Skip to main content
The Ultrasound Journal
Download PDF

Left atrial strain is associated with distinct inflammatory and immune profile in patients with COVID-19 pneumonia

The Ultrasound Journal volume 15, Article number: 2 (2023) Cite this article

Abstract

Introduction

SARS-CoV-2 infection is associated with multiple cardiac manifestations. Left atrial strain (LA-S) by speckle tracking echocardiography (STE) is a novel transthoracic echocardiography (TTE) measure of LA myocardial deformation and diastolic dysfunction, which could lead to early recognition of cardiac injury in severe COVID-19 patients with possible implications on clinical management, organ dysfunction, and mortality. Cardiac injury may occur by direct viral cytopathic effects or virus-driven immune activation, resulting in heart infiltration by inflammatory cells, despite limited and conflicting data are available on myocardial histology.

Purpose

We aimed to explore LA-S and immune profiles in COVID-19 patients admitted to the intensive care unit (ICU) to identify distinctive features in patients with cardiac injury.

Methods

We enrolled 30 patients > 18 years with positive SARS-CoV-2 RT-PCR, admitted to ICU. Acute myocardial infarction and pulmonary embolism were exclusion criteria. On days D1, D3, and D7 after ICU admission, patients performed TTE, hemogram, cardiac (pro-BNP; troponin) and inflammatory biomarkers (ESR; ferritin; IL1β; IL6; CRP; d-dimer; fibrinogen; PCT; adrenomedullin, ADM), and immunophenotyping by flow cytometry.

Results

Patient’s mean age was 60.7 y, with 63% males. Hypertension was the most common risk factor (73%; with 50% of patients under ACEi or ARA), followed by obesity (40%, mean BMI = 31 kg/m2). Cardiac dysfunction was detected by STE in 73% of patients: 40% left ventricle (LV) systolic dysfunction, 60% LV diastolic dysfunction, 37% right ventricle systolic dysfunction. Mortality, hospitalization days, remdesivir use, organ dysfunction, cardiac and serum biomarkers were not different between patients with (DYS) and without cardiac dysfunction (nDYS), except for ADM (increased in nDYS group at D7). From the 77 TTE, there was a striking difference between diastolic dysfunction evaluation by classic criteria compared to STE (28.6% vs. 57.1%, p = 0.0006). Lower reservoir (Ɛ) and contraction (ƐCT) LA-S correlated with IL-6 (Ɛ, p = 0.009, r =  − 0.47; ƐCT, p = 0.0002, r =  − 0.63) and central memory CD4 T-cells (ƐCT, p = 0.049, r =  − 0.24). Along all timepoints, DYS patients showed persistent low lymphocyte counts that recovered at D7 in nDYS patients. DYS patients had lower platelets at D3 and showed a slower recovery in platelet counts and CRP levels; the latter significantly decreased at D7 in nDYS patients (p = 0.009). Overall, patients recovered with an increasing P/F ratio, though to a lesser extent in DYS patients.

Discussion

Our study shows that LA-S may be a more sensitive marker for diastolic dysfunction in severe COVID-19, which could identify patients at risk for a protracted inflammatory state. A differential immune trait in DYS patients at ICU admission, with persistent lymphopenia, enriched CM T-cells, and higher IL-6 may suggest distinct inflammatory states or migration patterns in patients that develop cardiac injury.

Introduction

In severe COVID-19 patients, diagnostic transthoracic echocardiography (TTE) allows early recognition of cardiac injury with an impact on clinical management, reducing organ dysfunction and mortality [1, 2]. Notably, the expression of the cardiovascular disease seems to be a marker of a poor prognosis in COVID-19 [3]. More recently, the assessment of left atrial strain (LA-S), assessed by speckle tracking echocardiography (STE), has allowed a more accurate and reproducible analysis of left atrial function [4], correlating more accurately with left ventricle (LV) diastolic dysfunction (LVDD) [5] and with invasive hemodynamics [6]. By measuring less explored diastolic dysfunction parameters, such as LA-S, a broader spectrum of cardiac dysfunction may be recognized, allowing earlier and more effective management in COVID-19 patients.

