 9, C or on av iru s D is ea se 2 01 9; C R P, C -R ea ct iv e P ro te in ; h s- cT nI , h ig h se ns iti vi ty c ar di ac tr op on in I; IN R , I nt er na tio na l N or m al iz ed R at io ; I C U , I nt en si ve C ar e U ni t; IL , I nt er le uk in ; N T- pr oB N P, N -te rm in al p ro b ra in n at riu re tic p ep tid e; O R , O dd s R at io ; N /A , N ot A pp lic ab le ; P T, P to th ro m bi n Ti m e; P TT , P ar tia l p ro th ro m bi n tim e; T nT , T ro po ni n T. Tracy Anabella Hermansyah Acta Med Indones-Indones J Intern Med 392 Ta bl e 4. C ri tic al A pp ra is al o f t he in cl ud ed s tu di es u si ng P ro gn os is S tu di es Q ue st io nn ai re o f O xf or d C E E B M C ri te ri a S hi e t a l ( 20 20 ) G uo e t a l (2 02 0) Zh an g et a l (2 02 0) Zh ou e t a l (2 02 0) G ao e t a l ( 20 20 ) C he n et a l (2 02 0) S te fa ni ni e t a l (2 02 0) V a l i d i t y W as th e de fin ed re pr es en ta tiv e sa m pl e of p at ie nt s as se m bl ed a t a co m m on (u su al ly e ar ly ) p oi nt in th e co ur se o f th ei r di se as e Ye s. R ec ru ite d pa rti ci pa nt s w er e pa tie nt s co nfi rm ed w ith C O V ID 1 9 ac co rd in g to W H O in te rim g ui da nc e an d or ig in at ed fr om W uh an Ye s. R ec ru ite d pa rti ci pa nt s w er e pa tie nt s co nfi rm ed w ith C O V ID 19 a cc or di ng to W H O in te rim gu id an ce a nd or ig in at ed fro m W uh an U nc le ar . R ec ru ite d pa rti ci pa nt s w er e pa tie nt s su sp ec te d an d co nfi rm ed w ith C O V ID 1 9 ac co rd in g to W H O in te rim g ui da nc e an d or ig in at ed fr om W uh an . A ll pa tie nt s w ho un de rw en t h s- cT nI te st w ith in 4 8 ho ur s af te r ad m is si on w er e in cl ud ed Ye s. R ec ru ite d pa rti ci pa nt s w er e pa tie nt s co nfi rm ed w ith C O V ID 1 9 ac co rd in g to W H O in te rim gu id an ce a nd or ig in at ed fr om W uh an Ye s. R ec ru ite d pa rti ci pa nt s w er e pa tie nt s co nfi rm ed w ith C O V ID 1 9 ac co rd in g to W H O in te rim g ui da nc e an d or ig in at ed fr om W uh an Ye s. R ec ru ite d pa rti ci pa nt s w er e pa tie nt s co nfi rm ed w ith C O V ID 1 9 ac co rd in g to G ui da nc e fo r C or on a V iru s di se as e 20 19 by th e na tio na l h ea lth co m m is si on o f C hi na an d or ig in at ed fr om W uh an Ye s. Y es . R ec ru ite d pa rti ci pa nt s w er e pa tie nt s co nfi rm ed w ith C O V ID 1 9 ac co rd in g to W H O in te rim gu id an ce a nd or ig in at ed fr om Ita ly W as p at ie nt fo llo w - up s uffi ci en tly lo ng an d co m pl et e Ye s Ye s Ye s Ye s N o. b io m ar ke rs w er e on ly c ol le ct ed o n a si ng le te st a t a dm is si on Ye s Ye s W er e ou tc om e cr ite ri a ei th er ob je ct iv e or a pp lie d in a ‘b lin d’ fa sh io n? U nc le ar U nc le ar U nc le ar U nc le ar Ye s U nc le ar U nc le ar If su bg ro up s w ith di ffe re nt p ro gn os es ar e id en tifi ed , di d ad ju st m en t fo r im po rt an t pr og no st ic fa ct or s ta ke p la ce ? Ye s. A ge , co m or bi di tie s, cr ea tin in e le ve ls a nd pr o- B N P w er e ta ke n ac co un t i nt o th e an al ys is N o Ye s. A ge , S po 2, s er um cr ea tin in e, a nd d -d im er va lu e w er e ta ke n ac co un t in to th e an al ys is N o Ye s. S ex , a ge , hy pe rte ns io n, c or on ar y he ar t d is ea se , m yo gl ob in , C K -M B , tro po ni n I, ur ea , cr ea tin in e, w hi te b lo od ce ll, ly m ph oc yt e an d pr oc al ci to ni n is ta ke n ac co un t i nt o th e an al ys is N o Ye s. A ge , ly m ph oc yt e co un ts a nd D -d im er el ev at io n w er e ta ke n ac co un t i nt o th e an al ys is Vol 53 • Number 4 • October 2021 Elevation of Cardiac Biomarkers in COVID-19 393 I m p o r t a n c e W ha t w er e th e re su lts ? M or ta lit y ra te w as 51 .2 % a m on g pa tie nt s w ith c ar di ac in ju ry . M or ta lit y ra te w as 5 9. 