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Advanced cardiac imaging in the spectrum of COVID-19 related cardiovascular involvement

  • Anna Palmisano
    Correspondence
    Corresponding author at: Department of Radiology, Cardiovascular Imaging Unit, Experimental Imaging Center, San Raffaele Scientific Institute, Via Olgettina 58 – 60, 20132 Milan, Italy.
    Affiliations
    Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy

    School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy
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  • Michele Gambardella
    Affiliations
    School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy
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  • Tommaso D'Angelo
    Affiliations
    Diagnostic and Interventional Radiology Unit, Department of Biomedical Sciences and Morphological and Functional Imaging, University Hospital Messina, Messina, Italy

    Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
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  • Davide Vignale
    Affiliations
    Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy

    School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy
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  • Raffaele Ascione
    Affiliations
    Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy

    Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
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  • Marco Gatti
    Affiliations
    Department of Surgical Sciences, Radiology Unit, University of Turin, Via Genova 3, 10126 Turin, Italy
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  • Giovanni Peretto
    Affiliations
    School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy

    Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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  • Francesco Federico
    Affiliations
    School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy

    Cardio-Thoracic.Vascular Department, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy
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  • Amar Shah
    Affiliations
    Westchester Medical Center, Valhalla, NY, United States of America
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  • Antonio Esposito
    Affiliations
    Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy

    School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, Milan, Italy
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      Highlights

      • Cardiovascular involvement is common in COVID-19 and is associated with unfavorable prognosis.
      • CT can exclude coronary disease and pulmonary embolism, providing ancillary information for risk stratification.
      • CMR is useful to characterize myocardial alteration related to acute COVID-19, post-acute sequelae and vaccination.

      Abstract

      Cardiovascular involvement is a common complication of COVID-19 infection and is associated to increased risk of unfavorable outcome. Advanced imaging modalities (coronary CT angiography and Cardiac Magnetic Resonance) play a crucial role in the diagnosis, follow-up and risk stratification of patients affected by COVID-19 pneumonia with suspected cardiovascular involvement. In the present manuscript we firstly review current knowledge on the mechanisms by which SARS-CoV-2 can trigger endothelial and myocardial damage. Secondly, the implications of the cardiovascular damage on patient's prognosis are presented. Finally, we provide an overview of the main findings at advanced cardiac imaging characterizing COVID-19 in the acute setting, in the post-acute syndrome, and after vaccination, emphasizing the potentiality of CT and CMR, the indication and their clinical implications.

      Keywords

      1. Introduction

      Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic. COVID-19 is caused by the novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), that primarily manifests as an interstitial pneumonia and can rapidly progress towards severe acute respiratory distress syndrome [
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      Quantitative assessment of lung involvement on chest CT at admission: impact on hypoxia and outcome in COVID-19 patients.
      ]. Despite the respiratory system is the primary target, multiorgan involvement frequently occurs. Cardiovascular involvement in COVID-19 is common: an increase in levels of biomarkers of cardiac injury or dysfunction (troponin I and T, creatine kinase-MB, myoglobin, NT-proBNP) is described in up to 40% of cases, especially in patients with cardiovascular risk factors [
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      • Stefanini G.G.
      • Bragato R.
      • Silbiger J.J.
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      Characterization of myocardial injury in patients with COVID-19.
      ] and severe disease [
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      COVID-19 and cardiovascular disease: from bench to bedside.
      ,
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      ].
      Pre-existing cardiovascular risk factors and the occurrence of acute cardiac injury are both predictors of adverse events [
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      Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection.
      ,
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      ], being associated to more severe disease and higher mortality rate [
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      Quantitative assessment of lung involvement on chest CT at admission: impact on hypoxia and outcome in COVID-19 patients.
      ,
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      COVID-19 and cardiovascular disease: from bench to bedside.
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      Coronary calcium score as a predictor of outcomes in the hypertensive Covid-19 population: results from the italian (S) Core-Covid-19 registry.
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      Diabetes and mortality in patients with COVID-19: are we missing the link?.
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      Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.
      ,
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      Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.
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      Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: a post-hoc analysis of a prospective cohort study.
      ,
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      Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).
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      Association between COVID-19 and myocarditis using hospital-based administrative data — United States, March 2020-January 2021.
      ,
      • Jaiswal V.
      • Sarfraz Z.
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      ,
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      Return-to-work, disabilities and occupational health in the age of covid-19.
      ,
      • Cereda A.
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      • Vignale D.
      • Leone R.
      • Nicoletti V.
      • et al.
      The hidden interplay between sex and COVID-19 mortality: the role of cardiovascular calcification.
      ].
      The spectrum of SARS-CoV-2 cardiovascular manifestations is wide and encompasses multiple clinical presentations, including acute coronary syndromes (ACS), heart failure, myocarditis, and arrhythmias [
      • Hendren N.S.
      • Drazner M.H.
      • Bozkurt B.
      • Cooper L.T.
      Description and proposed management of the acute COVID-19 cardiovascular syndrome.
      ] and the underlying mechanism is complex, multifaceted, and still not completely understood [
      • Augoustides J.G.
      Cardiovascular consequences and considerations of coronavirus infection – perspectives for the cardiothoracic anesthesiologist and intensivist during the coronavirus crisis.
      ].
      Cardiac symptoms might persist months after recovery from COVID-19 [
      • Raman B.
      • Bluemke D.A.
      • Lüscher T.F.
      • Neubauer S.
      Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus.
      ]. The introduction of COVID-19 vaccination has significantly reduced the incidence of severe COVID-19. Nevertheless, several reports have raised concerns about myopericarditis occurrence after different types of COVID-19 vaccines [
      • Ammirati E.
      • Cavalotti C.
      • Milazzo A.
      • Pedrotti P.
      • Soriano F.
      • Schroeder J.W.
      • et al.
      Temporal relation between second dose BNT162b2 mRNA Covid-19 vaccine and cardiac involvement in a patient with previous SARS-COV-2 infection.
      ,
      • D’Angelo T.
      • Cattafi A.
      • Carerj M.L.
      • Booz C.
      • Ascenti G.
      • Cicero G.
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      Myocarditis after SARS-CoV-2 vaccination: a vaccine-induced Reaction?.
      ,
      • Abu Mouch S.
      • Roguin A.
      • Hellou E.
      • Ishai A.
      • Shoshan U.
      • Mahamid L.
      • et al.
      Myocarditis following COVID-19 mRNA vaccination.
      ].
      Advanced cardiac imaging plays a role in diagnosis and risk stratification of COVID-19 patients with cardiovascular complications. CT has a pivotal rule in ruling-out coronary artery disease and pulmonary embolism. Vascular evaluation may be coupled with the assessment of pneumonia severity and to myocardial tissue characterization, excluding myocardial scars [
      • Palmisano A.
      • Vignale D.
      • Tadic M.
      • Moroni F.
      • de Stefano D.
      • Gatti M.
      • et al.
      Myocardial late contrast enhancement CT in troponin-positive acute chest pain syndrome.
      ,
      • Pontone G.
      • Baggiano A.
      • Conte E.
      • Teruzzi G.
      • Cosentino N.
      • Campodonico J.
      • et al.
      “Quadruple rule-out” with computed tomography in a COVID-19 patient with equivocal acute coronary syndrome presentation.
      ]. Additionally, CT may provide quantitative information about subclinical comorbidities or COVID-19 related complications capable of improving risk stratification of COVID-19 patients [
      • Cereda A.
      • Toselli M.
      • Palmisano A.
      • Vignale D.
      • Khokhar A.
      • Campo G.
      • et al.
      Coronary calcium score as a predictor of outcomes in the hypertensive Covid-19 population: results from the italian (S) Core-Covid-19 registry.
      ,
      • Scoccia A.
      • Gallone G.
      • Cereda A.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • et al.
      Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.
      ,
      • Giannini F.
      • Toselli M.
      • Palmisano A.
      • Cereda A.
      • Vignale D.
      • Leone R.
      • et al.
      Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.
      ,
      • Dillinger J.G.
      • Benmessaoud F.A.
      • Pezel T.
      • Voicu S.
      • Sideris G.
      • Chergui N.
      • et al.
      Coronary artery calcification and complications in patients with COVID-19.
      ,
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.
      ,
      • Esposito A.
      • Palmisano A.
      • Toselli M.
      • Vignale D.
      • Cereda A.
      • Rancoita P.M.V.
      • et al.
      Chest CT-derived pulmonary artery enlargement at the admission predicts overall survival in COVID-19 patients: insight from 1461 consecutive patients in Italy.
      ] (Fig. 1). Cardiac Magnetic Resonance (CMR) is the imaging of choice for the non-invasive characterization of myocardium, allowing to accurately assess ventricular function, myocardial edema, and myocardial injury. CMR imaging is useful for the non-invasive detection of cardiac alteration related to acute COVID-19, post-acute sequelae, and vaccination [
      • Kato S.
      • Azuma M.
      • Fukui K.
      • Kodama S.
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      • Kitamura H.
      Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.
      ].
      Fig. 1
      Fig. 1Role of CT and CMR in the diagnostic algorithm of COVID-19 related cardiac complication. After clinical evaluation, patients with chest pain, ST elevation ACS, high pretest probability of CAD and high risk of mortality should be referred to emergent invasive coronary angiography (ICA). Patients with NSTEMI, atypical symptoms and ECG abnormality should be referred to CT. A triple rule-out protocol should be preferred for the simultaneous exclusion of pulmonary embolism (PE) and coronary artery disease (CAD). Patients with obstructive CAD should be referred to ICA for percutaneous intervention (PCI), while patients with non-obstructive CAD to tissue characterization. This could be obtained directly from CT, and in presence of scar and ECV alteration according to multidisciplinary evaluation a diagnostic confirmation with CMR can be performed.
      In patients with suspected long COVID-19 syndrome and post-vaccination symptoms, CMR is the first level examination. CT can have a role subsequently in order to exclude chronic PE or obstructive CAD in patients with long COVID-19 syndrome.
      In the present manuscript, we aim to provide an overview about indication, potentialities, and main findings of cardiothoracic CT and CMR in the most frequent scenarios of COVID-19 related manifestation.