Here, we aimed to explore diastolic dysfunction parameters and the immune profile in COVID-19 patients admitted to the intensive care unit (ICU) to identify distinctive immune features in patients with cardiac injury.

Materials and methods

We enrolled 30 patients > 18 years with positive SARS-CoV-2 RT-PCR test who were admitted to ICU between March and September 2022. Acute myocardial infarction and pulmonary embolism were exclusion criteria. On days D1, D3, and D7 after ICU admission, patients performed STE, hemogram, cardiac (pro-BNP; troponin) and inflammatory biomarkers (ESR; ferritin; IL1β; IL6; CRP; d-dimer; fibrinogen; PCT; adrenomedullin, ADM), and immunophenotyping by flow cytometry.

The presence of cardiac dysfunction (DYS vs. nDYS) was classified according to the European Society of Cardiology (ESC) and American Society of Echocardiography (ASE) guidelines for chamber quantification classification [7]: LV systolic dysfunction (LVSD) was defined as a calculated LVEF < 50% or LVGLS < 20%; RV systolic dysfunction was defined as RV FAC < 35%, TAPSE < 17 mm, S’ < 9.5 cm/s or RVGLS < 20%. LVDD dysfunction was classified by “classic” criteria according to 2016 ASE/EACVI guidelines [8] and by LA-S to assess contractile (ƐCT < 10%) and reservoir (Ɛ < 30%) functionality using definitions from previous studies [9] (Fig. 1).

Fig. 1
figure 1

Left atrium strain example with reservoir (Ɛ) and contraction (ƐCT) functions highlighted

Full size image

Results

The patient’s mean age was 60.7 years, with 63% males. Hypertension was the most common risk factor (73%, of which 50% of were under ACEi or ARA), followed by obesity (40%, mean BMI = 31 kg/m2). Cardiac dysfunction was detected by STE in 73% of patients: 40% LVSD, 60% LVDD, 37% right ventricle systolic dysfunction. Mortality, hospitalization days, remdesivir use, organ dysfunction, and cardiac and serum biomarkers were not different between patients with and without cardiac dysfunction. The 77 TTE evaluations showed a striking difference between diastolic dysfunction evaluation by classic criteria compared to LA-S (28.6% vs. 57.1%, p = 0.0006).

When comparing classic LVDD with LA-S LVDD (Table 1), the latter discriminated longer IVCT (DYS: 70 ms [51–79] vs. nDYS: 50 ms [42–64]) and pre-TE (DYS: 74 ms [67–88) vs. nDYS: 63 ms [42.5–81]), and slightly worse RV systolic function (RV FAC DYS: 41.51% [33.59–48.03] vs. nDYS: 48.61% [40.96–58.32]; RV GLS DYS: 21.85% [18.5–29.24] vs. nDYS: 26.95% [22.38–31.59]) and lower CI (DYS: 2.47 l/min/m2 [2.01–2.92] vs. nDYS: 2.83 l/min/m2 [2.24–4.11]).

Table 1 Comparison of echocardiographic, hemodynamic parameters and cardiac biomarkers between left ventricle diastolic dysfunction by classic criteria vs. left atrium strain
Full size table

Discussion

Our data regarding cardiac dysfunction prevalence in COVID-19 patients is in line with recent evidence, suggesting that 70% of patients with COVID-19 harboured a cardiac injury within the first ICU admission, identified by multimodal cardiac assessment [10]. This incidence is higher than other previously reported values that ranged from 12 to 30% [11,12,13]. The higher incidence reported by Doyen and collaborators [10] could be explained by either the longitudinal cardiac assessment or the use of a much more sensitive tool to detect LV diastolic dysfunction, as is the STE [5], being simultaneously in line with incidences reported in critically ill patients with sepsis not related to COVID-19 [14]. Thus, it confirms that COVID-19 patients experienced more LV diastolic than systolic dysfunction [15].

