Cardiac Involvement in COVID-19 Patients: A Contemporary Review
Abstract
:1. Introduction
2. Methods
3. Results and Critical Findings
3.1. ECG Results
3.2. Results of Cardiac Ultrasound and Advanced Imaging
3.3. Histopathological Tests Results
3.4. Therapies and Advanced Treatment
4. Discussion
4.1. Biomolecular Hypotheses about COVID-19-Induced Myocardial Injury
- (a)
- Myocardial damage due to the direct viral action on the tissue, or to extrapulmonary migration of infected alveolar macrophages. Thus, a direct myocardial damage through binding to ACE2 receptors because of viral action on the tissue or due to extra pulmonary migration of infected alveolar macrophages. SARS-CoV-2 uses spike protein to bind to ACE2 receptors on the myocardial cell membrane. In theory, following SARS-CoV-2’s engagement to the ACE2 receptors on the myocardium and the subsequent down-regulation of the receptors themselves, the accumulation of angiotensin II may enhance myocardial remodeling by diverting all its activity to type 1 angiotensin II receptors (AT1R) of the heart [1,70,71]. Interestingly, a polybasic furin site that structurally differentiates SARS-CoV-2 from SARS, when cleaved, expands the types of cells the virus can infect. The virus, by binding to ACE2 receptors throughout the body, facilitates cell entry through its spike protein, together with the cooperation of the serine protease transmembrane protease serine 2, heparan sulfate, and other proteases. The heart is one of the many organs with high ACE2 expression [72,73,74,75]. Tropism to other organs besides the lungs was studied from autopsy samples: SARS-CoV-2 genomic RNA was highest in the lungs, but the heart, kidneys, and liver also showed substantial amounts, and copies of the virus were detected in the heart of 16 of the 22 patients who died. In an autopsy series of 39 patients who died from COVID-19, the virus was undetectable in the myocardium in 38% of patients, while 31% had a high viral load greater than 1000 copies in the heart [76,77].
- (b)
- Via cell-mediated cytotoxicity in which CD8 T lymphocytes migrate to cardiomyocytes and cause inflammation of the myocardium. Cytokine release syndrome, proposed as the main mechanism underlying COVID-19-induced acute fulminant myocarditis, is thus unleashed [1,9,10,11]. This triggers the pro-inflammatory cytokine release syndrome, a severe systemic inflammatory response resulting in hypoxia and apoptosis of the cardiomyocytes. In fact, the released cytokines increase the activation of T lymphocytes, which release further cytokines with consequent positive feedback of immune activation and myocardial damage [9].
- (c)
- The mechanism of hyperactivation of the autoimmune system with possible interferon-mediated hyperactivation of the innate and adaptive immune system has also been proposed [78]. Myocarditis can cause the onset of arrhythmias, during the acute phase, due to a direct cytopathic effect, which causes electrical imbalance and ischemia due to microvascular and gap-junctions dysfunction due to reduced myocardial expression of connexins [79]. Thus, the main biomolecular mechanism responsible for heart damage, and in turn heart failure, is an abnormal state of systemic inflammation with low oxygen levels and thrombosis. In addition, the presence of the SARS-CoV-2 genome was detected in the myocardium [54].