6% am on g pa tie nt s w ith c ar di ac in ju ry . M or ta lit y ra te w as 7 6. 9% am on g pa tie nt s w ith ca rd ia c in ju ry . U ni va ria te O R of in -h os pi ta l de at h w ith el ev at io n of hs -c Tn I v al ue 80 .0 7 Th e A U C fo r i n- ho sp ita l de at h w as 0 .9 09 M or ta lit y ra te w as 72 % a nd 8 5% in pa tie nt s w ith in cr ea se d tro po ni n an d N t- pr oB N P c on ce nt ra tio ns co ns ec ut iv el y Th e A U C fo r a ll- ca us e m or ta lit y pr ed ic to r i s 0. 93 8 H ow p re ci se a re th e pr og no st ic es tim at es ? H R o f d ea th ti m e fro m s ym pt om o ns et w as 4 .2 6 [9 5% C I, 1. 92 -9 .4 9] H R o f d ea th ti m e fro m a dm is si on to st ud y en d po in t 3 .4 1 [9 5% C I, 1. 62 -7 .1 6] U nc le ar (n o C I w as st at ed ) H R o f d ea th in e le va tio n of hs -c Tn I v al ue 1 0. 9 [9 5% C I, 1. 28 -9 2. 93 ] 95 % C I, 10 .3 4- 62 0. 36 95 % C I, 0. 79 -0 .9 7 U nc le ar (n o C I w as st at ed ) 95 % C I 1 .0 6 to 9. 93 A p p l i c a b i l i t y C an I ap pl y th is va lid , i m po rt an t ev id en ce a bo ut pr og no si s to m y pa tie nt ? Ye s Ye s Ye s Ye s Ye s Ye s Ye s Tracy Anabella Hermansyah Acta Med Indones-Indones J Intern Med 394 U s i n g a m u l t i v a r i a b l e a d j u s t e d C o x proportional hazard regression model, Shi et al.21 reported a hazard ratio of death of 3.4 in patients with cardiac injury (95% confidence interval [CI], 1.62–7.16). Zhang et al.19 reported a hazard ratio of death among patients with high- sensitivity cardiac troponin I (hs-cTnI) elevation of 10.902 (95% CI, 1.279–92.927). Zhou et al.14 calculated the odds ratio of death in COVID-19 patients with elevated hs-cTnI levels with a univariate regression analysis, and they reported a value of 80.07 (95% CI, 10.34–620.36).19 Guo et al.17 reported a higher mortality rate in patients with elevated serum troponin T levels (59.6%) than in those with normal levels (8.9%).. A single-center study conducted by Gao et al.18 stated there is a significantly higher mortality rate in COVID-19 patients with high NT-proBNP compared with those with lower values (with a cut-off of 88.64 pg/ml); shown by the area under the curve (AUC) value of 0.909 (95% CI, 0.799–0.97) and hazard ratio of 1.373 (95% CI, 1.118–1.586, p<0.001) after adjusting for other risk factors (i.e sex, age, hypertension, coronary heart disease, myoglobin, CKMB, hs-TNI, urea and creatinine value. Both Chen et al.15 and Stefanini et al.16 reported higher concentrations of hs-cTnI (78% and 22.5%, respectively) and NT-proBNP markers (85% and 33.9%, respectively) in deceased patients compared with those who survived. In deceased patients (85% and 33.9%, respectively) compared to those who survived.15 DISCUSSION The World Health Organization (WHO) declared COVID-19 a global pandemic in early 2020.2 This novel strain of coronavirus disease has various clinical manifestations: It can be asymptomatic in some people or result in a severe condition, with acute respiratory distress syndrome (ARDS) or other organ failures, in others.3 Recent reports have shown evidence of myocardial injury involvement in COVID-19 patients, supported by the finding of elevated biomarkers, abnormal echocardiograph, and electrocardiograph in some hospitalized patients.1-2,,6 Outcomes of patients with such conditions are often undesirable, and there is a high association with death.1,6 The finding of this study suggests that a higher risk of death can be found in COVID-19 patients with elevated cardiac biomarkers, consistent with previous reviews on the risk of mortality outcomes from COVID-19, especially for troponin I and BNP.14,17,19-20. Shi et