key: cord-0851520-myb38d1n
authors: Martha, Januar Wibawa; Pranata, Raymond; Wibowo, Arief; Lim, Michael Anthonius
title: Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography and Mortality in COVID-19: A Systematic Review and Meta-analysis
date: 2021-02-11
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.029
sha: a7dad7b30c4288ea46b86558c8312a7b0c90784a
doc_id: 851520
cord_uid: myb38d1n

BACKGROUND: This systematic review and meta-analysis aimed to assess the association between the tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography and mortality in COVID-19. METHODS: We performed a systematic literature search using PubMed, Embase, and Scopus databases with keywords "COVID-19" OR "SARS-CoV-2" OR “2019-nCoV” AND “Tricuspid annular plane systolic excursion” OR “TAPSE” up until 20 January 2021. The main outcome was mortality; the effect estimate was reported in hazard ratio (HR) which was pooled from the unadjusted and adjusted effect estimate retrieved from the included studies. Mean difference of the TAPSE (in mm) between non-survivors and survivors were pooled. RESULTS: There were 641 patients from 7 studies included in this systematic review and meta-analysis. TAPSE was lower in non-survivors compared to survivors (mean difference -3.74 [-5.22, -2.26], p < 0.001; I(2): 85.5%, p < 0.001). Each 1 mm decrease in TAPSE was associated with increased mortality (HR 1.24 [1.18, 1.31], p < 0.001; I(2): 0.0%, p = 0.491). In pooled adjusted model, each 1 mm decrease in TAPSE was associated with increased mortality (HR 1.21 [1.11, 1.33], p < 0.001; I(2): 45.1%, p = 0.156). Meta-regression indicates that the difference in TAPSE between the non-survivors and survivors were affected by COPD (-0.183, p < 0.001) and PASP (-0.344, p = 0.039). but not age (p = 0.668), male (p = 0.821), hypertension (p = 0.101), diabetes (p = 0.603), CAD (p = 0.564), smoking (p = 0.140), and LVEF (p = 0.452). CONCLUSION: Every 1 mm decrease in TAPSE was associated with approximately 20% increase in mortality. PROSPERO ID: CRD42021232194.

This systematic review and meta-analysis aimed to assess the association between the tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography and mortality in COVID-19.

We performed a systematic literature search using PubMed, Embase, and Scopus databases with keywords "COVID-19" OR "SARS-CoV-2" OR "2019-nCoV" AND "Tricuspid annular plane systolic excursion" OR "TAPSE" up until 20 January 2021. The main outcome was mortality; the effect estimate was reported in hazard ratio (HR) which was pooled from the unadjusted and adjusted effect estimate retrieved from the included studies. Mean difference of the TAPSE (in mm) between non-survivors and survivors were pooled.

There were 641 patients from 7 studies included in this systematic review and meta-analysis.

TAPSE was lower in non-survivors compared to survivors (mean difference -3.74 [-5.22, -2.26 ], p<0.001; I 2 : 85.5%, p<0.001). Each 1 mm decrease in TAPSE was associated with increased J o u r n a l P r e -p r o o f 4 mortality (HR 1.24 [1.18, 1.31 ], p<0.001; I 2 : 0.0%, p=0.491). In pooled adjusted model, each 1 mm decrease in TAPSE was associated with increased mortality (HR 1.21 [1.11, 1.33 ], p<0.001; I 2 : 45.1%, p=0.156). Meta-regression indicates that the difference in TAPSE between the nonsurvivors and survivors were affected by COPD (-0.183, p<0 .001) and PASP (-0.344, p=0.039).

but not age (p=0.668), male (p=0.821), hypertension (p=0.101), diabetes (p=0.603), CAD (p=0.564), smoking (p=0.140), and LVEF (p=0.452).

Every 1 mm decrease in TAPSE was associated with approximately 20% increase in mortality.