4.2. Cardiovascular Signs and Symptoms during the Infection
4.3. Main Laboratory Markers of Cardiovascular Severe Prognosis
4.4. Instrumental Diagnostics
4.5. Histological Findings of Myocarditis
4.6. Management and Treatment Strategies
4.7. Knowledge Gaps and Future Directions
4.8. Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Authors | Study Design | Sample of Study | Presenting Symptoms | Cardiac Biomarker | Results | Treatment |
---|---|---|---|---|---|---|
Asif and Ali [17] | Case report | 64-year-old man | Dyspnea | Troponin: 0.17 ng/mL NT-proBNP: - | ECG: T Echo: - CMR: NR EMB/PM:NR | Aspirin, clopidogrel, heparin, azithromycin, hydroxychloroquine, meropenem, propofol, fentanyl, atracurium, vasopressin, tocilizumab |
Asif and Ali [17] | Case report | 71-year-old man | Fever, cough, and dyspnea | Troponin: 1.6 ng/mL NT-proBNP: - | ECG: ST, Q Echo: - CMR: NR EMB/PM:NR | Aspirin, clopidogrel, heparin, azithromycin, cefepime, vancomycin, tocilizumab, fentanyl, midazolam |
Beri et al. [18] | Case report | 72-year old man | Chest tightness, shortness of breath, cough, fatigue, and intermittent diarrhea | Troponin: - NT-proBNP: - | ECG: ST, TV Echo: ventricular dysfunction, cardiomegaly CMR: NR EMB/PM: NR | NR |
Bernal-Torres et al. [19] | Case report | 38-year-old woman | Palpitations, general malaise | Troponin: 1190 ng/mL NT-proBNP: 13,000 pg/mL | ECG: ST Echo: LVEF 30%, hypokinesia CMR: Edema+ Injury+ EMB/PM: NR | Methylprednisolone, immunoglobulin, hydroxychloroquine, azithromycin, lopinavir/ritonavir |
Beşler and Arslan [20] | Case report | 20-year-old man | Febrile sensation and chest pain | Troponin: 0.572 ng/mL NT-proBNP: 127 pg/L | ECG: - Echo: - CMR: Edema+ Injury+ EMB/PM:NR | Hydroxychloroquine, azithromycin, ceftriaxone, tigecycline, favipiravir, colchicine |
Cizgici et al. [21] | Case report | 78-year-old man | Chest pain and shortness of breath. | Troponin: 998.1 ng/mL NT-proBNP: 127 pg/mL | ECG: FA, ST Echo: - CMR: Edema+ Injury+ EMB/PM:NR | Furosemide, ACE-I, beta-blocker, COVID-19-specific therapy |
Coyle et al. [22] | Case report | 57-year-old man | Shortness of breath, fevers, cough, myalgia, decreased appetite, nausea, and diarrhea | Troponin: 7.33 ng/mL NT-proBNP: 1300 pg/mL | ECG: - Echo: Hypokinesia, LVEF 35–40% CMR: Edema+ Injury+ EMB/PM:NR | Hydroxychloroquine, methylprednisolone, azithromycin, ceftriaxone, colchicine |
Craver et al. [23] | Case report | 17-year-old man | Full cardiac arrest after a 2-day history of headache, dizziness, nausea, and vomiting | NR | ECG: NR Echo: NR CMR: NR EMB/PM: Immune cell infiltrate, necrosis | NR |
Dolhnikoff et al. [24] | Case report | 11-year-old boy | Fever, odynophagia, myalgia, and abdominal pain | Troponin: 0.342 ng/mL NT-proBNP: - | ECG: TV Echo: LVEF 31%, hypokinesia CMR: Edema+ Injury+ EMB/PM: viral particles in different cell lineages of the heart, including cardiomyocytes, endothelial cells, mesenchymal cells | Epinephrine, furosemide, ceftriaxone, azithromycin |
Doyen et al. [25] | Case report | 69-year-old man | Cough, fever, dyspnea | Troponin: 9002 ng/mL NT-proBNP: 22.600 pg/mL | ECG: T Echo: LVH CMR: Edema+ Injury+ EMB/PM: NR | Hydrocortisone, aspirin, fondaparinux |
Fried et al. [26] | Case report | 64-year-old woman | Chest pressure | Troponin: 18,6 ng/mL NT-proBNP: - | ECG: Sinusal tachy, ST Echo: LVEF 30%, pericardial effusion CMR: NR EMB/PM: NR | Hydroxychloroquine, dobutamine, IABP |