al. reported a higher mortality rate in patients with higher levels of hs-cTnI (42/82) compared with those without such elevated levels (15/334).11 This result was also in concordance with Zhang et al.’s finding, where the mortality rate was higher (up to 76.9%) among patients with hs-cTnI elevation compared with those without such biomarker elevation (20%).20 Zhou et al. reported a similar finding of a higher chance of death in patients with elevated hs-cTnI levels, using a specific cut- off of 28 pg/ml.14 This supports the hypothesis of myocardial injury involvement in COVID-19 related to SARS-CoV-2 structural S protein that binds to the ACE2 receptor of the myocardium, leading to possible cardiac injury and immune reactions throughout the body. Hs-cTnI has mainly been used to determine troponin levels in many studies. Only Guo et al. used a slightly different biomarker component, TnT, to assess patients’ troponin levels. Although this biomarker is less specific to define myocardial injury as a whole, other biomarkers of myocardial damage were also significantly elevated (CKMB, myoglobin, NT-proBNP), providing supporting evidence of myocardial injury in patients.17 Moreover, this study showed similar results to other studies that used hs-cTnI, underlining that the elevation of any troponin increases patients’ risk of death. The complex mechanism of the clinical manifestation and limited information regarding disease progression indicate the need for other biomarkers to be considered when assessing patients’ prognoses. Gao et al.18 reported that procalcitonin and white blood cells also make a significant contribution to predicting in- hospital deaths. Stefanini et al.15 and Chen et al.16 reported that the values of Nt-proBNP and BNP were also shown to be increased in accordance with the elevation of troponin levels. This highlighted the essential need for further investigation of biomarkers’ roles in myocardial Vol 53 • Number 4 • October 2021 Elevation of Cardiac Biomarkers in COVID-19 395 injury in COVID-19 patients and the associated prognoses, which should be conducted with better quality controls. Only Gao et al.18 included a bias control for the outcome analysis in the studies in this review, but an insufficient patient follow-up process was employed. All the other studies did not clearly state whether they were using blind assessment for the patients outcome or not. Blinding is crucial because unblinded investigators may search more aggressively for outcomes in people with known elevated cardiac biomarkers. Deciding on the underlying factors of mortality is a bit more complicated in patients with systematic diseases and requires blinding of the risk factors to ensure that it is unbiased. Moreover, Guo et al17, Chen et al15, Zhou et al14 did not make any adjustment for other prognostic factors so it may pose a significant threat to the validity of the study. Limitation the Study The sources we used in this systematic review have potential bias and flaws due to the limited time and resources in this pandemic condition. Pre-prints articles were also used due to the as-yet limited information regarding COVID-19. However, the author only included studies with relevant information. Under current pandemic circumstances, we believe our study may be beneficial to the medical society and general public. CONCLUSION Although limited, there is evidence of higher mortality rate in COVID-19 patients with elevated troponin and NT-proBNP levels. Our findings highlight the importance of evaluating myocardial injury biomarkers, especially in terms of the early analysis of troponin and NT- proBNP levels. This may guide clinicians in considering the required preventive measures against further deterioration in patients’ condition and avoiding fatal outcomes. REFERENCES 1. Atri D, Siddiqi HK, Lang J, Nauffal V, Morrow DA, Bohula EA. COVID-19 for the Cardiologist: A current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies. JACC: Basic to Translational Science. 