As cases of coronavirus disease 2019 are rising globally, finding reliable predictors of poor outcomes is critical to ensure effective use of valuable medical resources. (World Health Organization, 2021) Although the majority of COVID-19 cases exhibit only mild or no symptoms, a small proportion of patients experience severe symptoms and complications, including acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and multiorgan dysfunction. Some suggest that respiratory failure in COVID-19 differs from other types of ARDS, taking into account good tolerance to hypoxemia, preserved pulmonary system compliance, and prominent micro-and macrovascular thrombotic changes in relation with extensive endothelial injury. (D'Alto et al., 2020) Although COVID-19 exhibits unique features of disease, there appear to be significant similarities in pulmonary hemodynamic and their effect on cardiac function between COVID-19 pneumonia and non-COVID-19-related ARDS. (Stockenhuber et al., 2020) Multiple studies have found that individuals with underlying heart problems are associated with a higher risk of developing severe COVID-19 cases. (Raymond Pranata et al., 2020a) COVID-19 itself is associated with myocardial injury and impaired right ventricle (RV) strain, which are independent predictors of poor prognosis. (D'Alto et al., 2020; Wibowo et al., 2021) Meanwhile, left ventricle (LV) function is usually relatively unaffected in the majority of COVID-19 patients. (Moody et al., 2020) Acute cor pulmonale or right heart failure (RHF) is a J o u r n a l P r e -p r o o f 6 long-established complication of ARDS, in relation to disease severity and ventilatory strategies associated with permissive hypercapnia and pulmonary hyperinflation. . Tricuspid annular plane systolic excursion (TAPSE) measures the longitudinal right ventricular function. (Aloia et al., 2016) . TAPSE measurement using echocardiography is a simple and time efficient, moreover the bedside echocardiography machine is readily available in the critical care unit. Thus, TAPSE measurement may be valuable modality for prognostication in patients with COVID-19. This systematic review and meta-analysis aimed to assess the association between the TAPSE measured by echocardiography and mortality in COVID-19.

Systematic Reviews and Meta-Analyses (PRISMA) guideline. The protocol for this study is registered in PROSPERO (CRD42021232194).(Januar et al., 2021)

We include all studies that fulfilled all of the following criteria: 1) observational prospective/retrospective cohort and cross-sectional in design that report COVID-19 patients, 2) provide data on TAPSE, and 3) reported mortality. The main outcome was mortality, defined as clinically validated death or non-survivor.

We exclude studies that fulfilled at least one of the following criteria: 1) review articles, 2) commentaries, 3) case reports, 4) letters, 5) preprints, 6) conference abstracts, and 7) non-English language.

We performed a systematic literature search using PubMed, Embase, and Scopus databases with keywords "COVID-19" OR "SARS-CoV-2" OR "2019-nCoV" AND "Tricuspid annular plane 

Two authors performed independent data extraction from the eligible studies for the following data: 1) first author, 2) year of publication, 3) study design, 4) age, 5) male gender, 6) hypertension, 7) diabetes, 8) coronary artery disease, 9) smoking, 10) chronic obstructive pulmonary disease (COPD), 11) left ventricular ejection fraction (LVEF), 12) pulmonary artery systolic pressure (PASP), and 13) outcome of interest and its effect estimates.

TAPSE refers to the measurement of systolic displacement of the tricuspid lateral annulus, using the M-mode echocardiography. (Li et al., 2020) J o u r n a l P r e -p r o o f 8 The main outcome was mortality; the effect estimate was reported in hazard ratio (HR) which was pooled from the unadjusted and adjusted effect estimate retrieved from the included studies. Mean difference of the TAPSE (in mm) between non-survivors and survivors were pooled. Quality assessment of the included studies were performed using the Newcastle-Ottawa Scale (NOS) by two independent authors. Discrepancies were resolved by discussion.