Diastolic dysfunction is an elusive pathological condition due to the late definition of its diagnostic criteria, and these strict classical parameters are difficult to apply to critically ill patients, compromising its classification. Recently, some studies have tried to overcome this issue by simplifying and validating specific criteria. Clancy et al. [16] applied the 2016 America Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) guidelines, comparing with the previous 2009 ASE guidelines, achieving 60% of diastolic dysfunction on the first day, with a further 23% having an indeterminate diastolic function, where only 21% had confirmed diastolic dysfunction with 74% having indeterminate diastolic dysfunction, respectively. In addition, Lanspa et al. [17] proposed a simplified definition using only e′ and E/e′, categorizing 87% of patients, compared with 35% of patients using ASE 2009 guidelines. Both groups had similar clinical outcomes. Nevertheless, the massive diffusion of echocardiography provides a more precise appreciation of its burden in critically ill patients. Recently, Filippo Sanfilippo et al. reviewed and explained extensively the challenges of diagnosing diastolic dysfunction in critically ill patients [18].

In this context, a systematic echocardiographic evaluation of 100 COVID-19 patients by Szekely et al. revealed a LVDD as high as 90% in their cohort with a mean age of 66 years, despite a preserved LV ejection fraction [19]. Alongside the subclinical ventricular relaxation impairment (given the advanced age and co-morbidities such as systemic hypertension), the conglomeration of factors specific to COVID-19 such as systemic inflammatory milieu, endothelial dysfunction, microvascular thrombosis, arrhythmias, disturbed ventricular cross-talk (owing to the concomitant right ventricular dysfunction resulting from pulmonary hypertension), and myocardial oxygen supply–demand perturbations, can contribute significantly to the LVDD with a subsequent accentuated potential to culminate as heart failure with preserved ejection fraction (HFpEF) [15].

Few studies have addressed the evolution of the immune profile in COVID-19 patients with cardiac injury. Namely, Laing et al. [20] accomplished an exhaustive immunological analysis, where they identified discrete changes in the compartments of circulating B and myelomonocytic cells, along with profoundly altered T cell phenotypes, upregulation of several cytokines/chemokines and SARS-CoV-2-specific antibodies. Moreover, another group studied the association between the immune profile and cardiac injury in COVID-19 patients, suggesting that the numbers of T and B lymphocytes were significantly decreased in the group with cardiac injury [21].

Our study shows that LA-S may be a more sensitive marker for diastolic dysfunction in severe COVID-19, identifying patients at risk for a protracted inflammatory state.

In fact, we have previously described that a differential immune trait is present in patients at ICU admission, with persistent lymphopenia, enriched central memory CD4 T cells, and higher serum levels of IL-6, suggesting a distinct inflammatory state and migration patterns in patients that develop cardiac injury [22]. Thus, an improved comprehension of the likelihood of an altered diastology in COVID-19 patients is doubtlessly pivotal in staging a more well-directed management approach, wherein targeted echocardiographic surveillance, cardiac and immune-inflammatory biomarkers, combined heart–lung ultrasound and inodilators, can assist the overall management of this critically ill cohort.

Within our limitations, it is worth mentioning the small sample size that could have underpowered our study for more clinically significant outcomes such as mortality, mechanical ventilation, shock, ICU and hospital length of stay. Nevertheless, the repeated measures along the time course may have partially overcome this issue for the other results.

Conclusions

Our study shows that LA-S may be a more sensitive marker for diastolic dysfunction in severe COVID-19, particularly patients at ICU admission with persistent lymphopenia, enriched CM T-cells, and higher IL-6, which may suggest a differential immune trait in cardiac injury COVID-19 patients in ICU.

Availability of data and materials

The data sets used and/or analyzed during the current study are available from the corresponding author on request.

References

  1. Akhmerov A, Marbán E (2020) COVID-19 and the heart. Circulation Research

  2. Hendren NS, Drazner MH, Bozkurt B, Cooper LT (2020) Description and proposed management of the acute COVID-19 cardiovascular syndrome. Circulation 1:1

    Google Scholar 

  3. Huang Z, Huang P, Du B, Kong L, Zhang W, Zhang Y et al (2021) Prevalence and clinical outcomes of cardiac injury in patients with COVID-19: a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis (Internet) 31(1):2–13. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0939475320303902

  4. Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen T et al (2018) Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging 19(6):591–600