      2. COVID-19 related cardiovascular damage physiopathology

      Most frequently, COVID-19 related acute myocardial damage manifestation include [
      • Augoustides J.G.
      Cardiovascular consequences and considerations of coronavirus infection – perspectives for the cardiothoracic anesthesiologist and intensivist during the coronavirus crisis.
      ]: i) right ventricular dysfunction because of COVID-19 associated pulmonary embolism or pulmonary hypertension; ii) acute coronary ischemia because of focal epicardial coronary artery thrombosis (type 1 myocardial infarction) or diffuse myocardial ischemia sustained by extensive microvascular dysfunction, hypoxemia and vasoconstriction due to oxygen demand/supply mismatch (type 2 myocardial infarction) [
      • Hendren N.S.
      • Drazner M.H.
      • Bozkurt B.
      • Cooper L.T.
      Description and proposed management of the acute COVID-19 cardiovascular syndrome.
      ,
      • Bangalore S.
      • Sharma A.
      • Slotwiner A.
      • Yatskar L.
      • Harari R.
      • Shah B.
      • et al.
      ST-segment elevation in patients with Covid-19 - a case series.
      ,
      • Feuchtner G.M.
      • Barbieri F.
      • Luger A.
      • Skalla E.
      • Kountchev J.
      • Widmann G.
      • et al.
      Myocardial injury in COVID-19: the role of coronary computed tomography angiography (CTA).
      ], resulting from direct vascular infection, endotheliitis, microvascular remodeling, and thrombosis secondary to a hypercoagulability status; iii) myopericarditis following myocardial cell binding, direct/indirect cell damage due to ACE-2 receptor interaction or cytotoxic damage and microcirculation dysfunction as a result of the so-called cytokine storm; iv) vasoplegic shock due to sepsis and dysregulation of the renin-angiotensin system;
      Takotsubo syndrome [
      • Sala S.
      • Peretto G.
      • Gramegna M.
      • Palmisano A.
      • Villatore A.
      • Vignale D.
      • et al.
      Acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with SARS-CoV-2 respiratory infection.
      ] is also reported and considered to be due to unbalanced sympathetic stimulation.
      Additionally, COVID-19 patients may suffer from arrhythmias typically ranging from supraventricular arrhythmias in clinically stable patients [
      • Sala S.
      • Peretto G.
      • de Luca G.
      • Farina N.
      • Campochiaro C.
      • Tresoldi M.
      • et al.
      Low prevalence of arrhythmias in clinically stable COVID-19 patients.
      ], to major bradyarrhythmias, such as complete heart block and ventricular tachyarrhythmia in complicated infections [
      • Peretto G.
      • Villatore A.
      • Rizzo S.
      • Esposito A.
      • de Luca G.
      • Palmisano A.
      • et al.
      The Spectrum of COVID-19-associated myocarditis: a patient-tailored multidisciplinary approach.
      ,
      • Mazzone P.
      • Peretto G.
      • Radinovic A.
      • Limite L.R.
      • Marzi A.
      • Sala S.
      The COVID-19 challenge to cardiac electrophysiologists: optimizing resources at a referral center.
      ], triggered by hypoxia, electrolyte derangements, myocardial strain, inflammatory microenvironment and drug side effects [
      • Dherange P.
      • Lang J.
      • Qian P.
      • Oberfeld B.
      • Sauer W.H.
      • Koplan B.
      • et al.
      Arrhythmias and COVID-19: a review.
      ].
      Differently from other cardiotropic viruses, SARS-CoV-2 viral particles have been found inside endothelial cells and cardiac macrophages, but never inside cardiomyocytes [
      • Peretto G.
      • Villatore A.
      • Rizzo S.
      • Esposito A.
      • de Luca G.
      • Palmisano A.
      • et al.
      The Spectrum of COVID-19-associated myocarditis: a patient-tailored multidisciplinary approach.
      ,
      • Peretto G.
      • Sala S.
      • Caforio A.L.P.
      Acute myocardial injury, MINOCA, or myocarditis? Improving characterization of coronavirus-associated myocardial involvement.
      ,
      • Tavazzi G.
      • Pellegrini C.
      • Maurelli M.
      • Belliato M.
      • Sciutti F.
      • Bottazzi A.
      • et al.
      Myocardial localization of coronavirus in COVID-19 cardiogenic shock.
      ,
      • Baggiano A.
      • Rizzo S.
      • Basso C.
      • Pontone G.
      A patient with rapid worsening dyspnoea during Covid-19 pandemic.
      ], while macrophage infiltration, inflammation, and microthrombi were the most common finding at autopsy (48% of cases) [
      • Halushka M.K.
      • Vander Heide R.S.
      Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across 277 postmortem examinations.
      ].
      Immune-mediated mechanisms such as molecular mimicry are thought to contribute to persistent cardiac dysfunction due to a chronic and uncontrolled cytokine response also in post-acute and chronic phases.
      Cardiac complication according to the stage of the disease is reported in Table 1.
      Table 1Cardiac complication and physiopathology according to the stage of disease.
      Cardiac complicationPathophysiologyTime of onset
      Acute COVID-19- Right ventricular dysfunctionPulmonary embolism or pulmonary hypertension for hypercoagulability status, endothelial dysfunction, Hypoxemia and vasoconstrictionFrom acute symptom onset to symptoms resolution
      - Type I myocardial infarction- Endothelial dysfunction

      - Hypercoagulability status
      - Type II myocardial infarction- Endothelial dysfunction

      - Hypoxemia and vasoconstriction
      - Myocarditis, pericarditis- Direct viral injury

      - Cytotoxic damage due to cytokine storm
      - Takotsubo cardiomyopathy- Unbalanced sympathetic stimulation
      - Arrhythmias- Hypoxia, electrolyte derangements, myocardial inflammation
      Cardiac post-acute COVID-19 syndrome- Myocarditis

      - Pericarditis
      - Chronic inflammatory response for persistent viral reservoirs

      - Chronic autoimmune inflammation due to molecular mimicry
      3–4 weeks after COVID-19 onset
      - Microvascular ischemia and myocardial infarction- Endothelial dysfunction
      SARS-CoV-2 vaccination- Myocarditis, pericarditis- Delayed hypersensitivity reaction