Analysis was performed using STATA 16 (StataCorp LLC, Texas, US). The mean difference for the continuous variables were reported along its 95% confidence interval (95% CI). The unadjusted and adjusted HR were pooled using restricted-maximum likelihood (REML) random-effects meta-analysis regardless of heterogeneity. The pooled effect estimate was reported as HRs and its corresponding 95% CI. The p-values were considered statistically significant if the value was <0.05. I-squared (I 2 ) and Cochrane Q test were performed to assess the inter-study heterogeneity; an I 2 of >50% or p-value of <0.10 indicates significant heterogeneity. The potential for publication bias and small-study effects were assessed using the funnel-plot analysis and Egger's test. REML random effects meta-regression were performed to assess whether the difference in TAPSE between the non-survivors and survivors were affected by age, male, hypertension, diabetes, CAD, COPD, smoking, and LVEF, and PASP.

There were 641 patients from 7 studies included in this systematic review and meta-analysis [ Figure 1 , Table 1 ]. (Bursi et al., 2020; D'Alto et al., 2020; Lassen et al., 2020; Li et al., 2020; Liu et al., 2020; Sattarzadeh Badkoubeh et al., 2021; Stockenhuber et al., 2020) The baseline characteristics of the included studies and the risk of bias assessment using the NOS is displayed in Table 1 .

TAPSE was lower in non-survivors compared to survivors (mean difference -3.74 [-5.22, -2 .26], p<0.001; I 2 : 85.5%, p<0.001) [ Figure 2 ]. Each 1 mm decrease in TAPSE was associated with increased mortality (HR 1.24 [1.18, 1.31], p<0.001; I 2 : 0.0%, p=0.491) [ Figure 3 ]. In pooled adjusted model, each 1 mm decrease in TAPSE was associated with increased mortality (HR 1.21 [1.11, 1.33], p<0.001; I 2 : 45.1%, p=0.156) [ Figure 4 ].

Meta-regression indicates that the difference in TAPSE between the non-survivors and survivors were affected by COPD (-0.183, p<0.001) [ Figure 5A ] and PASP (-0.344, p=0.039) [ Figure 5B ]; but not age (p=0.668), male (p=0.821), hypertension (p=0.101), diabetes (p=0.603), CAD (p=0.564), smoking (p=0.140), and LVEF (p=0.452).

Funnel plot was asymmetrical [ Figure 6 ]. Egger's test showed no indication of small-study effects (p=0.497).

COVID-19 non-survivors have lower TAPSE compared to the survivors. Every 1 mm decrease in TAPSE was associated with approximately 20% increase in mortality.

There are several potential confounders that have been shown to be associated with mortality in COVID-19, these variables may also affect echocardiographic parameters. Pranata et al., 2021; Raymond Pranata et al., 2020b , 2020c , 2020d Regression analysis was performed in order to analyze whether these variables affect the mean difference in TAPSE between non-survivors and survivors. Meta-regression analysis indicates that the TAPSE difference between the non-survivors and survivors were reduced by the presence of COPD and higher PASP. Right ventricular function and PASP might be altered in patients with COPD, and thus explain the narrower margin between nonsurvivors and survivors. Meanwhile age, male gender, hypertension, diabetes, CAD, smoking, and LVEF did not influence the association.

Cardiac involvement in COVID-19 patients is generally detected by increased troponin levels with or without electrocardiogram (ECG) changes and can be associated with symptoms of chest pain and heart failure. (Stockenhuber et al., 2020) Elevated high-sensitivity cardiac J o u r n a l P r e -p r o o f troponin (HScTn) was quite prevalent in patients admitted with severe COVID-19, which likely explain RV rather than LV injury. HScTn is a powerful prognostic marker in COVID-19, with multiple potential causes, including myocarditis, coronary microvascular ischemia, stress cardiomyopathy, and tachycardiomyopathy. (Moody et al., 2020) Patients with proven myocardial damage are advised to undergo echocardiography as initial cardiac imaging, which appears to substantially alter clinical management in one-third of patients. (Stockenhuber et al., 2020) Likely echocardiography findings are: (1) swollen heart mostly due to pericardial effusion, characterized by excessive cardiac weight, thickened biventricular walls, and subsequent increase in biventricular mass; (2) hemodynamic disorder, reflected as reduced cardiac output and increased LV filling pressure; and (3) functional impairment, most commonly seen as RV systolic dysfunction rather than LV, with pulmonary hypertension and RV enlargement. (Liu et al., 2020; Sattarzadeh Badkoubeh et al., 2021) Dilated RV was defined as a RV basal diameter measured >41 mm, while RV systolic dysfunction was defined as a fractional area change (FAC) <35% or a TAPSE <17 mm.