2020. doi: https://doi.org/10.1016/j. jacbts.2020.04.002. 2. Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J. 2020;55(4):2000607. Published 2020 Apr 16. doi:10.1183/13993003.00607- 2020 3. WHO. Coronavirus disease 2019 (COVID-19) Situation Report – 97. Geneva, Switzerland. WHO; 2020. Accessed at 26/04/2020. Cited from https:// www.who.int/docs/default-source/coronaviruse/ situation-reports/20200426-sitrep-97-COVID-19. pdf?sfvrsn=d1c3e800_6 4. Zeng JH, Liu YX, Yuan J, et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights [published online ahead of print, 2020 Apr 10]. Infection. 2020;1‐5. doi:10.1007/s15010- 020-01424-5 5. Rizzo P, Vieceli Dalla Sega F, Fortini F, Marracino L, Rapezzi C, Ferrari R. COVID-19 in the heart and the lungs: could we «Notch» the inflammatory storm?. Basic Res Cardiol. 2020;115(3):31. Published 2020 Apr 9. doi:10.1007/s00395-020-0791-5 6. Zheng Y., Ma Y., Zhang J, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17:259– 60 (2020). https://doi.org/10.1038/s41569-020-0360-5 7. Hua A, O’Gallagher K, Sado D, Byrne J. Life- threatening cardiac tamponade complicating myo- pericarditis in COVID-19 [published online ahead of print, 2020 Mar 30]. Eur Heart J. 2020;ehaa253. doi:10.1093/eurheartj/ehaa253 8. Hu H, Ma F,Wei X, Fang Y. Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin, European Heart Journal. 2020, ehaa190. https://doi.org/10.1093/eurheartj/ehaa190 9. Gao et al. Role of Troponin I Proteolysis in the Pathogenesis of Stunned Myocardium. AHA J. 2020;80(3):393-9. https://doi.org/10.1161/01. res.0000435855.49359.47 10. Sharma S, Jackson PG, Makan J. Cardiac troponins. J Clin Pathol. 2004;57(10):1025‐6. doi:10.1136/ jcp.2003.015420 11. Babapoor-Farrokhran S, Gill D, Walker J, Rasekhi RT, Bozorgnia B, Amanullah A. Myocardial injury and COVID-19: Possible mechanisms. Life Sci. 2020;253:117723. doi:10.1016/j.lfs.2020.117723 12. C l e r k i n K J , F r i e d J A , R a i k h e l k a r J , e t a l . C o r o n a v i r u s D i s e a s e 2 0 1 9 ( C O V I D - 1 9 ) a n d Cardiovascular Disease [published online ahead of print, 2020 Mar 21]. Circulation. 2020;10.1161/ CIRCULATIONAHA.120.046941. 13. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal. pmed.1000100 Tracy Anabella Hermansyah Acta Med Indones-Indones J Intern Med 396 14. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study [published correction appears in Lancet. 2020;395(10229):1038] [published correction appears in Lancet. 2020 Mar 15. Chen Tao, Wu Di, Chen Huilong, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020; 368 16. Stefanini, et al. Early detection of elevated cardiac biomarkers to optimise risk stratification in patients with COVID-19. Heart. 2020;106:1512–8. 17. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with Coronavirus Disease 2019 (COVID-19) [published online ahead of print, 2020 Mar 27]. JAMA Cardiol. 2020;e201017. doi:10.1001/jamacardio.2020.1017 18. Gao L., Jiang D., Wen X, et al. Prognostic value of NT-proBNP in patients with severe COVID-19. Respir Res. 2020;21:83. https://doi.org/10.1186/s12931-020- 01352-w 19. Zhang, et al. Myocardial injury is associated with in-hospital mortality of confirmed or suspected COVID-19 in Wuhan, China: A single center retrospective cohort study 20. Preprint medRxiv. 2020. doi: https://doi.org/10.1101/ 2020.03.21.20040121. 21. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. Published online March 25, 2020. doi:10.1001/jamacardio.2020.0950