Hu et al. [27] | Case report | 37-year-old man | Chest pain, dyspnea, and diarrhea | Troponin: 10,000 ng/mL NT-proBNP: 2102 pg/mL | ECG: ST Echo: LVD, LVEF 27% CMR: NR EMB/PM:NR | Methylprednisolone, immunoglobulin, norepinephrine, diuretic, milrinone, pantoprazole, piperacillin/sulbactam |
Inciardi et al. [28] | Case report | 53-year-old woman | Fever and cough | Troponin: 0,24 ng/mL NT-proBNP: 5647 pg/mL | ECG: ST, T Echo: Hypokinesia, LVEF 40%, pericardial effusion CMR: Edema+ Injury+ EMB/PM: NR | Hydroxychloroquine, lopinavir/ritonavir, methylprednisolone, bisoprolol, kanrenone, furosemide |
Irabien- Ortiz et al. [29] | Case report | 59-year-old woman | Anginal chest pain in the absence of respiratory symptoms | Troponin: 1100 ng/mL NT-proBNP: 4421 pg/mL | ECG: ST Echo: LVH CMR: Edema+ Injury+ EMB/PM:NR | Immunoglobulins, methylprednisolone, ritonavir/lopinavir, interferon-B |
Jacobs et al. [30] | Case report | 48-year-old man | Fever, diarrhoea, cough, dysosmia, and dyspnea | Troponin: 14 932 ng/mL NT-proBNP: 9223 pg/mL | ECG: T Echo: LVH, hyperdynamic ventricular function CMR: NR EMB/PM: Immune cell infiltrate, edema, necrosis | Hydroxychloroquine, azithromycin, ECMO |
Juusela et al. [31] | Case report | 45-year-old woman, pregnant (39 weeks) | Contractions and emesis | Troponin: 0.046 ng/mL NT-proBNP: 114 pg/mL | ECG: - Echo: LVEF 40% CMR: NR EMB/PM:NR | Methylprednisolone, hydroxychloroquine, tocilizumab, cesarean |
Juusela et al. [31] | Case report | 26-year-old woman, pregnant (33 weeks) | Shortness of breath, dyspnea, | Troponin: 0.046 ng/mL NT-proBNP: <10 pg/mL | ECG: VT Echo: Hypokinesia, LVEF 40% CMR: - EMB/PM:NR | Metoprolol, cesarean |
Kim et al. [32] | Case report | 21-year-old woman | Coughing, sputum, diarrhea, and shortness of breath | Troponin: 1.26 ng/mL NT-proBNP: 1929 pg/mL | ECG: VE Echo: Severe LV systolic dysfunction CMR: Edema+ Injury+ EMB/PM: NR | NR |
Luetkens et al. [33] | Case report | 79-year-old man | Fatigue, shortness of breath, recurrent syncopes | Troponin: 63,5 ng/mL NT-proBNP: 1178 pg/mL | ECG: - Echo: Hypokinesia, LVEF 49% CMR: Edema+ Injury+ EMB/PM: NR | NR |
Naneishvili et al. [34] | Case report | 44-year-old woman | Fever, lethargy, muscle aches and two episodes of syncope | Troponin: 639 ng/mL NT-proBNP: - | ECG: FA Echo: LVEF 37%, LVH, pericardial effusion CMR: NR EMB/PM: NR | Methylprednisolone, remdesvir, amiodarone, milrinone, inotropic support |
Oberweis et al. [35] | Case report | 8-year-old male | Fever, coughing, weight loss, and severe fatigue | Troponin: 0.044 ng/mL NT-proBNP: 5112 pg/mL | ECG: ST Echo: LVEF 21%, pericardial effusion CMR: Edema+ Injury+ EMB/PM: NR | Heparin, dobutamine, immunoglobulins, milrinone, tocilizumab |
Oleszak et al. [36] | Case report | 52-year-old man | Cough, fever, shortness of breath, and a single episode of trace hemoptysis | Troponin: 0.017 ng/mL NT-proBNP: 1220 pg/mL | ECG: Sinusal tachy Echo: LVEF 25%, LVH CMR: NR EMB/PM: NR | Ceftriaxone, azithromycin, hydroxychloroquine, furosemide |
Paul et al. [37] | Case report | 35-year-old man | Chest pain and fatigue | Troponin: 2885 ng/mL NT-proBNP: - | ECG: repolarization changes Echo: - CMR: Edema+ Injury+ EMB/PM:NR | Ramipril, bisoprolol |
Pavon et al. [38] | Case report | 64-year-old man | Chest pain and dyspnea | Troponin: 1843 ng/L NT-proBNP: - | ECG: - Echo: LVEF 40% CMR: Edema+ Injury+ EMB/PM: NR | Piperacillin/tazobactam |