Decreased RV systolic function is an independent predictor of all-cause death, with almost 2fold increase in mortality hazard. (Moody et al., 2020) Reduced RV function as measured by echocardiography as an absolute RV longitudinal strain (RVLS) of <20% was significantly correlated with increased mortality. Hence, measuring RVLS in patients with a clinical suspicion of heart failure or a finding of elevated troponin levels may effectively forecast J o u r n a l P r e -p r o o f clinical outcomes and determine whether high-level intervention is required. (Stockenhuber et al., 2020; Wibowo et al., 2021) Multiple studies has found that RV strain and TAPSE were associated with higher severity and mortality. (Bursi et al., 2020; D'Alto et al., 2020; Lassen et al., 2020; Li et al., 2020; Liu et al., 2020; Sattarzadeh Badkoubeh et al., 2021; Stockenhuber et al., 2020) LV function is usually preserved or hyperdynamic in COVID-19 patients. (Moody et al., 2020) If affected, this may be secondary to RV volume and excess pressure due to ventricular interdependence. Direct cardiac complications have been observed as acute myocardial damage, myocarditis, and takotsubo cardiomyopathy. (Lassen et al., 2020) Increasing evidence of DIC and venous thromboembolism, characterized by elevated D-dimer, in severe and critically ill COVID-19 patients suggests that RV injury may be secondary to pulmonary thrombosis. Widespread small pulmonary arteriolar fibrin thrombi and widespread alveolar capillary thrombi specific to COVID-19, compared with influenza cases, support the concept that RV dilatation is partly due to pressure overload. Moody et al., 2020; Stockenhuber et al., 2020) TAPSE was shown to be associated with the pulmonary embolism occurence in patients with COVID-19. (Scudiero et al., 2021) Myocardial injury and hyperinflammation in COVID-19-induced cytokine storm could be an additional cause of ARDS-related acute RHF. Yonas et al., 2020) In non-COVID-19related ARDS, poor RV function identified by echocardiography has been found to be a predictor of patient deterioration and poor overall outcome. (Stockenhuber et al., 2020) A J o u r n a l P r e -p r o o f non-English study was excluded, it indicates that TAPSE was not correlated with mortality, however there is only 5 non-survivors in the study. (Calderón-Esquivel et al., 2020) .

The use of echocardiography for early assessment of RV function in patients with clinical suspicion or evidence of heart problems offers valuable insights for clinical care.

Echocardiographic parameters, especially TAPSE measurement, PASP, and pericardial effusion, should be considered an important cardiac screening in COVID-19 patients. (Bursi et al., 2020; Sattarzadeh Badkoubeh et al., 2021) We found that RV dysfunction, depicted by lower TAPSE, may explain the ultimate mechanism directly or indirectly associated with the poor prognosis of COVID-19. Every 1 mm decrease in TAPSE was associated with approximately 20% increase in mortality. It would be useful to combine these echocardiographic parameters for prognostication of COVID-19 patients.

Most of the studies were retrospective, which is a potential source of bias. The available data did not suffice the requirement for performing diagnostic test meta-analysis which will be useful in determining post-test probability for mortality in patients with TAPSE below a specific cut-off point If reported. The meta-regression analysis was limited to several commonly reported comorbidities. 

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CS: Cross-Sectional, LVEF: Left Ventricular Ejection Fraction, NOS: Newcastle Ottawa Scale, PASP: Pulmoary Artery Systolic Pressure, PC: Prospective Cohort, RC: Retrospective Cohort