COVID-19, ACE2, and the Cardiovascular Consequences1,2
- Viral infections are dependent on cellular entry of the virus that afterward uses the cellular machinery of the host to replicate multiple viral copies, which are subsequently shed by the host cell.
- Coronaviruses such as SARS-CoV-2 and SARS-CoV-1 are known to use the host protein angiotensin-converting enzyme-2 as a co-receptor to gain intracellular entry into the lungs, heart and brain.
- ACE2 is a membrane-bound peptidase with the majority of the protein that comprises the NH2-terminal peptide domain, including the catalytic site oriented extracellularly.
- ACE2 is expressed in essentially all tissues, with greatest activity in the ileum and kidney, followed by adipose tissue, heart, brain stem, lung, vasculature, stomach, liver, and nasal and oral mucosa based on activity data in the mouse that generally parallel ACE2 mRNA levels in humans.
- As to the mechanism for the intracellular entry by SARS- CoV-2 and SARS-CoV, the viral coat expresses a protein termed SPIKE (S protein) that contains a receptor-binding region that binds to the extracellular domain of ACE2 with high affinity.
- ACE2 internalization by SARS-CoV-2 would potentially result in down-regulation of ACE2 expression and consequent unabated angiotensin II activity ➡ LV hypertrophy and fibrosis, impaired LV function, arrhythmias.
- Reduced expression of ACE2 in the vasculature may promote endothelial dysfunction and inflammation and exacerbate existing atherosclerosis, hypertension and diabetes.
Cardiac involvement is a prominent feature in COVID-19 and is associated with a worse prognosis.
Direct myocardial injury by virus SARS-CoV-2 enters human cells by binding to angiotensin-converting enzyme 2 (ACE2) receptor, a membrane bound which is highly expressed both in heart and lungs. The binding of SARS-CoV-2 to ACE2 can result in alteration of ACE2 signaling pathways ➡ acute myocardial injury.
Altered myocardial oxygen demand-supply relationship due to systemic infection, respiratory failure and hypoxia ➡ acute myocardial injury.
Systemic inflammation acute systemic inflammatory response and cytokine storm ➡ acute myocardial injury.
Plaque rupture and coronary thrombosis systemic inflammation and increased shear stress due to increased coronary blood flow can precipitate plaque rupture, whereas prothrombotic state may induce intracoronary thrombus formation ➡ acute myocardial infarction.
Adverse effects of various therapies antiviral drugs, corticosteroids, chloroquine and other therapies aimed at treating COVID-19 can have deleterious effects on the CV system ➡ arrhythmias, myocardial fibrosis.
Electrolyte imbalances above all hypokalemia due to interaction of COVID with RAAS ➡ precipitate arrhythmias.
Combinations of different mechanisms.
Potential Mechanisms for Acute Effect of Viral Infection on CV System5
COVID-19 and the Cardiovascular Consequences4,6
The overall incidence of acute cardiac injury varies between 8% and 12% of the positive cases.
Acute cardiac injury has been consistently shown to be a strong negative prognostic marker in patients with COVID-19. The severity of COVID-19 is associated with acute cardiac injury, and acute cardiac injury is associated with death.
Both tachy– and brady-arrhythmias are known to occur in COVID-19. A study describing clinical profile and outcomes in 138 Chinese patients with COVID-19 reported 16.7% incidence of arrhythmia. The incidence was much higher (44.4%) in those requiring ICU admission as compared to those not requiring ICU admission (8.9%).
CV co-morbidities increase the mortality rate. Chinese Center for Disease Control and Prevention described clinical outcomes in 44672 confirmed cases of COVID- 19; overall mortality rate = 2.3%; in patients with hypertension = 6%; patients with CVD = 10%.
These data highlight the need to effectively monitor heart health in order to limit cardiac complications in patients infected with COVID-19.
Cardiac Complications in COVID-19 patients Chinese experience7-11
The echocardiographic features in COVID-19 patients12
Role of Echocardiography in Patients with Suspected or Proven COVID-1913
Recommendation of UK Intensive Care Society Indications - management
Monitoring of left heart function in patients with acute cardiomyopathy, presumably secondary to viral myocarditis.
Monitoring of right heart function in patients who are at risk of suffering acute cor pulmonale secondary to.
- hypoxic vasoconstriction
- ventilator induced lung injury
- pulmonary embolism ➡ patients with COVID are at a higher risk of disseminated intravascular coagulation14
- thrombotic complications in ICU patients with COVID is 31%
Echocardiographic Features of COVID-19-induced Fulminant Myocarditis in China15
A 63-year-old male was admitted to the hospital due to coughing of white sticky sputum and fever up to 39.3°, accompanied by shortness of breath and chest tightness after activity. He had no history of heart disease or hypertension.
