key: cord-0941499-qn1fygda
authors: Malagoli, Alessandro; Rossi, Luca; Zanni, Alessia; Muto, Federico; Tosetti, Alberto; Tondi, Stefano
title: Sustained right ventricular dysfunction in severe COVID‐19: The role of disseminated intravascular coagulation
date: 2022-03-11
journal: Echocardiography
DOI: 10.1111/echo.15332
sha: f19ccb9a8b680489a5b47cd7e9329d75fe8abd82
doc_id: 941499
cord_uid: qn1fygda

BACKGROUND: Acute right ventricular (RV) failure is common in patients hospitalized with COVID‐19. Compared to the conventional echocardiographic parameters, right ventricular longitudinal strain (RVLS) is more sensitive and accurate for the diagnosis of RV systolic dysfunction. OBJECTIVE: Our purpose was to investigate the sustained RV dysfunction echo‐quantified by RVLS in patients recovered from severe COVID‐19. Furthermore, we aimed to assess whether disseminated intravascular coagulation (DIC) has a key role to predict the impaired RV strain. METHODS: Of 198 consecutive COVID‐19 patients hospitalized from March 1, 2020, to April 15, 2020, 45 selected patients who survived from severe COVID‐19 were enrolled in the study and referred to our echo‐lab for transthoracic echocardiography 6‐months after discharge. RVLS was calculated as the mean of the strain values of RV free wall. DIC was defined with a validated scoring system: DIC score equal to or more than 5 is compatible with overt‐DIC. Categories of acute respiratory distress syndrome (ARDS) were defined based on PaO(2)/FiO(2) ratio. RESULTS: A total 26 of 45 patients showed impaired RVLS at 6‐months’ follow‐up. DIC score was significantly higher in patients with worse RVLS than in those with better RVLS (4.8 ± .5 vs. 3.6 ± .6, p =.03). Stages of ARDS did not modulate this relationship. Finally, overt‐DIC results the only independent predictor of sustained RV dysfunction (OR 1.233, 95% CI 1.041–1.934, p =.043). CONCLUSIONS: Sustained RV impairment frequently occurs in patients recovered from severe COVID‐19. DIC plays a key role, resulting in an independent predictor of sustained RV dysfunction.

caused by a positive-sense RNA virus named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More than 130 million people have been diagnosed with COVID-19 worldwide. 1 The clinical spectrum of COVID-19 appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury. 2, 3 Recent reports suggest that acute right ventricular (RV) dysfunction is also common in patients hospitalized with COVID-19 as a direct consequence of elevations in RV afterload due to pulmonary embolism or pneumonia. 4 Moreover, in-hospital adverse RV remodeling (dysfunction/dilation) has been demonstrated to be of prognostic value. 5 These observations are aligned with those of a large prospective international registry of 1216 inpatients with COVID- 19. 6 Data are also available about sustained RV involvement in patients after their recovered from COVID-19. 7, 8 However, most of them had moderate type or did not even require hospitalization, making these findings unreliable to reflect the full spectrum-covering patients for the diagnosis of RV systolic dysfunction. 9 It has also been proven to be of clinical value in patients hospitalized with COVID-19. 10 Accumulated evidence reveals that an acquired syndrome known as COVID-19-associated coagulopathy (CAC) is common as part of the systemic inflammatory response syndrome, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in the most severely ill patients. 11, 12 Despite its established prognostic value in the acute setting, whether DIC has a relationship with sustained RV dysfunction in severely ill patients who survive their illness remains unknown. Furthermore, whether categories of ARDS could modulate this relationship has not been explored yet.

Accordingly, the purpose of the present study was to establish the evidence of sustained RV dysfunction echo-quantified by RVLS in patients recovered from severe type, refining the role of DIC as a potential predictor of impaired RV strain.

This was a single-center, observational study performed at Baggio- 

Clinical data were carefully obtained by reviewing each patient's medical records. Demographics included cardiovascular indices and baseline medication regimen at the time of hospital admission, as was subsequent inpatient initiation of COVID-19-related therapies.

Biomarker data encompassed pre-specified indices generally associated with adverse prognosis (e.g., high-sensitivity troponin I, C reactive protein, D-dimer, and white blood count). For patients with biomarkers obtained at multiple time points, peak values were used for study-related data analyses. ARDS was diagnosed based on the Berlin Definition. 14 Accordingly, categories of ARDS were defined based on PaO 2 /FiO 2 ratio: mild (200-300 mmHg), moderate (100-200 mmHg), and severe (<100 mmHg). DIC was defined according to the International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria by a 5-step diagnostic algorithm to calculate a score. 15 Briefly,

(1) the presence of clinical conditions known to be associated with DIC like a severe infection is a conditio sine qua non for the use of the algorithm; (2) the scoring system is based on a combination of several laboratory tests (D-dimer, prothrombin time, platelet count, and fibrinogen); (3) a DIC score equal or more than 5 is compatible with overt-DIC, whereas a score of less than 5 may be indicative for non-overt DIC.

