Association between right ventricular dysfunction and mortality in COVID‐19 patients: A systematic review and meta‐analysis

Abstract There is limited evidence about the prognostic utility of right ventricular dysfunction (RVD) in patients with coronavirus disease 2019 (COVID‐19). We assessed the association between RVD and mortality in COVID‐19 patients. We searched electronic databases from inception to February 15, 2021. RVD was defined based on the following echocardiographic variables: tricuspid annular plane systolic excursion (TAPSE), tricuspid S′ peak systolic velocity, fractional area change (FAC), and right ventricular free wall longitudinal strain (RVFWLS). All meta‐analyses were performed using a random‐effects model. Nineteen cohort studies involving 2307 patients were included. The mean age ranged from 59 to 72 years and 65% of patients were male. TAPSE (mean difference [MD], −3.13 mm; 95% confidence interval [CI], −4.08–−2.19), tricuspid S′ peak systolic velocity (MD, −0.88 cm/s; 95% CI, −1.68 to −0.08), FAC (MD, −3.47%; 95% CI, −6.21 to −0.72), and RVFWLS (MD, −5.83%; 95% CI, −7.47–−4.20) were significantly lower in nonsurvivors compared to survivors. Each 1 mm decrease in TAPSE (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.08–1.37), 1% decrease in FAC (aHR, 1.09; 95% CI, 1.04–1.14), and 1% increase in RVFWLS (aHR, 1.33; 95% CI, 1.19–1.48) were independently associated with higher mortality. RVD was significantly associated with higher mortality using unadjusted risk ratio (2.05; 95% CI, 1.27–3.31), unadjusted hazard ratio (3.37; 95% CI, 1.72–6.62), and adjusted hazard ratio (aHR, 2.75; 95% CI, 1.52–4.96). Our study shows that echocardiographic parameters of RVD were associated with an increased risk of mortality in COVID‐19 patients.

arrhythmias, and myocarditis/pericarditis. 2 The right ventricular compromise is increasingly recognized as an important complication in COVID-19 patients. 3 However, there is conflicted data about its prognostic utility in this population. Therefore, we performed a systematic review and meta-analysis to assess the association between right ventricular dysfunction (RVD) and mortality in COVID-19 patients.

| METHODS
This review was reported according to the preferred reporting items for systematic reviews and meta-analyses statement. 4

| Search strategy
We searched in the following databases: PubMed, Embase, Scopus, and Web of Science. The search was conducted from inception to February 15, 2021. The complete search strategy is available in Table S1. There were no restrictions on publication date or language.
Furthermore, we performed a manual search of reference lists of included studies and relevant reviews to identify additional studies.

| Eligibility criteria
The inclusion criteria were the following: (i) Cohort studies that included adult patients (≥18 years old) diagnosed with COVID-19 by reverse transcription-polymerase chain reaction and (ii) Studies that assessed the association between RVD assessed by echocardiography and mortality. We excluded commentaries, conference abstracts, systematic reviews, and narrative reviews.

| Study selection
We downloaded all articles from electronic search to EndNote X8 software and duplicate records were removed. Titles and abstracts were independently screened by two review authors (Carlos Diaz-Arocutipa and Jose Saucedo-Chinchay) to identify relevant articles.
Additionally, the same review authors (Carlos Diaz-Arocutipa and Jose Saucedo-Chinchay) independently examined the full-text of each article and registered reasons for the exclusion. Any disagreement on title/abstract and full-text selection was resolved by consensus.

| Echocardiographic parameters
We assess any of the following echocardiographic parameters: tricuspid annular plane systolic excursion (TAPSE), tricuspid S 0 peak systolic velocity, fractional area change (FAC), and right ventricular free wall longitudinal strain (RVFWLS). In addition, if available, the investigatordefined RVD was also evaluated.

| Data extraction
The information from each study was independently extracted by two review authors (Carlos Diaz-Arocutipa and Jose Saucedo-Chinchay) using a standardized data extraction form that was previously piloted.
Any disagreement was resolved by consensus. We extracted the following data: first author name, year of publication, country, study design, sample size, population, age, sex, comorbidities, timing of echocardiographic evaluation, echocardiographic parameters of right ventricular function, and mortality.

| Risk of bias assessment
The Newcastle-Ottawa scale (NOS) was used to assess the risk of bias of cohort studies. 5 Each study was classified into the following groups: low risk of bias (8-9 points), moderate risk of bias (5-7 points), and high risk of bias (0-4 points). The risk of bias was independently evaluated by two review authors (Carlos Diaz-Arocutipa and Jose Saucedo-Chinchay) and any disagreement was resolved by consensus.