    Article  Google Scholar 

  5. Frydas A, Morris DA, Belyavskiy E, Radhakrishnan AK, Kropf M, Tadic M et al (2020) Left atrial strain as sensitive marker of left ventricular diastolic dysfunction in heart failure. ESC Hear Fail

  6. Cameli M, Sparla S, Losito M, Righini FM, Menci D, Lisi M et al (2016) Correlation of left atrial strain and doppler measurements with invasive measurement of left ventricular end-diastolic pressure in patients stratified for different values of ejection fraction. Echocardiography 1:1

    Google Scholar 

  7. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American society of echocardiography and the European association of cardiovascular imaging. Eur Heart J Cardiovasc Imaging 1:1

    Google Scholar 

  8. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF III, Dokainish H, Edvardsen T et al (2016) Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr (Internet). 2016/04/03. 29(4):277–314. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27037982

  9. Singh A, Addetia K, Maffessanti F, Mor-Avi V, Lang RM (2017) LA strain for categorization of LV diastolic dysfunction. JACC Cardiovasc Imaging 1:1

    Google Scholar 

  10. Doyen D, Dupland P, Morand L, Fourrier E, Saccheri C, Buscot M et al (2021) Characteristics of cardiac injury in critically ill patients with coronavirus disease 2019. Chest 1:1

    Google Scholar 

  11. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 1:1

    CAS  Google Scholar 

  12. Catena C, Colussi G, Bulfone L, Da Porto A, Tascini C, Sechi LA (2021) Echocardiographic comparison of COVID-19 patients with or without prior biochemical evidence of cardiac injury after recovery. J Am Soc Echocardiogr 1:1

    Google Scholar 

  13. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T et al (2020) Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol 1:1

    Google Scholar 

  14. Garry D, Newton J, Colebourn C. Tissue Doppler indices of diastolic function in critically ill patients and association with mortality—a systematic review. J Intensive Care Soc [Internet] 2016/02/01. 2016;17(1):51–62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28979458

  15. Tian L, Duan F, Li X, Zhou C. Incidence, risk factors and prognostic effect of imaging left ventricular diastolic dysfunction in patients with COVID-19: protocol for a systematic review. BMJ Open [Internet] 2022 Apr 27;12(4):e059281. Available from: https://doi.org/10.1136/bmjopen-2021-059281

  16. Clancy DJ, Scully T, Slama M, Huang S, McLean AS, Orde SR (2017) Application of updated guidelines on diastolic dysfunction in patients with severe sepsis and septic shock. Ann Intensive Care [Internet] 7(1):121. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29260409

  17. Lanspa MJ, Gutsche AR, Wilson EL, Olsen TD, Hirshberg EL, Knox DB et al (2016) Application of a simplified definition of diastolic function in severe sepsis and septic shock. Crit Care [Internet] 20(1):243. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27487776

  18. Sanfilippo F, Bignami EG, Astuto M, Messina A, Cammarota G, Maggiore SM et al (2022) Understanding left ventricular diastolic dysfunction in anesthesia and intensive care patients: a glass with progressive shape change. Minerva Anestesiol [Internet] 88(11). Available from: https://www.minervamedica.it/index2.php?show=R02Y2022N11A0950

  19. Szekely Y, Lichter Y, Taieb P, Banai A, Hochstadt A, Merdler I et al (2020) Spectrum of cardiac manifestations in COVID-19: a systematic echocardiographic study. Circulation 1:1

    Google Scholar 

  20. Laing AG, Lorenc A, del Molino del Barrio I, Das A, Fish M, Monin L et al (2020) A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat Med [Internet] 2020 Oct 1 [cited 2021 Apr 23];26(10):1623–35. Available from: https://doi.org/10.1038/s41591-020-1038-6

  21. Zhou W, Song L, Wang X, Xu Z, Wang S, Wang J et al (2021) Cardiac injury prediction and lymphocyte immunity and inflammation analysis in hospitalized patients with coronavirus disease (COVID-19). Int J Cardiol 1:1

  22. Gonzalez FA, Ângelo-Dias M, Martins C, Gomes R, Bacariza J, Fernandes A et al (2022) Characteristic immune dynamics in COVID-19 patients with cardiac dysfunction. J Clin Med [Internet]. 2022 Mar 28;11(7):1880. Available from: https://www.mdpi.com/2077-0383/11/7/1880

Download references

Acknowledgements

The authors thank Pedro Pereira from Canon, Portugal, for providing the 2D Wall Motion Tracking software for speckle tracking echocardiography.