Radbel et al. [39] | Case report | 40-year-old man | Fever, dry cough, and dyspnea | Troponin: 30,39 ng/mL NT-proBNP: - | ECG: ST Echo: hypokinesia CMR: NR EMB/PM: NR | Hydroxychloroquine, azithromycin, tocilizumab |
Rauf et al. [40] | Case report | 5-year-old boy | Fever, abdominal pain and loose stools, bulbar conjunctivitis, and extremity edema | Troponin: 29 ng/mL NT-proBNP: 8000 pg/mL | ECG: - Echo: LVEF 35%, hypokinesia CMR: NR EMB/PM: NR | Inotropic support, immunoglobulins, aspirin, steroids, diuretics |
Sala et al. [41] | Case report | 43-year-old woman | Chest pain and dyspnea | Troponin: 106 ng/mL NT-proBNP: 512 pg/mL | ECG: ST Echo: Hypokinesia, LVEF 43% CMR: Edema+ Injury+ EMB/PM: Immune cell infiltrate, edema, necrosis | Lopinavir/ritonavir, hydroxychloroquine |
Sardari et al. [42] | Case report | 31-year-old man | Dyspnea on exertion and low-grade fever | Troponin: <0.03 ng/mL NT-proBNP: - | ECG: - Echo: Mild LV systolic dysfunction CMR: Edema+ Injury+ EMB/PM:NR | Bisoprolol, lisinopril |
Tavazzi et al. [43] | Case report | 69-year-old woman | Dyspnea, cough, and weakness | Troponin: 4332 ng/mL NT-proBNP: - | ECG: - Echo: LVD, LVEF 27% CMR: NR EMB/PM: viral particles within the interstitial cells of the myocardium, edema, necrosis | IABP, ECMO |
Trogen et al. [44] | Case report | 17-year-old man | Fever and neck pain, diarrhea | Troponin: 2.97 ng/mL NT-proBNP: 2124 pg/mL | ECG: T Echo: LVEF 40% CMR: Edema+ Injury+ EMB/PM: NR | Hydroxychloroquine, piperacillin-tazobactam, enoxaparin |
Warchoł et al. [45] | Case report | 74-year-old man | Palpitations, general malaise | Troponin: 102 ng/mL NT-proBNP: 2451 pg/mL | ECG: VT Echo: LVEF 25% CMR: Edema - Injury+ EMB/PM: NR | Metoprolol, amiodarone |
Yuan et al. [46] | Case report | 33-year-old man | Chest pain, fever, and muscle ache | Troponin: - NT-proBNP: - | ECG: - Echo: VT CMR: Edema+ Injury- EMB/PM:NR | NR |
Zeng et al. [47] | Case report | 63-year-old man | Shortness of breath and chest tightness after activity | Troponin: 11.37 g/L NT-proBNP: 22.600 pg/mL | ECG: Sinusal tachy Echo: dyskinesia, LVD, LVEF 32% CMR: NR EMB/PM: NR | High-flow oxygen, CCRTlopinavir-ritonavir, interferon α-1b, methylprednisolone, immunoglobulin, piperacillin-tazobactam |
Cairns et al. [48] | Case report | 58-year-old female | Developed cardiogenic shock after fever, diarrhoea, and vomiting | Troponin 3532.9 ng/L NT-proBNP: NR | ECG: NR Echo: TTE showed 3–4 cm pericardial effusion with evidence of cardiac tamponade CMR: NR EMB/PM: NR | Pericardial drain, vasopressor support, intravenous amoxicillin, oral doxycycline initially, escalated to piperacillin/tazobactam, furosemide, intravenous immunoglobulin (2 g/kg) |
Beaudry et al. [49] | 15-year-old female | Epigastric pain, nasal congestion, and rhinorrhea. Pyrexia (38.9°C), tachycardia, and worsening respiratory failure | Troponin 2.48 ng/mL NT-proBNP: 8328 pg/mL | ECG: sinus tachycardia Echo: severely diminished LV ejection CMR: NR EMB/PM: cardiomyocytes with interstitial lymphoplasmacytic infiltrate and mixed inflammation surrounding cardiac vessels | Mechanical ventilation (intensive care unit), norepinephrine infusion cefepime, metronidazole, doxycycline | |