Transthoracic echocardiography was performed in a standard manner with the same equipment (Vivid E95; GE Medical Systems, Milwaukee, WI) by a single cardiologist (AM) with expertise in echocardiographic recording and interpretation, blinded to all clinical data. Images were obtained using a 3.5-MHz transducer in the parasternal and apical views (standard long-axis, two-, and four-chamber images), and measurements were performed after a 5-min run-in period for stabilization and equilibration. All included patients had at least fair image quality.

Cardiac chamber quantification was defined in accordance with consensus guidelines. 16 As recommended, a dedicated RV-focused apical four-chamber view was used to measure the right ventricle. RV systolic function was evaluated using tricuspid annular plane excursion Imaging. 17 All analyses were performed offline by a single experienced investigator (AM) using a commercially available semiautomated two-dimensional strain software (EchoPAC version 112; GE Medical Systems). Digital cine loops of two-dimensional grayscale RV images were acquired in the RV-focused apical four-chamber view, during breath-hold with a stable electrocardiographic recording, and were stored for offline analysis. The frame rate was set between 60 and 80 frames per second as recommended to combine temporal resolution with adequate spatial definition and to enhance the feasibility of the frame-to-frame tracking technique. RV free wall endocardial border was traced in end-systole and the automatically generated region of interest was adjusted to exclude the pericardium. RVLS was calculated as the mean of the strain values in the three segments (basal, mid, and apical) of RV free wall ( Figure 1 ). RVLS > -20% indicates RV systolic dysfunction. 16 

Continuous variables were expressed as mean ± standard deviation 

All 45 patients referred for transthoracic echocardiography 6-months after discharge were alive with no re-hospitalization for any cause. We divided our study population into two groups according to the RVLS 

The acute effect of COVID-19 on RV activity has recently been much debated. Because the right ventricle mainly acts as a passive conduit in cardiac functioning, it is easily affected by a slight increase in pulmonary vascular resistance. 18 It seems that the pathophysiological pathways of COVID-19 including increased RV afterload after ARDS and pulmonary embolism are possible mechanisms for RV dysfunction in COVID-19 patients. 19 Emerging evidence suggests that acute

and was frequently in those with more severe types. RV contractile dysfunction appeared to occur after geometric remodeling, with RV dysfunction present in less than one-quarter of inpatients with RV dilation. 5 Conversely, the long-term RV sequelae of COVID-19 have not been fully explored yet. Sustained RV cardiac involvement was found using magnetic resonance imaging in a subgroup of patients recovered from COVID-19; however, most included patients had mildor moderate-type previously. 8 The present study is the first to show the sustained RV impairment by STE in patients recovering from a severe type of COVID-19. Whereas RV dysfunction was present in more than half of our population, RV dilation rarely occurred at 6-months followup. RV dilation is frequent in hospitalized patients with COVID-19

infection. 20 It likely depends on multifactorial mechanisms includes thrombotic events, hypoxemic vasoconstriction, cytokine milieu, and direct viral damage. We can only speculate on the nature of our findings, but we conclude that dilation is an early response of the thinwalled right ventricle to acute and temporary increased afterload;

instead, RV dysfunction is sustained damage concerning RV myocyte loss due to lasting detrimental effect. We have provided no evidence to support that RV dysfunction is permanent. It is also possible that the recovery of RV systolic function is a slow process. Future studies are warranted to clarify that statement. 

The main limitation of this report is the relatively small, single-center cohort studied. However, the inclusion criteria were quite selective, limiting the eligibility for this study. Almost half of the screened patients were excluded because they had known cardiopathy, as it would have hampered data interpretation because of heterogeneity.

Thus, larger studies adequately powered are warranted to confirm our results. Secondly, our cohort was retrospectively identified but all measurements were performed prospectively and retrieved unaltered.

Thus, our results are highly applicable to clinical practice. Lastly, our findings would have been more relevant if RV dysfunction had been confirmed by advanced cardiac imaging, as well as associated with increased pulmonary vascular resistance.

Sustained RV impairment frequently occurs in patients recovered from severe COVID-19. Whether it may be helpful for risk stratification is uncertain, and needs to be further investigated. Our findings provide new insight on the role of the DIC, showing its value as an independent predictor of sustained dysfunction assessed by the recent application of speckle-tracking echocardiography to the right ventricle.

The corresponding author is grateful to Giovanni Benfari, MD, for the support in Figure 2 .

An interactive web-based dashboard to track COVID-19 in real time

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

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Prognostic utility of right ventricular remodeling over conventional risk stratification in patients with COVID-19

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Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

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Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Sustained right ventricular dysfunction in severe COVID-19: The role of disseminated intravascular coagulation

All authors have no conflict of interest.

Alessandro Malagoli MD https://orcid.org/0000-0001-9119-4311