The EchoCrit Group is a collaboration group of the Intensive Care Department of Hospital Garcia de Orta, Almada, Portugal, dedicated to the advanced Echocardiography and POCUS in critical care, formed by the following physicians: Rui Gomes, Jacobo Bacariza, Rita Varudo, João Leote, Vera Pereira, Dário Batista, Vânia Brito, Corinna Lohmann, João Gouveia, Joana Manuel, Liliana Santos, Sara Lança, Lucinda Oliveira, Tiago Ferreira, Joana Ferreira, João Sampaio, José Seoane, Inês Pimenta, Cristina Martins, Ricardo Meireles, Francisco D’Orey, Maria Inês Ribeiro, Antero Fernandes (Head of Intensive Care Department). The authors would like the names of the individual members of the Group to be searchable through their individual PubMed records.

Funding

Type of funding sources: Foundation—015_595935779—Foundation for Science and Technology (FCT), in collaboration with the Agency for Clinical Research and Biomedical Innovation (AICIB), open special funding, “RESEARCH 4 COVID-19”, to R&D projects and initiatives that respond to the needs of the National Health Service (SNS) as a response to this and future pandemics in a very short time horizon. Project: “Early recognition of cardiac injury associated with COVID-19 and clinical outcomes.”

Author information

Authors and Affiliations

  1. Intensive Care Department, Hospital Garcia de Orta, Almada, Portugal

    Filipe André Gonzalez, Rui Gomes, Jacobo Bacariza & Antero Fernandes

  2. NOVA Medical School|Faculdade de Ciências Médicas, NMS|FCM, Universidade Nova de Lisboa, Lisbon, Portugal

    Miguel Ângelo-Dias, Catarina Martins & Luis Miguel Borrego

  3. Immunoallergy Department, Hospital da Luz Lisboa, Lisbon, Portugal

    Luis Miguel Borrego

Authors
  1. Filipe André Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miguel Ângelo-Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catarina Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacobo Bacariza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antero Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luis Miguel Borrego
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

EchoCrit Group

Contributions

FAG created the project, the protocol design and the methodology, had full access to all of the data in the study and took responsibility for the data's integrity and the data analysis's accuracy. FAG, RG and JB did all the echocardiographic examinations. MAD and CM did all the cytometry analysis and interpretation. MAD did all the statistics. FG, MAD, CM, LMB, RG, JB and AF contributed substantially to the writing and revision of the manuscript. The EchoCrit Group carried out the protocol design and data annotation. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Filipe André Gonzalez.

Ethics declarations

Ethics approval and consent to participate

This was a prospective observational study on current practice, and all collected data were the standard monitoring and intervention data used in critical care. All monitoring and intervention attitudes have been extensively described in the literature, and patients were assessed and treated routinely. Data were anonymously collected, and all information allowing patient identification was not collected. Patient anonymity was maintained both during data processing and publishing. A patient number was used in all echocardiograms recorded for later review by an expert. According to local legislation, consent from the patient or next of kin to record data and to draw blood was obtained before study enrolment, and the Ethics Committees approved the study of Hospital Garcia de Orta and NOVA Medical School (CE nº 44-2020-CEFCM).

Consent for publication

All the patients (or next of kin) signed a consent form for personal data collection and scientific use, such as publication. Nevertheless, all information that eventually can identify the patient is anonymized or not published.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This project occurred in the Intensive Care Department in Hospital Garcia de Orta, Almada, Portugal

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gonzalez, F.A., Ângelo-Dias, M., Martins, C. et al. Left atrial strain is associated with distinct inflammatory and immune profile in patients with COVID-19 pneumonia. Ultrasound J 15, 2 (2023). https://doi.org/10.1186/s13089-022-00302-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13089-022-00302-5