Garot J et al. [50] | 69-year-old man | Fever, asthenia, and abdominal pain, hypotension, hypoxemia, anuria, and multi-organ failure (MOF) | Troponin 8066 pg/mL NT-proBNP: NR | ECG: no signs of ischemia Echo: non-dilated and severe, diffuse LV hypokinesia (LV ejection fraction: 30%) CMR: NR EMB/PM: Abundant myocardial edema, interstitial inflammation (predominance of mononucleated leucocytes) associated with cardiomyocytes dystrophies and strong granular cytoplasmic staining of cardiomyocytes for SARS coronavirus nucleocapsid protein | Veno-arterial unit and extracorporeal membrane oxygenation (VA-ECMO), noradrenalin, dobutamine |
Authors | Study Design | Sample of Study | Results | Treatment | Conclusion |
---|---|---|---|---|---|
Buja et al. [51] | Case series | 23 | Lymphocytic myocarditis, lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates | N/A | COVID-19 is a systemic disease with major involvement of the lungs and heart. |
Chen et al. [52] | Retrospective study | 99 | Pneumonia, abnormal CT, cardiac injury, secondary infection | Mechanical respirators and circulatory support systems, including IABP, Impella, and ECMO | COVID-19 infection might deteriorate rapidly, eventually followed by fulminant myocarditis. More attention should be paid to patients with extremely increased cardiac troponin I levels and new-onset arrhythmias. |
Deng et al. [53] | Retrospective study | 112 | High troponin level and pulmonary hypertension indicating myocardial injury | N/A | Myocardial injury is due to systemic consequences rather than direct injury by Sars-CoV2. |
Escher et al. [54] | Retrospective study | 104 | EMB: active myocarditis according to the Dallas criteria, necrosis | N/A | Evidence of SARS-CoV-2 genomes detection in EMB. |
Guo et al. [55] | Retrospective single-center case | 187 | Hypertension, coronary heart disease, cardiomyopathy, elevated TnT level exhibited myocardial injury | Antiviral therapy, antibiotics, respiratory support | Myocardial injury is essentially connected with the lethal outcome. |
Halushka et al. [56] | Meta-analysis | 22 studies with 277 patients | Macro or microvascular thrombi, inflammation, or intraluminal megakaryocytes | N/A | COVID-19-related cardiac histopathological findings are common, while myocarditis is rare. |
Han et al. [57] | Single-center study | 273 | High blood levels of CKMB, MYO, Ultra-TnI, NTproBNP indicating acute cardiac injury | Monitoring of the myocardiac enzyme profiles | Higher concentrations of CK-MB, MYO, ultra-TnI, and NT- proBNPin venous blood signified the severity and case fatality rate (CFR) of COVID-19. |
Khalid et al. [58] | Case series | 2 | Abnormal ECG and Echo, high blood levels of TnI, and NTproBNP | Dual antiplatelet therapy, heparin, dobutamine, norepinephrine, ECMO | Cases of COVID-19 infection with myocardial involvement may have distinct mechanistic pathways and outcomes. |
Nunes Duarte-Neto et al. [59] | Case series | 10 | Hypertrophy of cardiomyocytes, myocardial fibrosis, interstitial edema fibrin thrombi (2 mild lymphomononuclear myocarditis) | N/A | COVID-19 is a systemic disease with major effects in the lungs and the involvement of various organs including the heart. |
Puntmann et al. [60] | Cohort study | 100 | hsTnT values significantly elevated, EMB: active lymphocytic inflammation, CMR: myocardial fibrosis and/or edema | Antiviral, antibiotic, steroid, hydrochloroquine | The combination of histological findings as well as the increase relative to age-matched, sex-matched, and risk-factor-matched controls makes this a COVID-19-related inflammatory process. |