      - Molecular mimicry

      - Systemic inflammatory response
      Within 14 days after second shot

      3. Cardiac imaging in COVID-19

      Transthoracic echocardiography is the first imaging technique used in the diagnostic work-up [
      • Beitzke D.
      • Salgado R.
      • Francone M.
      • Kreitner K.F.
      • Natale L.
      • Bremerich J.
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      Cardiac imaging procedures and the COVID-19 pandemic: recommendations of the european Society of Cardiovascular Radiology (ESCR).
      ] of COVID-19 patients with suspected cardiovascular involvement providing information directly at bedside.
      Bonnemain et al. [
      • Bonnemain J.
      • Ltaief Z.
      • Liaudet L.
      The right ventricle in COVID-19.
      ] reviewed 151 articles about echocardiogram in COVID-19 patients and found right ventricle (RV) alteration as the most common finding, with RV dilation in up to 49% of patients and RV systolic dysfunction in up to 40%. RV alterations resulted correlated to the severity of lung involvement and to pulmonary hypertension [
      • Bonnemain J.
      • Ltaief Z.
      • Liaudet L.
      The right ventricle in COVID-19.
      ] and were associated to increased level of biomarkers of cardiac injury (troponin and NT-pro-BNP), inflammation (C-reactive protein), and pro-thrombotic status (D-dimer). In a prospective multicenter study including 1216 hospitalized acute COVID-19 patients, 55% of them had abnormal echocardiograms, however the underlying cause of alteration was not identified in most cases [
      • Dweck M.R.
      • Bularga A.
      • Hahn R.T.
      • Bing R.
      • Lee K.K.
      • Chapman A.R.
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      Global evaluation of echocardiography in patients with COVID-19.
      ]. Therefore, echocardiography plays a crucial role in selecting patients for advanced cardiac imaging, reducing unnecessary exams and diagnostic delays. The diagnostic flow-chart varied according to national and international guidelines and institution according to local expertise and resource availability [
      • Beitzke D.
      • Salgado R.
      • Francone M.
      • Kreitner K.F.
      • Natale L.
      • Bremerich J.
      • et al.
      Cardiac imaging procedures and the COVID-19 pandemic: recommendations of the european Society of Cardiovascular Radiology (ESCR).
      ]. The flow-chart we used is reported in Fig. 1.
      However, CT is the imaging modality of choice for the evaluation of cardiothoracic complications related to COVID-19 [
      • Hothi S.S.
      • Jiang J.
      • Steeds R.P.
      • Moody W.E.
      Utility of non-invasive cardiac imaging assessment in coronavirus disease 2019.
      ], providing useful information in a short time also in unstable patients, while reducing exposure time of patients and personnel [
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      • Mannelli L.
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      Non-invasive coronary imaging in patients with COVID-19: a narrative review.
      ,
      • Skulstad H.
      • Cosyns B.
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      • Galderisi M.
      • di Salvo G.
      • Donal E.
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      COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel.
      ].
      In a recent position paper, Cosyns et al. [
      • Cosyns B.
      • Lochy S.
      • Luchian M.L.
      • Gimelli A.
      • Pontone G.
      • Allard S.D.
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      The role of cardiovascular imaging for myocardial injury in hospitalized COVID-19 patients.
      ] stated that the pre-test probability of coronary artery disease may represents the primary guidance in the diagnostic work-up of COVID-19 patients with myocardial injury and that coronary computed tomography angiography (CCTA) should be preferred for patients with low-to-intermediate risk of acute coronary syndrome (ACS) because of its high negative predictive value. However, Stefanini et al. found out that 39% of COVID-19 patients with STEMI had negative invasive coronary angiography (ICA) probably for the higher prevalence of type-2 MI in patients during the acute phase of COVID-19. These data further supported the use of CCTA in COVID-19 patients [
      • Stefanini G.G.
      • Montorfano M.
      • Trabattoni D.
      • Andreini D.
      • Ferrante G.
      • Ancona M.
      • et al.
      ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes.
      ], also having the advantage to simultaneously rule-out coronary artery disease (CAD) and pulmonary embolism (PE) using a triple rule-out scanning protocol [
      • Palmisano A.
      • Vignale D.
      • Tadic M.
      • Moroni F.
      • de Stefano D.
      • Gatti M.
      • et al.
      Myocardial late contrast enhancement CT in troponin-positive acute chest pain syndrome.
      ,
      • Pontone G.
      • Baggiano A.
      • Conte E.
      • Teruzzi G.
      • Cosentino N.
      • Campodonico J.
      • et al.
      “Quadruple rule-out” with computed tomography in a COVID-19 patient with equivocal acute coronary syndrome presentation.
      ] and to refine risk stratification of COVID-19 patients with the quantification of coronary artery calcium score (CAC) [
      • Cereda A.
      • Toselli M.
      • Palmisano A.
      • Vignale D.
      • Khokhar A.
      • Campo G.
      • et al.
      Coronary calcium score as a predictor of outcomes in the hypertensive Covid-19 population: results from the italian (S) Core-Covid-19 registry.
      ,
      • Scoccia A.
      • Gallone G.
      • Cereda A.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • et al.
      Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.
      ,
      • Giannini F.
      • Toselli M.
      • Palmisano A.
      • Cereda A.
      • Vignale D.
      • Leone R.
      • et al.
      Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.
      ,
      • Cereda A.
      • Toselli M.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • Nicoletti V.
      • et al.
      The hidden interplay between sex and COVID-19 mortality: the role of cardiovascular calcification.
      ,
      • Dillinger J.G.
      • Benmessaoud F.A.
      • Pezel T.
      • Voicu S.
      • Sideris G.
      • Chergui N.
      • et al.
      Coronary artery calcification and complications in patients with COVID-19.
      ,
      • Koch V.
      • Gruenewald L.D.
      • Albrecht M.H.
      • Eichler K.
      • Gruber-Rouh T.
      • Yel I.
      • et al.
      Lung opacity and coronary artery calcium score: a combined tool for risk stratification and outcome prediction in COVID-19 patients.
      ].
      CT assessment offers the additional advantage of COVID-19 pneumonia severity assessment [
      • Esposito A.
      • Palmisano A.
      • Cao R.
      • Rancoita P.
      • Landoni G.
      • Grippaldi D.
      • et al.
      Quantitative assessment of lung involvement on chest CT at admission: impact on hypoxia and outcome in COVID-19 patients.
      ] and to reveal subclinical CV risk factors such as liver steatosis [
      • Boyce C.J.
      • Pickhardt P.J.
      • Kim D.H.
      • Taylor A.J.
      • Winter T.C.
      • Bruce R.J.
      • et al.
      Hepatic steatosis (fatty liver disease) in asymptomatic adults identified by unenhanced low-dose CT.
      ], myosteatosis [
      • Derstine B.A.
      • Holcombe S.A.
      • Ross B.E.
      • Wang N.C.
      • Su G.L.
      • Wang S.C.
      Skeletal muscle cutoff values for sarcopenia diagnosis using T10 to L5 measurements in a healthy US population.
      ], and epicardial fat volume and attenuation [
      • Conte C.
      • Esposito A.
      • de Lorenzo R.
      • di Filippo L.
      • Palmisano A.
      • Vignale D.
      • et al.
      Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: a post-hoc analysis of a prospective cohort study.
      ,
      • Palmisano A.
      • Esposito A.
      • Gnasso C.
      • Nicoletti V.
      • Leone R.
      • de Lorenzo R.
      Myosteatosis significantly predicts persistent dyspnea and mobility problems in COVID-19 survivors.
      ]. Finally, CT may offer the opportunity to characterize myocardial scar and extracellular volume fraction (ECV) with the addition of a late contrast enhancement scan [
      • Palmisano A.
      • Vignale D.
      • Tadic M.
      • Moroni F.
      • de Stefano D.
      • Gatti M.
      • et al.
      Myocardial late contrast enhancement CT in troponin-positive acute chest pain syndrome.
      ,
      • Pontone G.
      • Baggiano A.
      • Conte E.
      • Teruzzi G.
      • Cosentino N.
      • Campodonico J.
      • et al.
      “Quadruple rule-out” with computed tomography in a COVID-19 patient with equivocal acute coronary syndrome presentation.
      ,
      • Esposito A.
      • Palmisano A.
      • Barbera M.
      • Vignale D.
      • Benedetti G.
      • Spoladore R.
      • et al.
      Cardiac computed tomography in troponin-positive chest pain: sometimes the answer lies in the late iodine enhancement or extracellular volume fraction map.
      ,
      • Scully P.R.
      • Bastarrika G.
      • Moon J.C.
      • Treibel T.A.
      Myocardial extracellular volume quantification by cardiovascular magnetic resonance and computed tomography.
      ]. This may be particularly useful and effective especially in the emergency setting [
      • Palmisano A.
      • Vignale D.
      • Tadic M.
      • Moroni F.
      • de Stefano D.
      • Gatti M.
      • et al.
      Myocardial late contrast enhancement CT in troponin-positive acute chest pain syndrome.
      ], providing a full range of diagnosis with a single examination requiring few minutes, without the need of CMR [
      • Pontone G.
      • Baggiano A.
      • Conte E.
      • Teruzzi G.
      • Cosentino N.
      • Campodonico J.
      • et al.
      “Quadruple rule-out” with computed tomography in a COVID-19 patient with equivocal acute coronary syndrome presentation.
      ] (Fig. 2).
      Fig. 2
      Fig. 2The spectrum of CT potentialities in the setting of COVID-19.
      Therefore, a comprehensive CT acquisition protocol in suspected acute myocardial damage should include: i) precontrast CT scan for the assessment of pneumonia severity and calcium score; ii) an angiographic triple rule out scan for exclusion of CAD, PE and acute aortic injury, acquired with retrospective gating in order to obtain multiphase reconstruction (0–90% of R-R interval) for the assessment of wall motion alteration; iii) a late contrast enhancement scan acquired 5 to 10 min after contrast administration for the assessment of myocardial scars and for ECV quantification [
      • Palmisano A.
      • Vignale D.
      • Tadic M.
      • Moroni F.
      • de Stefano D.
      • Gatti M.
      • et al.
      Myocardial late contrast enhancement CT in TroponinPositive acute chest pain syndrome.
      ,
      • Palmisano A.
      • Vignale D.
      • Benedetti G.
      • del Maschio A.
      • de Cobelli F.
      • Esposito A.
      Late iodine enhancement cardiac computed tomography for detection of myocardial scars: impact of experience in the clinical practice.
      ,
      • Esposito A.
      • Palmisano A.
      • Barbera M.
      • Vignale D.
      • Benedetti G.
      • Spoladore R.
      • et al.
      Cardiac computed tomography in troponin-positive chest pain: sometimes the answer lies in the late iodine enhancement or extracellular volume fraction map.
      ,
      • Esposito A.
      • Palmisano A.
      • Antunes S.
      • Colantoni C.
      • Rancoita P.M.V.
      • Vignale D.
      • et al.
      Assessment of remote myocardium heterogeneity in patients with ventricular tachycardia using texture analysis of late iodine enhancement (LIE) cardiac computed tomography (cCT) images.
      ,
      • Palmisano A.
      • Vignale D.
      • Peretto G.
      • Busnardo E.
      • Calcagno C.
      • Campochiaro C.
      • et al.
      Hybrid FDG-PET/MR or FDG-PET/CT to detect disease activity in patients with persisting arrhythmias after myocarditis.
      ] Table 2.
      Table 2CT protocol in suspected COVID-19 related cardiovascular injury.
      CT scanIndicationParametersInformationSeverity cut-off value
      Non-contrast scan-Pneumonia assessment









      -Coronary artery calcium
      Standard

      Large FOV for pneumonia evaluation





      Cardiac FOV

      prospective ECG-gated

      scan at 75% of the R-R interval
      - Pneumonia severity

      - Coronary artery calcium

      - Total thoracic calcium

      - Main pulmonary artery diameter/Hypertension

      - Epicardial adipose tissue attenuation

      - Liver steatosis

      - Myosteatosis
      >50% lung volume
      Cut-off values associated with increased mortality in COVID-19 setting.
      • Esposito A.
      • Palmisano A.
      • Cao R.
      • Rancoita P.
      • Landoni G.
      • Grippaldi D.
      • et al.
      Quantitative assessment of lung involvement on chest CT at admission: impact on hypoxia and outcome in COVID-19 patients.
      ,
      • Esposito A.
      • Palmisano A.
      • Toselli M.
      • Vignale D.
      • Cereda A.
      • Rancoita P.M.V.
      • et al.
      Chest CT-derived pulmonary artery enlargement at the admission predicts overall survival in COVID-19 patients: insight from 1461 consecutive patients in Italy.


      >400 AU
      Cut-off values associated with increased mortality in COVID-19 setting.
      • Dillinger J.G.
      • Benmessaoud F.A.
      • Pezel T.
      • Voicu S.
      • Sideris G.
      • Chergui N.
      • et al.
      Coronary artery calcification and complications in patients with COVID-19.


      ≥1068 cc
      Cut-off values associated with increased mortality in COVID-19 setting.
      • Giannini F.
      • Toselli M.
      • Palmisano A.
      • Cereda A.
      • Vignale D.
      • Leone R.
      • et al.
      Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.


      ≥31 mm
      Cut-off values associated with increased mortality in COVID-19 setting.
      • Esposito A.
      • Palmisano A.
      • Toselli M.
      • Vignale D.
      • Cereda A.
      • Rancoita P.M.V.
      • et al.
      Chest CT-derived pulmonary artery enlargement at the admission predicts overall survival in COVID-19 patients: insight from 1461 consecutive patients in Italy.






      ≥−96.3 HU
      Cut-off values associated with increased mortality in COVID-19 setting.
      • Conte C.
      • Esposito A.
      • de Lorenzo R.
      • di Filippo L.
      • Palmisano A.
      • Vignale D.
      • et al.
      Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: a post-hoc analysis of a prospective cohort study.


      ≤−40 HU
      Cut-off values derived from population studies or other clinical settings.
      • Boyce C.J.
      • Pickhardt P.J.
      • Kim D.H.
      • Taylor A.J.
      • Winter T.C.
      • Bruce R.J.
      • et al.
      Hepatic steatosis (fatty liver disease) in asymptomatic adults identified by unenhanced low-dose CT.


      <34.3 (F) and <38.5 (M) HU
      Cut-off values derived from population studies or other clinical settings.
      • Derstine B.A.
      • Holcombe S.A.
      • Ross B.E.
      • Wang N.C.
      • Su G.L.
      • Wang S.C.
      Skeletal muscle cutoff values for sarcopenia diagnosis using T10 to L5 measurements in a healthy US population.
      Angiographic scan-Pulmonary embolism









      - CAD







































      -Triple-rule out
      Chest FOV,

      Single energy or DECT, standard parameters





      Cardiac FOV. Retrospective gating with automatic tube current modulation (100% in 60–80% or 40–80% for HR <65 bpm or >65 bpm with 4% current in other phases).

      80 kVp for BMI < 20; 100 kVp for BMI ≥ 20 and <30; 120 kVp for BMI ≥ 30







      Same for CAD protocol but chest FOV
      - Pulmonary artery embolism

      - Oligoemia

      - RV dysfunction







      - Obstructive CAD

      - Wall motion abnormalities





































      - Obstructive CAD

      - Pulmonary artery embolism

      - Acute aortic injury
      Presence

      Presence

      RV/LV diameter ratio > 0.9
      Cut-off values associated with increased mortality in COVID-19 setting.
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.


      IVC reflux
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.




