Implications of Cardiac Markers in Risk-Stratification and Management for COVID-19 Patients

Pengping Li; Wei Wu; Tingting Zhang; Ziyu Wang; Jie Li; Mengyan Zhu; Yuan Liang; Wenhua You; Kening Li; Rong Ding; Bin Huang; Lingxiang Wu; Weiwei Duan; Yi Han; Xuesong Li; Xin Tang; Xin Wang; Han Shen; Qianghu Wang; Hong Yan; Xinyi Xia; Yong Ji; Hongshan Chen

Disclosures

Crit Care. 2021;25(158) 

In This Article

Abstract and Introduction

Abstract

Background: COVID-19 has resulted in high mortality worldwide. Information regarding cardiac markers for precise risk-stratification is limited. We aim to discover sensitive and reliable early-warning biomarkers for optimizing management and improving the prognosis of COVID-19 patients.

Methods: A total of 2954 consecutive COVID-19 patients who were receiving treatment from the Wuhan Huoshenshan Hospital in China from February 4 to April 10 were included in this retrospective cohort. Serum levels of cardiac markers were collected after admission. Coronary artery disease diagnosis and survival status were recorded. Single-cell RNA-sequencing and bulk RNA-sequencing from different cohorts of non-COVID-19 were performed to analyze SARS-CoV-2 receptor expression.

Results: Among 2954 COVID-19 patients in the analysis, the median age was 60 years (50–68 years), 1461 (49.5%) were female, and 1515 (51.3%) were severe/critical. Compared to mild/moderate (1439, 48.7%) patients, severe/critical patients showed significantly higher levels of cardiac markers within the first week after admission. In severe/critical COVID-19 patients, those with abnormal serum levels of BNP (42 [24.6%] vs 7 [1.1%]), hs-TNI (38 [48.1%] vs 6 [1.0%]), α- HBDH (55 [10.4%] vs 2 [0.2%]), CK-MB (45 [36.3%] vs 12 [0.9%]), and LDH (56 [12.5%] vs 1 [0.1%]) had a significantly higher mortality rate compared to patients with normal levels. The same trend was observed in the ICU admission rate. Severe/critical COVID-19 patients with pre-existing coronary artery disease (165/1,155 [10.9%]) had more cases of BNP (52 [46.5%] vs 119 [16.5%]), hs-TNI (24 [26.7%] vs 9.6 [%], α- HBDH (86 [55.5%] vs 443 [34.4%]), CK-MB (27 [17.4%] vs 97 [7.5%]), and LDH (65 [41.9%] vs 382 [29.7%]), when compared with those without coronary artery disease. There was enhanced SARS-CoV-2 receptor expression in coronary artery disease compared with healthy controls. From regression analysis, patients with five elevated cardiac markers were at a higher risk of death (hazards ratio 3.4 [95% CI 2.4–4.8]).

Conclusions: COVID-19 patients with pre-existing coronary artery disease represented a higher abnormal percentage of cardiac markers, accompanied by high mortality and ICU admission rate. BNP together with hs-TNI, α- HBDH, CK-MB and LDH act as a prognostic biomarker in COVID-19 patients with or without pre-existing coronary artery disease.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has led to an ongoing global outbreak. Many affected patients develop interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), both associated with poor prognosis and high mortality.[1,2] In addition to respiratory symptoms, patients also exhibit multi-organ dysfunction such as cellular immune deficiency, coagulation activation, and myocardial, hepatic, and kidney injury.[3,4]

With the rapid increase in confirmed cases, the cardiovascular manifestations induced by SARS-CoV-2 have generated considerable concern. A study of 138 hospitalized patients with COVID-19 showed that 7.2% had an acute myocardial injury.[5] Huang et al. reported that 12% of COVID-19 patients were diagnosed as having an acute myocardial injury.[6] COVID-19 patients with underlying coronary artery disease (CAD) who develop myocardial injury were found to have poorer in-hospital outcomes.[7,8] However, sensitive and reliable markers for the early detection of myocardial damage and mortality risk assessment in patients with COVID-19 have not been well established. Moreover, to date, sensitive and reliable markers for the early detection of myocardial damage and mortality risk assessment in patients with COVID-19 have not been well established. Thus, a detailed analysis of clinical data is needed to identify early indicators of myocardial damage and mortality.

High-sensitivity troponin I (hs-TNI), α-hydroxybutyrate dehydrogenase (α-HBDH), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH) are released into circulation when myocardial necrosis occurs and are, therefore, established as serum cardiac markers of myocardial injury.[9] In addition, serum levels of brain natriuretic peptide (BNP) can be an indicator of heart failure and utilized to differentiate non-cardiogenic from cardiogenic pulmonary edema.[10,11] Several recent studies have investigated the association between hs-TNI and mortality in patients with COVID-19.[12,13] However, the association between the serum levels of cardiac markers and clinical outcomes in patients with and without pre-existing CAD has not been well established.

Previous studies have shown that angiotensin-converting enzyme 2 (ACE2) could be the receptor for SARS-CoV-2.[14] It further confirmed that the SARS-CoV-2 could efficiently use ACE2 as a receptor for cellular entry, with an estimated 10- to 20-fold higher affinity to ACE2 than SARS-CoV.[15,16] The receptor's expression and distribution decide the organ damage degree of virus infection, which has a significant implication for understanding its pathogenesis and designing therapeutic strategies.[17] Single-cell RNA sequencing (scRNA-seq) examines the gene expression information from individual cells with optimized next-generation sequencing technologies, providing a higher resolution of cellular differences and a better understanding of an individual cell's function. Some studies analyzed the mRNA expression profile of the SARS-CoV-2 receptor in different organs based on the public scRNA-seq database.[17,18]

In this single-center retrospective study from a cohort of 3,046 patients confirmed with COVID-19 at Wuhan Huoshenshan Hospital in China, the effectiveness of using cardiac markers including BNP, hs-TNI, α-HBDH, CK-MB, and LDH to predict mortality in patients with and without CAD upon admission was investigated. To characterize the expression patterns of SARS-CoV-2 receptors in the heart, scRNA-seq of non-COVID-19 cohorts was performed.

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