| Statistical analyses
We performed all meta-analyses using a random-effects model. The between-study variance was estimated using the Paule-Mandel estimator. 6 We pooled unadjusted and adjusted effect measures for binary variables and mean differences (MD) with their 95% confidence interval (95% CI) for continuous variables. In the case of studies that have only reported median and interquartile range, the mean and SD were estimated using the method published by Wan et al. 7 Heterogeneity among studies was evaluated using the chi-squared test (threshold p < .10) and I 2 statistic. Heterogeneity was defined as low if I 2 < 30%, moderate if I 2 = 30%-60%, and high if I 2 > 60%. Publications bias was assessed by visual inspection of funnel plots. Statistical tests for funnel plot asymmetry were not performed since at least 10 studies per outcome are required. Subgroup analyses were performed according to the type of population (consecutive vs. nonconsecutive) and proportion of mechanically ventilated patients (<50% vs. ≥50%). All meta-analyses were conducted using the meta package from R 3.6.3 (www.r-project.org). A two-tailed p < .05 was considered statistically significant.

| Study characteristics
The main characteristics of the included studies were summarized in Table 1 Table S2. The echocardiographic parameters evaluated and the definitions of mortality and RVD can be found in Table S3.

| Risk of bias assessment
According to the NOS assessment, 10 studies had a moderate risk of bias and nine studies had a low risk of bias (Table S4). None of the studies was scored as high risk of bias.
Funnel plots did not show asymmetry ( Figure S6).  that ultimately results in RVD. We found that RVD was independently associated with an almost threefold increase in mortality in COVID-19 patients. Overall, our finding highlights the possible prognostic value of the right ventricular function assessment that can potentially improve the risk stratification of these patients.

How RVD impacts clinical outcomes in COVID-19 patients
remains incompletely understood. RVD may contribute to the rapid hemodynamic deterioration of these patients by affecting the left ventricular forward stroke volume. 31 Another possible explanation is that the presence of myocardial damage will provide the pathological substrate for malignant ventricular arrhythmias, predisposing to sudden cardiac death. However, although we found that RVD increases the risk of death in COVID-19 patients, it is also possible the option of a common cause for both problems.
In the context of COVID-19, the two main pathophysiological mechanisms that may explain RVD include increased afterload and impaired contractility. 32 Although both mechanisms can coexist, the first mechanism seems to predominate because the right ventricle is highly sensitive to changes in afterload.
There are some clinical conditions associated with SARS-CoV-2 infection that can lead to increased afterload such as pulmonary thromboembolism, acute respiratory distress syndrome, and mechanical ventilation in intubated patients. 32 Many studies have shown an elevated incidence of pulmonary thromboembolism in COVID-19 patients. 33  Acute respiratory distress syndrome is a major cause of death in COVID-19 patients with an incidence of up to 68% in hospitalized patients. 37 RVD is an independent predictor of mortality in ARDS patients and its development is attributed to the increased pulmonary vascular resistance, which is mediated by vascular remodeling, right ventricular-pulmonary arterial uncoupling, and thrombosis/vasoconstriction of the pulmonary vasculature. 38 Mechanical ventilation, especially when high levels of positive end-expiratory pressure are required, reduces venous return and increases pulmonary vascular resistance. 39 Considering that up to 33% of hospitalized patients with COVID-19 are mechanically ventilated, 40 the potential damage that this invasive therapy may cause to the right ventricle should be considered in all cases. Thus, the management of this equipment should be adequately optimized in order to reduce the risk of RVD.
Currently, it is recognized that several cardiac cells such as cardiomyocytes, pericytes, and fibroblasts can also express the ACE2 receptor and are therefore susceptible to infection by SARS-CoV-2. 36 Many cases of acute myocarditis in patients with COVID-19 have been described in the literature and it is considered a cause of right and/or left heart failure. 41 Interestingly, there are published autopsy reports that have shown lymphocytic infiltrates in the right ventricular myocardium of these patients. 35 Overall, it appears that direct viral damage, exacerbated systemic inflammatory response, and other pathogenic mechanisms such as epicardial and microvascular coronary artery disease secondary to thrombosis also contribute to the development of ventricular dysfunction in COVID-19 patients. 27 The assessment of right ventricular systolic function has historically been a difficult task given its complex geometric shape. Although echocardiography has some limitations, it remains the most commonly used imaging tool worldwide. 42 TAPSE, tricuspid S 0 peak systolic velocity, and FAC are the most frequently used echocardiographic parameters to evaluate right ventricular systolic function in daily clinical practice. 42,43 Of note, these parameters can assess both longitudinal (e.g., TAPSE and tricuspid S 0 peak systolic velocity) and radial function (e.g., FAC) of the right ventricle. 44 More recent techniques such as speckle-tracking echocardiography are increasingly used to estimate the global and regional systolic function. 43  Therefore, the prevalence of RVD may be even higher in the COVID-19 setting. Finally, since most of the included studies did not report adjusted effects, there is an increased risk of bias in their pooled estimates. Although we also reported meta-analyses of adjusted estimates of available studies, there is still a possibility of residual confounding. Thus, our results should be interpreted with caution.

| CONCLUSION
Our review shows that RVD was associated with an increased risk of mortality in COVID-19 patients. Among echocardiographic parameters, TAPSE, FAC, and RVFWLS were independently associated with higher mortality. Although our results need to be confirmed by prospective studies with larger sample sizes, they suggest that echocardiographic assessment of right ventricular systolic function may add prognostic information during the risk stratification of COVID-19 patients.

CONFLICT OF INTEREST
None of the authors reported any conflicts of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.