      ≥50%
      • Cury R.C.
      • Abbara S.
      • Achenbach S.
      • Agatston A.
      • Berman D.S.
      • Budoff M.J.
      CAD-RADS(TM) coronary artery disease - reporting and data system. An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Radiology (ACR) and the North American Society for Cardiovascular Imaging (NASCI). Endorsed by the American College of Cardiology.


      presence





































      ≥50%
      Cut-off values derived from population studies or other clinical settings.
      • Cury R.C.
      • Abbara S.
      • Achenbach S.
      • Agatston A.
      • Berman D.S.
      • Budoff M.J.
      CAD-RADS(TM) coronary artery disease - reporting and data system. An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Radiology (ACR) and the North American Society for Cardiovascular Imaging (NASCI). Endorsed by the American College of Cardiology.


      Presence

      Presence
      Late contrast enhancementMyocardial tissue characterizationCardiac FOV.

      Single energy: 80KV, p prospective ECG-gating at 75% of the R-R interval

      5–10 minute post contrast
      Myocardial scar

      Extracellular volume fraction
      Presence

      ≥27%
      Cut-off values derived from population studies or other clinical settings.
      • Scully P.R.
      • Bastarrika G.
      • Moon J.C.
      • Treibel T.A.
      Myocardial extracellular volume quantification by cardiovascular magnetic resonance and computed tomography.
      ,
      • Palmisano A.
      • Vignale D.
      • Tadic M.
      • Moroni F.
      • de Stefano D.
      • Gatti M.
      • et al.
      Myocardial late contrast enhancement CT in TroponinPositive acute chest pain syndrome.
      Abbreviation: CAD: coronary artery disease, FOV: field-of-view; LV: left ventricle, RV: right ventricle, IVC: inferior vena cava.
      a Cut-off values associated with increased mortality in COVID-19 setting.
      b Cut-off values derived from population studies or other clinical settings.
      Late contrast enhancement scan needs higher contrast volume compared to standard CCTA, with a total iodine dose of 600 mg per kilogram of body weight [
      • Palmisano A.
      • Vignale D.
      • Benedetti G.
      • del Maschio A.
      • de Cobelli F.
      • Esposito A.
      Late iodine enhancement cardiac computed tomography for detection of myocardial scars: impact of experience in the clinical practice.
      ,
      • Esposito A.
      • Palmisano A.
      • Antunes S.
      • Maccabelli G.
      • Colantoni C.
      • Rancoita P.M.V.
      • et al.
      Cardiac CT with delayed enhancement in the characterization of ventricular tachycardia structural substrate: relationship between CT-segmented scar and electro-anatomic mapping.
      ].
      However, tissue characterization in CT has still limited application worldwide mainly for limited contrast-to-noise ratio, requiring experience for scar detection [
      • Palmisano A.
      • Vignale D.
      • Benedetti G.
      • del Maschio A.
      • de Cobelli F.
      • Esposito A.
      Late iodine enhancement cardiac computed tomography for detection of myocardial scars: impact of experience in the clinical practice.
      ], hence CMR remains the gold standard for non-invasive characterization of myocardial tissue. CMR should be considered in COVID-19 patients with high pretest probability for acute myocardial injury, in particular in those with chest pain and unobstructed coronary arteries to differentiate between acute myocarditis, Takotsubo cardiomyopathy, and MINOCA [
      • Beitzke D.
      • Salgado R.
      • Francone M.
      • Kreitner K.F.
      • Natale L.
      • Bremerich J.
      • et al.
      Cardiac imaging procedures and the COVID-19 pandemic: recommendations of the european Society of Cardiovascular Radiology (ESCR).
      ,
      • Collet J.P.
      • Thiele H.
      • Barbato E.
      • Bauersachs J.
      • Dendale P.
      • Edvardsen T.
      • et al.
      2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.
      ,
      • Skulstad H.
      • Cosyns B.
      • Popescu B.A.
      • Galderisi M.
      • di Salvo G.
      • Donal E.
      • et al.
      COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel.
      ], avoiding diagnostic and treatment delay.
      Several authors [
      • Beitzke D.
      • Salgado R.
      • Francone M.
      • Kreitner K.F.
      • Natale L.
      • Bremerich J.
      • et al.
      Cardiac imaging procedures and the COVID-19 pandemic: recommendations of the european Society of Cardiovascular Radiology (ESCR).
      ,
      • Skulstad H.
      • Cosyns B.
      • Popescu B.A.
      • Galderisi M.
      • di Salvo G.
      • Donal E.
      • et al.
      COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel.
      ,
      • D’Angelo T.
      • Grigoratos C.
      • Mazziotti S.
      • Bratis K.
      • Pathan F.
      • Blandino A.
      High-throughput gadobutrol-enhanced CMR: a time and dose optimization study.
      ] proposed short CMR protocols to improve resource allocation and to reduce the infection risk (Table 3). A tailored CMR protocol should include cine-sequences for functional assessment, T2-based imaging to evaluate myocardial edema (i.e., T2w-STIR and T2 mapping), and T1-based imaging (i.e., T1 mapping and late gadolinium enhancement evaluation) to evaluate myocardial edema, hyperemia/capillary leak, necrosis, and pre-existing fibrosis. To exclude pulmonary embolism, a 3D pulmonary angiography could be acquired during gadolinium injection [
      • Catapano F.
      • Marchitelli L.
      • Cundari G.
      • Cilia F.
      • Mancuso G.
      • Pambianchi G.
      • et al.
      Role of advanced imaging in COVID-19 cardiovascular complications.
      ], while, to assess lung pathology, a breath hold T2-w sequence can be used [
      • Beitzke D.
      • Salgado R.
      • Francone M.
      • Kreitner K.F.
      • Natale L.
      • Bremerich J.
      • et al.
      Cardiac imaging procedures and the COVID-19 pandemic: recommendations of the european Society of Cardiovascular Radiology (ESCR).
      ] Table 3.
      Table 3Short CMR protocol in suspected COVID-19 cardiac damage.
      TimelineSequencePlanes and coverageFinding
      PrecontrastBlack Blood STIR T2w sequenceEntire ventricle coverageEdema
      T2 mapping3 short axis

      (base, mid, apex)
      Edema
      Native T1 mapping3 short axis

      (base, mid, apex)
      Edema, fibrosis
      Gadolinium injectionFLASH 3D pulmonary angiography3D entire chestPulmonary embolism
      2–5 min post contrastSSFP cineEntire ventricle coverageVolume and function
      10 min post contrastInversion recovery or 3D-PSIREntire ventricle coverageMyocardial scar
      15 min post contrastPost-contrast

      T1 mapping
      3 short axis

      (base, mid, apex)
      Extracellular volume fraction
      OptionalT2wChestPneumonia
      Based on the high rate of myocarditis in patients with COVID-19 myocardial injury, mapping techniques are crucial for the identification of subtle myocardial inflammation according to the updated Lake Louise criteria [
      • Ferreira V.M.
      • Schulz-Menger J.
      • Holmvang G.
      • Kramer C.M.
      • Carbone I.
      • Sechtem U.
      • et al.
      Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations.
      ], while the evaluation of standard CMR criteria are enough for the identification of Takotsubo cardiomyopathy [
      • Eitel I.
      • von Knobelsdorff-Brenkenhoff F.
      • Bernhardt P.
      • Carbone I.
      • Muellerleile K.
      • Aldrovandi A.
      • et al.
      Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy.
      ] and MINOCA [
      • Gatti M.
      • Carisio A.
      • D’Angelo T.
      • Darvizeh F.
      • Dell’Aversana S.
      • Tore D.
      • et al.
      Cardiovascular magnetic resonance in myocardial infarction with non-obstructive coronary arteries patients: a review.
      ] also in COVID-19 setting.
      Main CT and CMR findings according to the stage of disease are reported in Table 4.
      Table 4Main cardiac complication at CT and CMR according to the stage of disease.
      ReferencePatients (n)Age (y); male (%)Follow-up timeCardiovascular symptom or signs (%)Main CT findingsMain CMR findings
      Acute cardiovascular complications
      LV function alterationsKato et al.
      • Kato S.
      • Azuma M.
      • Fukui K.
      • Kodama S.
      • Nakayama N.
      • Kitamura H.
      Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.
      1414NR; NRNRNRMean difference in LVEF between COVID-19 patients and controls = −2.84 (CI, −5.11 to −0.56)
      Takotsubo cardiomyopathyOjha et al.
      • Ojha V.
      • Verma M.
      • Pandey N.N.
      • Mani A.
      • Malhi A.S.
      • Kumar S.
      • et al.
      Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients.
      199NR; 57NRNRTakotsubo cardiomyopathy in 1.5%
      Esposito et al.
      • Esposito A.
      • Palmisano A.
      • Natale L.
      • Ligabue G.
      • Peretto G.
      • Lovato L.
      • et al.
      Cardiac magnetic resonance characterization of myocarditis-like acute cardiac syndrome in COVID-19.
      1052 ± 6; 203 (IQR, 2–4) days after symptoms onsetChest pain (80%)

      Dyspnea (20%)
      Takotsubo cardiomyopathy in 20%
      Myocardial edemaOjha et al.
      • Ojha V.
      • Verma M.
      • Pandey N.N.
      • Mani A.
      • Malhi A.S.
      • Kumar S.
      • et al.
      Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients.
      199NR; 57NRNRMyocardial edema in 63% of patients by increased T2 mapping values
      Kato et al.
      • Kato S.
      • Azuma M.
      • Fukui K.
      • Kodama S.
      • Nakayama N.
      • Kitamura H.
      Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.
      1414NR; NRNRNRMyocardial edema in 39.5% of patients by increased T2 mapping/T2w images
      Myocarditis or pericarditisPontone et al.
      • Pontone G.
      • Baggiano A.
      • Conte E.
      • Teruzzi G.
      • Cosentino N.
      • Campodonico J.
      • et al.
      “Quadruple rule-out” with computed tomography in a COVID-19 patient with equivocal acute coronary syndrome presentation.
      159; 11 day after COVID-19 disease diagnosisDyspnea and chest painSubepicardial (non-ischemic) late iodine enhancement (LIE) in the basal-mid inferolateral wall of the left ventricle
      Peretto et al.
      • Peretto G.
      • Villatore A.
      • Rizzo S.
      • Esposito A.
      • de Luca G.
      • Palmisano A.
      • et al.
      The Spectrum of COVID-19-associated myocarditis: a patient-tailored multidisciplinary approach.
      751 ± 9; 570–12 days after COVID-19 disease diagnosisHeart-failure presentation (57%);

      ACS-like presentation (43%)
      Mid-basal septal or infero-lateral active myocarditis. In only one patient (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome
      Esposito et al.
      • Esposito A.
      • Palmisano A.
      • Natale L.
      • Ligabue G.
      • Peretto G.
      • Lovato L.
      • et al.
      Cardiac magnetic resonance characterization of myocarditis-like acute cardiac syndrome in COVID-19.
      1052 ± 6; 203 (IQR, 2–4) days after symptoms onsetChest pain (80%)

      Dyspnea (20%)
      Acute myocarditis in 80%.