Rajpal et al. [61] | Prospective study | 26 | CMR: myocardial edema and myocardial injury, pericardial effusion | N/A | CMR may provide an excellent risk-stratification assessment for myocarditis in athletes who have recovered from COVID-19. |
Ruan et al. [62] | Retrospective multi-center study | 150 | Predictors of a fatal outcome included age, underlying diseases, secondary infection, and elevated inflammatory indicators in the blood | N/A | The infection of SARS-CoV-2 may cause fulminant myocarditis, and patients with cardiovascular diseases have a significantly increased risk of death when they are infected with SARS-CoV-2. |
Shi et al. [63] | Cohort study | 416 | Abnormal ECG, bilateral pneumonia, ground-glass opacity, mottling | Antiviral therapy, oxygen, glucocorticoids, intravenous immunoglobulin therapy, antibiotic therapy | The data and findings support cardiac injury as a complication in COVID-19 patients. |
Yang et al. [64] | Meta-analysis | 6 studies with 1527 patients | Hypertension, cardiac cerebrovascular disease, and diabetes | N/A | COVID-19 might aggravate the damage to the heart. |
Types of Post-COVID Conditions | ||
---|---|---|
Long COVID-19 | COVID-19 Multiorgan Effects | COVID-19 Treatment or Hospitalization Effects |
A range of symptoms that can last weeks or months after first being infected or can appear weeks after infection. Can happen to anyone who has had COVID-19, even if the illness was mild, or they had no symptoms. Tiredness or fatigue, difficulty thinking or concentrating (sometimes referred to as “brain fog”), headache, loss of smell or taste, orthostatic dizziness, fast-beating or pounding heart (also known as heart palpitations), chest pain, difficulty breathing or shortness of breath, cough, joint or muscle pain, depression or anxiety, fever, symptoms that get worse after physical or mental activities. | Multiorgan effects can affect most, if not all, body systems, including heart, lung, kidney, skin, and brain functions. Can also include conditions that occur after COVID-19, like multisystem inflammatory syndrome (MIS) and autoimmune condition. | Longer-term effects of COVID-19 treatment or hospitalization (some of these effects are similar to those related to hospitalization for other respiratory infections or other conditions). Can include severe weakness and post-traumatic stress disorder (PTSD involves long-term reactions to a stressful event), and post-intensive care syndrome (PICS). |
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Carretta, D.M.; Silva, A.M.; D’Agostino, D.; Topi, S.; Lovero, R.; Charitos, I.A.; Wegierska, A.E.; Montagnani, M.; Santacroce, L. Cardiac Involvement in COVID-19 Patients: A Contemporary Review. Infect. Dis. Rep. 2021, 13, 494-517. https://doi.org/10.3390/idr13020048
Carretta DM, Silva AM, D’Agostino D, Topi S, Lovero R, Charitos IA, Wegierska AE, Montagnani M, Santacroce L. Cardiac Involvement in COVID-19 Patients: A Contemporary Review. Infectious Disease Reports. 2021; 13(2):494-517. https://doi.org/10.3390/idr13020048
Chicago/Turabian StyleCarretta, Domenico Maria, Aline Maria Silva, Donato D’Agostino, Skender Topi, Roberto Lovero, Ioannis Alexandros Charitos, Angelika Elzbieta Wegierska, Monica Montagnani, and Luigi Santacroce. 2021. "Cardiac Involvement in COVID-19 Patients: A Contemporary Review" Infectious Disease Reports 13, no. 2: 494-517. https://doi.org/10.3390/idr13020048