      LGE was positive in only 3 patients with thin and shadowed sub-epicardial striae
      Ojha et al. (66)199NR; 57NRNRMyocarditis in 40.2% of population in inferior/infero-lateral basal segments of the LV
      Kato et al.
      • Kato S.
      • Azuma M.
      • Fukui K.
      • Kodama S.
      • Nakayama N.
      • Kitamura H.
      Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.
      1414NR; NRNRNRPrevalence of myocarditis in 17.6%

      Pericardial LGE enhancement in 11.9%
      Myocardial ischemic alterationsOjha et al.
      • Ojha V.
      • Verma M.
      • Pandey N.N.
      • Mani A.
      • Malhi A.S.
      • Kumar S.
      • et al.
      Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients.
      199NR; 57NRNRIschemic pattern of LGE (subendocardial in coronary distribution) in 10%
      Pulmonary embolismLoffi et al.
      • Loffi M.
      • Regazzoni V.
      • Toselli M.
      • Cereda A.
      • Palmisano A.
      • Vignale D.
      Incidence and characterization of acute pulmonary embolism in patients with SARS-CoV-2 pneumonia: a multicenter Italian experience.
      33367 (IQR, 57–67); 67Examinations performed at admission in EDInadequate clinical response to high oxygen flow therapy; high D-dimer levels; signs of right ventricle dysfunction at echocardiographyPE in 33% of patients with bilateral distribution 49% of patients. 71% of the patients showed PE mainly located in lung consolidation areas
      Grillet et al.
      • Grillet F.
      • Behr J.
      • Calame P.
      • Aubry S.
      • Delabrousse E.
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      10066 ± 13; 709 ± 5 days after symptoms onset39% recovered in ICUPE in 23% of patients;

      PE more frequent in ICU patients (74% vs 29%)
      Pulmonary artery hypertensionEsposito et al.
      • Esposito A.
      • Palmisano A.
      • Toselli M.
      • Vignale D.
      • Cereda A.
      • Rancoita P.M.V.
      • et al.
      Chest CT-derived pulmonary artery enlargement at the admission predicts overall survival in COVID-19 patients: insight from 1461 consecutive patients in Italy.
      76169.25 (IQR, 58.01–76.87); 71Examinations performed at admission in EDNREnlarged main pulmonary artery diameter (≥ 31 mm) is a predictor of mortality
      RV alterationsPlanek et al.
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.
      18958 (IQR, 46.75–73.25); 56NRNRSeptal flattening and IVC reflux are associated with higher risk of 60-day mortality and MACE
      Vasculitis and epicardial adipose tissue inflammationFeuchtner et al.
      • Feuchtner G.M.
      • Barbieri F.
      • Luger A.
      • Skalla E.
      • Kountchev J.
      • Widmann G.
      • et al.
      Myocardial injury in COVID-19: the role of coronary computed tomography angiography (CTA).
      148; 01 day after COVID-19 disease diagnosisChest painIrregular coronary walls thickening and perivascular edema, defined as a perivascular fat attenuation index of >−70HU
      Conte et al.
      • Conte C.
      • Esposito A.
      • de Lorenzo R.
      • di Filippo L.
      • Palmisano A.
      • Vignale D.
      • et al.
      Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: a post-hoc analysis of a prospective cohort study.
      19260 (IQR 53–70); 543 (1.0; 6.5) days after hospital admission59% presented ARDSMedian epicardial adipose tissue was 95.8 (99.1; 93.0) HU and correlated with systemic inflammation
      Post-acute cardiovascular complications
      RV dysfunctionCassar et al.
      • Cassar M.P.
      • Tunnicliffe E.M.
      • Petousi N.
      • Lewandowski A.J.
      • Xie C.
      • Mahmod M.
      Symptom persistence despite improvement in cardiopulmonary health - insights from longitudinal CMR, CPET and lung function testing post-COVID-19.
      5855 ± 13; 58.62–3 months and

      6 months after COVID-19 infection
      Shortness of breath (43.5%)

      Palpitations (28.3%)

      Chest pain (17.4%)
      Reduction of RV function compared to controls at 2–3 months follow-up
      Clark et al.
      • Clark D.E.
      • Dendy J.M.
      • Li D.L.
      • Crum K.
      • Dixon D.
      • George-Durrett K.
      • et al.
      Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case-control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
      1926.5 (23−31); 98139 days after COVID-19 infectionAbnormal ECG or transthoracic echocardiogram (48%)

      Chest pain (42%)

      Palpitations (10%)
      RVEF reduction compared to controls
      Tanacli et al.
      • Tanacli R.
      • Doeblin P.
      • Götze C.
      • Zieschang V.
      • Faragli A.
      • Stehning C.
      COVID-19 vs. classical myocarditis associated myocardial injury evaluated by cardiac magnetic resonance and endomyocardial biopsy.
      3248 ± 14; 5995 ± 59 days after COVID-19 infectionFatigue (28%)

      Arrhythmia (28%)
      RV dysfunction in 28% with RV stroke volume significantly lower compared to controls
      LV dysfunctionKotecha et al.
      • Kotecha T.
      • Knight D.S.
      • Razvi Y.
      • Kumar K.
      • Vimalesvaran K.
      • Thornton G.
      • et al.
      Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.
      14864 ± 12; 70Median 68 days after COVID-19 infectionNRLV dysfunction in 11%
      Myocardial edemaBreitbart et al.
      • Breitbart P.
      • Koch A.
      • Schmidt M.
      • Magedanz A.
      • Lindhoff-Last E.
      • Voigtländer T.
      • et al.
      Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.
      5645.7 ± 12.2; 46.470.7 ± 66 days after COVID-19 infectionFatigue (75.0%)

      Chest pain (71.4%)

      Shortness of breath (66.1%)
      Diffuse myocardial edema in 5.3% of patients by increased T2 mapping values
      Huang et al.
      • Huang L.
      • Zhao P.
      • Tang D.
      • Zhu T.
      • Han R.
      • Zhan C.
      • et al.
      Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.
      2638 (32–45); 3847 (36–58) days after COVID-19 infectionChest distress (23%)

      Palpitations (88%)

      Chest pain (12%)
      Myocardial edema in 54% of patients, involving 33% of LV segments by increased T2 signal
      Tanacli et al.
      • Tanacli R.
      • Doeblin P.
      • Götze C.
      • Zieschang V.
      • Faragli A.
      • Stehning C.
      COVID-19 vs. classical myocarditis associated myocardial injury evaluated by cardiac magnetic resonance and endomyocardial biopsy.
      3248 ± 14; 5995 ± 59 days after COVID-19 infectionFatigue (28%)

      Arrhythmia (28%)
      Diffuse myocardial edema in 13% of patients by increased T2 mapping values
      Myocarditis or pericarditisBreitbart et al.
      • Breitbart P.
      • Koch A.
      • Schmidt M.
      • Magedanz A.
      • Lindhoff-Last E.
      • Voigtländer T.
      • et al.
      Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.
      5645.7 ± 12.2; 46.470.7 ± 66 days after COVID-19 infectionFatigue (75.0%)

      Chest pain (71.4%)

      Shortness of breath (66.1%)
      Active myocarditis in 1.8%

      Non-ischemic subepicardial LGE in 10.7%
      Cassar et al.
      • Cassar M.P.
      • Tunnicliffe E.M.
      • Petousi N.
      • Lewandowski A.J.
      • Xie C.
      • Mahmod M.
      Symptom persistence despite improvement in cardiopulmonary health - insights from longitudinal CMR, CPET and lung function testing post-COVID-19.
      5855 ± 13; 58.62–3 months and 6 months after COVID-19 diseaseShortness of breath (43.5%)

      Palpitations (28.3%)

      Chest pain (17.4%)
      Non-ischemic subepicardial LGE in 10.7%
      Clark et al.
      • Clark D.E.
      • Dendy J.M.
      • Li D.L.
      • Crum K.
      • Dixon D.
      • George-Durrett K.
      • et al.
      Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case-control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
      1926.5 (23–31); 98Median 139 days after COVID-19 infectionAbnormal ECG or transthoracic echocardiogram (48%)

      Chest pain (42%)

      Palpitations (10%)
      Active myocarditis in 1 patient (2%)

      Non-ischemic subepicardial LGE in 8%
      Huang et al.
      • Huang L.
      • Zhao P.
      • Tang D.
      • Zhu T.
      • Han R.
      • Zhan C.
      • et al.
      Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.
      2638 (32–45); 3847 (36–58) days after COVID-19 infectionChest distress (23%)

      Palpitations (88%)

      Chest pain (12%)
      Non-ischemic subepicardial LGE in 31%
      Kotecha et al.
      • Kotecha T.
      • Knight D.S.
      • Razvi Y.
      • Kumar K.
      • Vimalesvaran K.
      • Thornton G.
      • et al.
      Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.
      14864 ± 12; 70Median 68 days after COVID-19 infectionNRActive myocarditis in 8%

      Non-ischemic subepicardial LGE in 26%
      Tanacli et al.
      • Tanacli R.
      • Doeblin P.
      • Götze C.
      • Zieschang V.
      • Faragli A.
      • Stehning C.
      COVID-19 vs. classical myocarditis associated myocardial injury evaluated by cardiac magnetic resonance and endomyocardial biopsy.
      3248 ± 14; 5995 ± 59 days after COVID-19 infectionFatigue (28%)

      Arrhythmia (28%)
      Active myocarditis in 9%

      Pericarditis in 25%

      Non-ischemic subepicardial LGE in 25%
      Myocardial ischemic alterationsKotecha et al.
      • Kotecha T.
      • Knight D.S.
      • Razvi Y.
      • Kumar K.
      • Vimalesvaran K.
      • Thornton G.
      • et al.
      Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.
      14864 ± 12; 70Median 68 days after COVID-19 infectionNRIschemic LGE in 23%
      Post-vaccine complications
      Myocarditis or pericarditisFronza et al.
      • Fronza M.
      • Thavendiranathan P.
      • Chan V.
      • Karur G.R.
      • Udell J.A.
      • Wald R.M.
      • et al.
      Myocardial injury pattern at MRI in COVID-19 vaccine-associated myocarditis.
      2131 ± 14; 8133 (25–41) days after COVID-19 vaccinationChest pain (100%) 3 (IQR, 1–7) days after 2nd dose (81%) or first dose (19%) of COVID-19 mRNA vaccinesNon-ischemic sub-epicardial LGE in 81% of patients; hyperintense signal on T2-weighted imaging in 79%
      Ammirati et al.
      • Ammirati E.
      • Cavalotti C.
      • Milazzo A.
      • Pedrotti P.
      • Soriano F.
      • Schroeder J.W.
      • et al.
      Temporal relation between second dose BNT162b2 mRNA Covid-19 vaccine and cardiac involvement in a patient with previous SARS-COV-2 infection.
      156; 13 days after 2nd dose of COVID-19 BNT162b2 mRNA vaccineChest painNon-ischemic subepicardial LGE involving the basal and apical segments of the infero-lateral wall, colocalized with signs suggestive for edema on T2 weighted images
      D'Angelo et al.
      • D’Angelo T.
      • Cattafi A.
      • Carerj M.L.
      • Booz C.
      • Ascenti G.
      • Cicero G.
      • et al.
      Myocarditis after SARS-CoV-2 vaccination: a vaccine-induced Reaction?.
      130; 13 days after 2nd dose of COVID-19 BNT162b2 mRNA vaccineDyspnea and chest painNon-ischemic subepicardial LGE and increased myocardial and pericardial signal intensity on T2-weighted images
      Abu Mouch et al.
      • Abu Mouch S.
      • Roguin A.
      • Hellou E.
      • Ishai A.
      • Shoshan U.
      • Mahamid L.
      • et al.
      Myocarditis following COVID-19 mRNA vaccination.
      622; 124–72 h (83%) or 16 days (17%) after 2nd dose of COVID-19 mRNA vaccinesChest painNon-ischemic subepicardial LGE and increased myocardial signal intensity on T2-weighted images
      RV: right ventricle; LV: left ventricle; IQR: interquartile range; CI: confidence interval EF: ejection fraction; LGE: late gadolinium enhancement; MACE: major adverse cardiovascular events; IVC: inferior vena cava; ED: emergency department; NR: not reported.

      4. Acute cardiovascular damage: the role of CT

      Right ventricle dysfunction due to pulmonary embolism or hypertension is the most frequent alteration occurring in the acute setting [
      • Bonnemain J.
      • Ltaief Z.
      • Liaudet L.
      The right ventricle in COVID-19.
      ] and CT is indicated to rule-out PE when D-dimer levels are significantly elevated. In COVID-19 patients, PE was found to affect up to 30% of hospitalized patients and to involve vessels mainly located in areas of parenchymal consolidation [
      • Loffi M.
      • Regazzoni V.
      • Toselli M.
      • Cereda A.
      • Palmisano A.
      • Vignale D.
      Incidence and characterization of acute pulmonary embolism in patients with SARS-CoV-2 pneumonia: a multicenter Italian experience.
      ]. Additionally, vessel enlargement within or outside pulmonary opacities, dilated distal subsegmental vessels touching pleura or fissures, and the mosaic attenuation pattern were reported to be probably related to vascular inflammation, endothelial damage, micro-thrombosis, and dysfunctional vasoregulation [
      • Grillet F.
      • Behr J.
      • Calame P.
      • Aubry S.
      • Delabrousse E.
      Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography.
      ].
      Inflammatory thrombogenic vasculopathy leads to increased pulmonary peripheral resistance and pulmonary hypertension. Enlarged pulmonary artery on CT scan is a biomarker of pulmonary hypertension, and a main pulmonary artery diameter ≥ 31 mm was found to be an independent predictor of COVID-19 outcome [
      • Esposito A.
      • Palmisano A.
      • Toselli M.
      • Vignale D.
      • Cereda A.
      • Rancoita P.M.V.
      • et al.
      Chest CT-derived pulmonary artery enlargement at the admission predicts overall survival in COVID-19 patients: insight from 1461 consecutive patients in Italy.
      ]. This measurement would be highly reliable compared to the ratio between main pulmonary artery diameter (PA) to aorta calliper (Ao) for the risk of false negative results due to enlarged ascending aorta. The extraction of both these measurements does not require administration of contrast agent and can be obtained from standard non-contrast chest CT performed for lung assessment. On the other hand, CCTA and triple rule-out CT may show ancillary findings suggestive for right ventricle (RV) dysfunction. RV dysfunction is a common occurrence in COVID-19 pneumonia associated to severity of lung involvement and pulmonary hypertension [
      • Bonnemain J.
      • Ltaief Z.
      • Liaudet L.
      The right ventricle in COVID-19.
      ]. CT findings suggestive of RV dilation/dysfunction are RV strain (RV to LV diameter ratio > 0.9), septal flattening due to increased RV pressure, and contrast agent reflux in the inferior vena cava (IVC) [
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.
      ] (Fig. 2). Planek et al. [
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.
      ] investigated the predictive values of these parameters in a cohort of 245 COVID-19 patients and found that septal flattening and IVC reflux were independently associated with higher risk of 60-day mortality and MACE. All these data are easy to be extracted and should be routinely reported to improve the identification of high-risk patients.
      CCTA is indicated in patients with COVID-19 pneumonia with elevated troponin serum levels and non-ST elevation for the exclusion of an ACS [
      • Skulstad H.
      • Cosyns B.
      • Popescu B.A.
      • Galderisi M.
      • di Salvo G.
      • Donal E.
      • et al.
      COVID-19 pandemic and cardiac imaging: EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel.
      ], reducing useless ICAs. Moreover, because NSTEMI management depends on patients' cardiovascular risk, CCTA can improve risk stratification.
      CCTA can quickly rule out or confirm the presence of clinically significant CAD and identify the features of vulnerable plaques, such as low attenuation (<30 HU), positive remodeling, spotty calcifications [
      • Cury R.C.
      • Abbara S.
      • Achenbach S.
      • Agatston A.
      • Berman D.S.
      • Budoff M.J.
      CAD-RADS(TM) coronary artery disease - reporting and data system. An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Radiology (ACR) and the North American Society for Cardiovascular Imaging (NASCI). Endorsed by the American College of Cardiology.
      ], and napkin-ring sign, becoming an essential tool for selecting patients eligible for invasive imaging [
      • Licu R.-A.
      • Blîndu E.
      • Opincariu D.
      • Benedek T.
      Vulnerable plaques producing an acute coronary syndrome exhibit a different CT phenotype than those that remain silent.
      ] or for identifying coronary wall alteration due to COVID-19 related vasculitis [
      • Feuchtner G.M.
      • Barbieri F.
      • Luger A.
      • Skalla E.
      • Kountchev J.
      • Widmann G.
      • et al.
      Myocardial injury in COVID-19: the role of coronary computed tomography angiography (CTA).
      ].
      Coronary artery calcium score (CAC) is an established biomarker for risk stratification in patients with suspected CAD and its value has been also documented in COVID-19 setting [
      • Dillinger J.G.
      • Benmessaoud F.A.
      • Pezel T.
      • Voicu S.
      • Sideris G.
      • Chergui N.
      • et al.
      Coronary artery calcification and complications in patients with COVID-19.
      ]. Several studies [
      • Scoccia A.
      • Gallone G.
      • Cereda A.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • et al.
      Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.
      ,
      • Giannini F.
      • Toselli M.
      • Palmisano A.
      • Cereda A.
      • Vignale D.
      • Leone R.
      • et al.
      Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.
      ,
      • Cereda A.
      • Toselli M.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • Nicoletti V.
      • et al.
      The hidden interplay between sex and COVID-19 mortality: the role of cardiovascular calcification.
      ,
      • Dillinger J.G.
      • Benmessaoud F.A.
      • Pezel T.
      • Voicu S.
      • Sideris G.
      • Chergui N.
      • et al.
      Coronary artery calcification and complications in patients with COVID-19.
      ] showed that elevated CAC score, specially >400 AU, is associated to poor prognosis. Female patients showed lower mortality compared to men. However, this gender mortality gap disappears in the subgroup of patients with CAC >100 AU [
      • Cereda A.
      • Toselli M.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • Nicoletti V.
      • et al.
      The hidden interplay between sex and COVID-19 mortality: the role of cardiovascular calcification.
      ], suggesting that the differences in outcomes can be at least partially explained by the gender difference in cardiovascular risk profiles and that CAC is a risk modifier. This could be explained by the biological meaning of CAC, being a biomarker of vascular senescence and atherosclerosis, therefore suggestive for higher susceptibility to endothelial damage. Additionally, CAC resulted associated to hypertension [
      • Cereda A.
      • Toselli M.
      • Palmisano A.
      • Vignale D.
      • Khokhar A.
      • Campo G.
      • et al.
      Coronary calcium score as a predictor of outcomes in the hypertensive Covid-19 population: results from the italian (S) Core-Covid-19 registry.
      ], a comorbidity commonly associated to COVID-19 infection and severity. Moreover, CAC revealed subclinical CAD in COVID-19 patients [
      • Scoccia A.
      • Gallone G.
      • Cereda A.
      • Palmisano A.
      • Vignale D.
      • Leone R.
      • et al.
      Impact of clinical and subclinical coronary artery disease as assessed by coronary artery calcium in COVID-19.
      ], improving risk stratification. Furthermore, calcium score of the aortic valve, known marker of aortic stenosis, and of the thoracic aorta, marker of atherosclerosis, resulted prognosticators together with CAC [
      • Giannini F.
      • Toselli M.
      • Palmisano A.
      • Cereda A.
      • Vignale D.
      • Leone R.
      • et al.
      Coronary and total thoracic calcium scores predict mortality and provides pathophysiologic insights in COVID-19 patients.
      ,
      • Planek M.I.C.
      • Ruge M.
      • du Fay de Lavallaz J.M.
      • Kyung S.B.
      • Gomez J.M.D.
      • Suboc T.M.
      Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.
      ].
      Additionally, from the same CT examination, information about epicardial adipose tissue attenuation (EAT) (Fig. 2, Table 2), a marker of inflammation associated to plaque vulnerability [
      • Iacobellis G.
      Epicardial adipose tissue in contemporary cardiology.
      ] and COVID-19 severity [
      • Conte C.
      • Esposito A.
      • de Lorenzo R.
      • di Filippo L.
      • Palmisano A.
      • Vignale D.
      • et al.
      Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: a post-hoc analysis of a prospective cohort study.
      ,
      • Iacobellis G.
      • Secchi F.
      • Capitanio G.
      • Basilico S.
      • Schiaffino S.
      • Boveri S.
      • et al.
      Epicardial fat inflammation in severe COVID-19.
      ], could be extracted.
      EAT attenuation ranges between −45 HU and −195 HU while it is increased in case of inflammation [
      • Iacobellis G.
      Epicardial adipose tissue in contemporary cardiology.
      ]. However, different cut-off values were found in previous studies on COVID-19 patients, probably due to methodological issues (e.g., segmentation method, analysis) and to the limited sample size [
      • Conte C.
      • Esposito A.
      • de Lorenzo R.
      • di Filippo L.
      • Palmisano A.
      • Vignale D.
      • et al.
      Epicardial adipose tissue characteristics, obesity and clinical outcomes in COVID-19: a post-hoc analysis of a prospective cohort study.
      ,
      • Onnis C.
      • Muscogiuri G.
      • Paolo Bassareo P.
      • Cau R.
      • Mannelli L.
      • Cadeddu C.
      Non-invasive coronary imaging in patients with COVID-19: a narrative review.
      ,
      • Iacobellis G.
      • Secchi F.
      • Capitanio G.
      • Basilico S.
      • Schiaffino S.
      • Boveri S.
      • et al.
      Epicardial fat inflammation in severe COVID-19.
      ].
      Vascular evaluation can be combined with the assessment of lung parenchyma, providing information about COVID-19 pneumonia severity and disease stage [
      • Esposito A.
      • Palmisano A.
      • Cao R.
      • Rancoita P.
      • Landoni G.
      • Grippaldi D.
      • et al.
      Quantitative assessment of lung involvement on chest CT at admission: impact on hypoxia and outcome in COVID-19 patients.
      ,
      • Palmisano A.
      • Scotti G.M.
      • Ippolito D.
      • Morelli M.J.
      • Vignale D.
      • Gandola D.
      • et al.
      Chest CT in the emergency department for suspected COVID-19 pneumonia.
      ] and identifying other diagnosis responsible of symptoms and laboratory markers alteration.

      5. Acute cardiovascular damage: the role of CMR

      In May 2020, Sala et al. [
      • Sala S.
      • Peretto G.
      • Gramegna M.
      • Palmisano A.
      • Villatore A.
      • Vignale D.
      • et al.
      Acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with SARS-CoV-2 respiratory infection.
      ] firstly described cardiovascular involvement studied with CMR and endomyocardial biopsy in a 43-year-old woman affected by COVID-19 with severe myocardial edema and reverse Takotsubo motion pattern, diagnosed as acute myocarditis at histology. Initial reports on COVID-19 patients with acute myocardial injury that underwent CMR [
      • Peretto G.
      • Villatore A.
      • Rizzo S.
      • Esposito A.
      • de Luca G.
      • Palmisano A.
      • et al.
      The Spectrum of COVID-19-associated myocarditis: a patient-tailored multidisciplinary approach.
      ,
      • Esposito A.
      • Palmisano A.
      • Natale L.
      • Ligabue G.
      • Peretto G.
      • Lovato L.
      • et al.
      Cardiac magnetic resonance characterization of myocarditis-like acute cardiac syndrome in COVID-19.
      ] showed myocarditis as the most frequent finding, with diffuse myocardial edema and minimal or negligible LGE, followed by Takotsubo cardiomyopathy.
      These initial data were confirmed by Ojha et al. [
      • Ojha V.
      • Verma M.
      • Pandey N.N.
      • Mani A.
      • Malhi A.S.
      • Kumar S.
      • et al.
      Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients.
      ] that firstly conducted a meta-analysis on COVID-19 patients who underwent CMR. The most common diagnosis (40.2%) in a total of 34 studies and 199 patients was myocarditis, while CMR was negative in 21% of cases, a finding partially due to the time gap between symptoms onset and CMR, which reached up to 71 days. The most common findings were increased T1 (73%) and T2 (63%) myocardial mapping values, with LGE being less common (43%). When present, LGE had non-ischemic pattern involving a few segments with subepicardial distribution (81%) in the inferior/infero-lateral basal segments of the left ventricle.
      Kato et al. [
      • Kato S.
      • Azuma M.
      • Fukui K.
      • Kodama S.
      • Nakayama N.
      • Kitamura H.
      Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.
      ] published an updated meta-analysis in 2022 that included 10.462 COVID-19 patients who underwent CMR and found a minimal reduction in left (−2.84%) and right (−2.69%) ventricular ejection fraction in COVID-19 patients compared to controls, with LV LGE abnormalities in 27.5%, pericardial involvement in 11.9%, T1 mapping alteration in 39.5%, T2 mapping or T2-weighted sequences alterations in 38.1%, with a prevalence of myocarditis of 17.6%.
      These confirm that LV involvement is common in COVID-19 patients, CMR is useful in detecting cardiac abnormalities, and myocarditis is the most common finding. It was reported an 18-fold increased risk to develop myocarditis in COVID-19 [
      • Boehmer T.K.
      • Kompaniyets L.
      • Lavery A.M.
      • Hsu J.
      • Ko J.Y.
      • Yusuf H.
      • et al.
      Association between COVID-19 and myocarditis using hospital-based administrative data — United States, March 2020-January 2021.
      ], independently of patients' age, related to multisystem inflammatory syndrome [
      • Boehmer T.K.
      • Kompaniyets L.
      • Lavery A.M.
      • Hsu J.
      • Ko J.Y.
      • Yusuf H.
      • et al.
      Association between COVID-19 and myocarditis using hospital-based administrative data — United States, March 2020-January 2021.
      ].
      Advanced CMR imaging techniques (i.e. mapping techniques) outperform “traditional” techniques such as LGE in COVID-19 patients (Fig. 3) due to the absent or limited necrosis [
      • Tanacli R.
      • Doeblin P.
      • Götze C.
      • Zieschang V.
      • Faragli A.
      • Stehning C.
      COVID-19 vs. classical myocarditis associated myocardial injury evaluated by cardiac magnetic resonance and endomyocardial biopsy.
      ,
      • Haberka M.
      • Rajewska-Tabor J.
      • Wojtowicz D.
      • Jankowska A.
      • Miszalski-Jamka K.
      • Janus M.
      • et al.
      Perimyocardial injury specific for SARS-CoV-2-induced myocarditis in comparison with non-COVID-19 myocarditis: a multicenter CMR study.
      ].
      Fig. 3
      Fig. 3CMR of acute left ventricle dysfunction during COVID-19. A 39-year-old male presented to the emergency department for fever, caught and dyspnea. Nasopharyngeal swab was positive for SARS-CoV 2 infection. Laboratory tests showed increased troponin T level (42,6 ng/mL, normal value <14 ng/mL) and a moderate depression of left ventricle systolic function (ejection fraction <40%) was documented at echocardiography. CMR was performed 8 days later and showed a slight diffuse hypokinesia of left ventricle (LV ejection fraction 51%) with absent focal edema on short-tau inversion recovery images (A) and absent LGE (B), but diffuse alteration of T2 values (B) (56 ms, normal value ≤ 50 ms; C), of native T1 (D) (1084 ms, normal value ≤ 1045 ms E) and of extracellular volume fraction (G) (28%, normal value ≤ 27%; H) with higher values in mid-apical septum and mid-apical anterior wall (arrows in B, D and G). These findings were suggestive for acute myocarditis according to 2018 Lake Louise criteria. Endomyocardial biopsy confirmed these findings, showing diffuse edema and macrophage infiltrate. After 1 month, the patient was discharged with complete resolution of cardiac alteration.

      6. Cardiac post-acute COVID-19 syndrome

      Cardiac post-acute COVID-19 syndrome (cPACS) is generally defined as the persistence of COVID-19 cardiovascular symptoms or signs for >3–4 weeks after recovery, mainly including lasting chest pain, shortness of breath, palpitations, or troponin levels elevation. Mechanisms responsible for persistence of post-acute cardiac damage are still poorly understood. Possible explanations are chronic inflammatory response for persistent viral reservoirs, autoimmune inflammation due to molecular mimicry, and chronic thromboembolic pulmonary hypertension [
      • Raman B.
      • Bluemke D.A.
      • Lüscher T.F.
      • Neubauer S.
      Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus.
      ]. In cPACS patients with suspected myocardial involvement, CMR is highly recommended [
      • Gluckman T.J.
      • Bhave N.M.
      • Allen L.A.
      • Chung E.H.
      • Spatz E.S.
      • Ammirati E.
      • et al.
      ACC expert consensus decision pathway on cardiovascular sequelae of COVID-19 in adults: myocarditis and other myocardial involvement, post-acute sequelae of SARS-CoV-2 infection, and return to play: a report of the american College of Cardiology Solution set Oversight Committee.
      ] to exclude ischemia, preexisting cardiomyopathies and to assess COVID-19 associated myocardial alteration, including myocardial inflammation, scar, and pericardial effusion. Persistent troponin rise was mainly associated to active myocardial inflammation and reported in 14% to 54% of screened cPACS patients [
      • Tanacli R.
      • Doeblin P.
      • Götze C.
      • Zieschang V.
      • Faragli A.
      • Stehning C.
      COVID-19 vs. classical myocarditis associated myocardial injury evaluated by cardiac magnetic resonance and endomyocardial biopsy.
      ,
      • Breitbart P.
      • Koch A.
      • Schmidt M.
      • Magedanz A.
      • Lindhoff-Last E.
      • Voigtländer T.
      • et al.
      Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.
      ,
      • Clark D.E.
      • Dendy J.M.
      • Li D.L.
      • Crum K.
      • Dixon D.
      • George-Durrett K.
      • et al.
      Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case-control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
      ,
      • Huang L.
      • Zhao P.
      • Tang D.
      • Zhu T.
      • Han R.
      • Zhan C.
      • et al.
      Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.
      ] with higher prevalence in patients with severe disease [
      • Huang L.
      • Zhao P.
      • Tang D.
      • Zhu T.
      • Han R.
      • Zhan C.
      • et al.
      Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.
      ]. Edema was in fewer cases associated to LGE (8–31%) [
      • Breitbart P.
      • Koch A.
      • Schmidt M.
      • Magedanz A.
      • Lindhoff-Last E.
      • Voigtländer T.
      • et al.
      Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.
      ,
      • Clark D.E.
      • Dendy J.M.
      • Li D.L.
      • Crum K.
      • Dixon D.
      • George-Durrett K.
      • et al.
      Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case-control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
      ,
      • Huang L.
      • Zhao P.
      • Tang D.
      • Zhu T.
      • Han R.
      • Zhan C.
      • et al.
      Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.
      ,
      • Wang H.
      • Li R.
      • Zhou Z.
      • Jiang H.
      • Yan Z.
      • Tao X.
      Cardiac involvement in COVID-19 patients: mid-term follow up by cardiovascular magnetic resonance.
      ] mainly with non-ischemic pattern involving the infero-lateral wall. Ischemic LGE has been reported less frequently. In a case control study on 90 hospitalized patients with troponin-positive COVID-19 infection [
      • Thornton G.D.
      • Shetye A.
      • Knight D.S.
      • Knott K.
      • Artico J.
      • Kurdi H.
      Myocardial perfusion imaging after severe COVID-19 infection demonstrates regional ischemia rather than global blood flow reduction.
      ], CMR performed 2 months after recovery showed post-myocarditis scar in 34% of cases and post-ischemic scar in 17% of cases. Notably, 36% of patients showed adenosine-induced regional perfusion defects. Similar findings were reported by Kotecha et al. [
      • Kotecha T.
      • Knight D.S.
      • Razvi Y.
      • Kumar K.
      • Vimalesvaran K.
      • Thornton G.
      • et al.
      Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.
      ] on a large series (148) of cPACS patients, with myocarditis-like scar involving three or less myocardial segments as the most frequent finding (26%) (Fig. 4), followed by post ischemic scar (19%); 26% of patients had inducible ischemia. Most patients with inducible ischemia or ischemic scar (66%) had no previous history of coronary artery disease. Despite in cPACS patients LV function seem to be preserved, subclinical alterations were reported in term of strain reduction within 2 and 4 months after moderate to severe COVID-19 infection, respectively [
      • Li X.
      • Wang H.
      • Zhao R.
      • Wang T.
      • Zhu Y.
      • Qian Y.
      • et al.
      Elevated extracellular volume fraction and reduced global longitudinal strains in participants recovered from COVID-19 without clinical cardiac findings.
      ], mainly associated to edema at early stage and LGE in late stage [
      • Li X.
      • Wang H.
      • Zhao R.
      • Wang T.
      • Zhu Y.
      • Qian Y.
      • et al.
      Elevated extracellular volume fraction and reduced global longitudinal strains in participants recovered from COVID-19 without clinical cardiac findings.
      ,
      • Cassar M.P.
      • Tunnicliffe E.M.
      • Petousi N.
      • Lewandowski A.J.
      • Xie C.
      • Mahmod M.
      Symptom persistence despite improvement in cardiopulmonary health - insights from longitudinal CMR, CPET and lung function testing post-COVID-19.
      ]. Notably, right ventricle dysfunction has been reported as a possible indirect effect of COVID-19 related lung disease and improves over time returning to normality 6 months after recovery [
      • Clark D.E.
      • Dendy J.M.
      • Li D.L.
      • Crum K.
      • Dixon D.
      • George-Durrett K.
      • et al.
      Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case-control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
      ,
      • Huang L.
      • Zhao P.
      • Tang D.
      • Zhu T.
      • Han R.
      • Zhan C.
      • et al.
      Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging.
      ,
      • Cassar M.P.
      • Tunnicliffe E.M.
      • Petousi N.
      • Lewandowski A.J.
      • Xie C.
      • Mahmod M.
      Symptom persistence despite improvement in cardiopulmonary health - insights from longitudinal CMR, CPET and lung function testing post-COVID-19.
      ].
      Fig. 4
      Fig. 4CMR of a 33-year-old male with persistent palpitation and tachycardia especially during physical activity at 1 year after COVID-19 recovery. Holter ECG documented frequent ectopic ventricular beats. Hence, CMR was performed. CMR showed preserved left and right ventricle ejection fraction, without wall motion alteration. No edema was evident on short-tau inversion recovery images (A) neither on T2 maps (B and C). LGE images (F) showed a thin subepicardial scar on the inferior mid-ventricular wall, associated to increased native T1 (arrows in D, values in E) and ECV values (arrows in H, values in G). These findings were suggestive for post-myocarditis scar.
      In asymptomatic patients recovered from mild-to-moderate COVID-19 infection, there is no increased risk in long-term cardiac sequelae. In a prospective study, no differences were identified at CMR performed 6 months post-infection between 74 asymptomatic healthcare workers and age, sex, and ethnicity matched controls [
      • Joy G.
      • Artico J.
      • Kurdi H.
      • Seraphim A.
      • Lau C.
      • Thornton G.D.
      • et al.
      Prospective case-control study of cardiovascular abnormalities 6 months following mild COVID-19 in healthcare workers.
      ]. Similarly, Petersen et al. [
      • Petersen E.L.
      • Goßling A.
      • Adam G.
      • Aepfelbacher M.
      • Behrendt C.A.
      • Cavus E.
      • et al.
      Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: the Hamburg City health study COVID programme.
      ] found non-significant CMR alterations in a population of 443 asymptomatic post-COVID patients compared to 1380 matched controls.

      7. Cardiac Imaging findings after SARS-CoV-2 vaccine

      The COVID-19 vaccines have determined a substantial worldwide decline in morbidity and mortality, with reduction of hospitalization related to severe disease. All approved vaccines have shown to provide benefits that obscure their potential risks across different age groups [
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • Anis E.
      • Singer S.R.
      • Khan F.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      ].
      Since the beginning of the vaccination program, more reports have been raising concerns for the association of myopericarditis to different types of COVID-19 vaccines [
      • Ammirati E.
      • Cavalotti C.
      • Milazzo A.
      • Pedrotti P.
      • Soriano F.
      • Schroeder J.W.
      • et al.
      Temporal relation between second dose BNT162b2 mRNA Covid-19 vaccine and cardiac involvement in a patient with previous SARS-COV-2 infection.
      ,
      • D’Angelo T.
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      • Ascenti G.
      • Cicero G.
      • et al.
      Myocarditis after SARS-CoV-2 vaccination: a vaccine-induced Reaction?.
      ,
      • Abu Mouch S.
      • Roguin A.
      • Hellou E.
      • Ishai A.
      • Shoshan U.
      • Mahamid L.
      • et al.
      Myocarditis following COVID-19 mRNA vaccination.
      ].
      In pre-COVID-19 era, vaccine-related myocarditis or pericarditis had a reported incidence of 0.1%, according to Vaccine Adverse Event Reporting System (VAERS) files collected between 1990 and 2018. Of these, 79% of cases were observed in males [
      • Su J.R.
      • McNeil M.M.
      • Welsh K.J.
      • Marquez P.L.
      • Ng C.
      • Yan M.
      • et al.
      Myopericarditis after vaccination, vaccine adverse event reporting system (VAERS), 1990–2018.
      ]. Since COVID-19 vaccines rollout, a rate of 12.6 cases of myocarditis per million doses has been related to the second vaccine shot, in individuals aged between 12 and 39 years.
      However, VAERS data collection system cannot be used to determine the real incidence of vaccine adverse events, since it is primarily a safety signal detection and hypothesis-generating system [
      • Shimabukuro T.T.
      • Nguyen M.
      • Martin D.
      • DeStefano F.
      Safety monitoring in the vaccine adverse event reporting system (VAERS).
      ]. Certainly, myocarditis has been described as the most frequent vaccine-related adverse event occurring mainly in patients having smallpox vaccination rather than in patients receiving vaccines for single-stranded RNA viruses [
      • Halsell J.S.
      • Riddle J.R.
      • Atwood J.E.
      • Gardner P.
      • Shope R.
      • Poland G.A.
      • et al.
      Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.
      ].
      However, an association between mRNA COVID-19 vaccines (mRNA-1273 [Moderna] and BNT162b2 [Pfizer-BioNTech]) myocarditis and pericarditis cases has been found, particularly after the second shot of vaccination [
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis with COVID-19 mRNA vaccines.
      ].
      Most of the reported cases presented abnormal ECG with ST elevation and elevated cardiac troponin peaking three days after vaccination, usually within 14 days of COVID-19 vaccination [
      • Sinagra G.
      • Porcari A.
      • Merlo M.
      • Barillà F.
      • Basso C.
      • Ciccone M.M.
      • et al.
      Myocarditis and pericarditis following mRNA COVID-19 vaccination. Expert opinion of the italian Society of Cardiology.
      ].
      Most subjects had rapid recovery and high antibody levels for SARS-CoV-2 spike protein suggesting effective immunization. Echocardiogram was abnormal in only 40% of cases, with a minimal percentage of patients presenting reduced left ventricular ejection fraction [
      • Bozkurt B.
      • Kamat I.
      • Hotez P.J.
      Myocarditis with COVID-19 mRNA vaccines.
      ]. Conversely, CMR showed abnormalities in all tested patients, depicting findings such as myocardial edema and subepicardial late gadolinium enhancement suggestive of myocarditis.
      Recently, Fronza et al. showed that COVID-19 vaccine-related myocarditis has different imaging patterns compared to other causes of myocarditis such as COVID-19-related myocarditis, independently from patients' age or sex and from interval between symptoms onset and imaging [
      • Fronza M.
      • Thavendiranathan P.
      • Chan V.
      • Karur G.R.
      • Udell J.A.
      • Wald R.M.
      • et al.
      Myocardial injury pattern at MRI in COVID-19 vaccine-associated myocarditis.
      ].
      In particular, the authors found that, in vaccine-related myocarditis, right and left ventricular ejection fraction, strain values, and myocardial native T1-value are less altered, while LGE is less extensive and mainly involves the infero-lateral segments compared to other causes of myocarditis (Fig. 5A ).
      Fig. 5
      Fig. 5CMR of a 30-year-old male with COVID-19 vaccine-related myocarditis. LGE imaging performed along three-chambers view 5 days after the onset of patient's symptoms (A) shows subepicardial enhancement along the infero-lateral myocardial segments (arrows) with minimal involvement of the anterior wall in the apical region (arrowhead). Cardiac MRI performed 3-months later (B) shows almost complete resolution of myocardial LGE in the same segments.
      The etiology of myocardial inflammation following COVID-19 vaccination is still unknown. Different mechanisms have been proposed: i) a delayed hypersensitivity reaction, with sensitization occurring after the first COVID-19 vaccine shot; ii) a mechanism of molecular mimicry between the SARS-CoV-2 spike proteins, encoded by the mRNA vaccines, and cardiomyocyte antigens, which may provoke an immune response in predisposed subjects; iii) a systemic inflammatory response triggered by the antigenic mRNA, leading to myocardial inflammation.
      However, almost all reports confirm that symptoms resolution, as well as diagnostic markers and imaging findings normalization, is rapid either with or without treatment (Fig. 5B).
      Clinicians should be aware of the existing risk of myocarditis and pericarditis related to COVID-19 vaccination, especially in young male individuals presenting with chest pain shortly after vaccination.

      8. Conclusions

      Advanced cardiac imaging in COVID-19 provides effective and non-invasive characterization of COVID-19 related cardiovascular manifestations and improves risk stratification, minimizing the use of unnecessary and invasive procedures and speeding-up the diagnostic pathways.
      The choice of the most appropriate imaging modality and acquisition protocol needs to be tailored to patient's clinical features and suspicion. CT angiography allows accurately characterizing vessels involvement. Moreover, independently by the selected protocol, CT can provide a multiplicity of ancillary information useful for a more comprehensive patients' characterization and risk stratification. CMR has the advantage of enabling accurate myocardial tissue characterization, being able to exclude preexisting cardiomyopathies and to identify subclinical cardiac injury, myocardial inflammation, and abnormalities potentially affecting quality of life or increasing risk of future events.

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