(a) left ventricular diameter was enlarged and ejection fraction was decreased
(b) edema of left ventricular wall and improvement of ejection fraction;
(c) normal left ventricular ejection fraction and wall thickness
The echocardiographic left ventricular M-mode images of the 1st day (a), the 10th day (b) and the 17th day after admission (c).
American Society of Echocardiography Guidelines
Cardiovascular disease is the comorbidity that carries with it the highest death rate in COVID-19 patients, at about 10.5 percent.
For this reason, risk of cardiovascular complications in the setting of COVID-19, including pre-existing cardiac disease, acute cardiac injury and drug-related myocardial damage, will require the use of echocardiography in the care of some patients with suspected or confirmed COVID-19.
The provision of echocardiographic services remains crucial during the novel coronavirus (COVID-19, SARSCoV-2) outbreak.
To minimize risks to cardiac ultrasound staff, the American Society of Echocardiography (ASE) commissioned a group of experts to issue a statement outlining recommendations to improve safety and reduce the potential for COVID-19 cross contamination.
Apical 4-chamber view to assess the right/left ventricle ratio
Strain echocardiography to detect left ventricular segmental contraction abnormalities
Measurement of tricuspid regurgitation velocity to estimate pulmonary artery pressure
EACVI recommendations on precautions, indications, prioritization, and protection for patients and healthcare personnel
- A focused cardiac ultrasound study (FoCUS) is recommended to reduce the duration of exposure
- The need for echocardiography might expand further as we understand more about COVID-19, with early reports indicating that patients with established cardiovascular disease and cardiovascular risk factors have worse prognosis than others, and are more likely to be admitted to hospital and need respiratory support
- Echocardiography should be restricted to patients with cardiovascular instability or signs of right ventricular dysfunction or pulmonary hypertension.
- Lung ultrasound to detect COVID-19 pneumonia is also useful. Thickening of the pleurae, the appearance of B-lines, and lung consolidation indicate pneumonia, with pleural effusions rarely reported. Due to its bedside availability, scanning of the lungs by ultrasound can be performed as a quick diagnostic tool
Procedure & Cleaning
- The echocardiographic study will usually be performed in the ICU or in emergency rooms in critically ill patients. Less critical patients are usually examined in their ward rooms. Dedicated room(s) may be prepared in the echocardiographic lab, where unnecessary equipment can be removed to facilitate cleaning of the room.
- Protecting the echocardiographic machines with custom-made covers may be possible if available, but, if not, other protective equipment can be fashioned using local businesses and some ingenuity. It is, however, important not to cover the screen in a way that reduces the view for the echocardiographer.
- To facilitate cleaning of the scanner, all additional 3-D and single-Doppler probes should be removed before scanning starts, if they are not needed for proper diagnosis. ECG leads should also be removed.
- Moderately warm water and a mild detergent are the basis for equipment cleaning in all cardiac imaging machines, including the echocardiographic probe. An ordinary water-soluble disinfectant should also be added, but not on the membrane. A non-alcoholic disinfectant should be used on the echocardiographic probe
- Patients placed in the left lateral position with the scanner positioned on the right side of the bench will result in the longest possible distance. A surgical mask on the patient will also reduce contamination by air droplets
Suggested considerations and precautions before and during cardiac imaging as recommended by EACVI
ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic
- Autopsies of patients with COVID-19 infection revealed infiltration of the myocardium by interstitial mononuclear inflammatory cells.
- COVID-19 infections are associated with increased cardiac biomarker levels due to myocardial injury that are associated with infection-induced myocarditis and ischaemia.
- Myocarditis appears in COVID-19 patients several days after initiation of fever.
- Mechanisms of SARS-CoV-2-induced myocardial injury may be related to upregulation of ACE2 in the heart and coronary vessels.
- Echocardiography can be performed bedside to screen for CV complications and guide treatment. POCUS, FoCUS and critical care echocardiography are probably the preferred modalities to image patients with COVID-19.
- In COVID-19 infected patients, echocardiography should focus solely on the acquisition of images needed to answer the clinical question in order to reduce patient contact with the machine and health-care personnel.
Our best proposal to fight against Covid-19
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- South AM, et al. COVID-19, ACE2 and cardiovascular consequences. Am J Physiol 2020
- Vaduganathan M, et al. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 2020
- Akhmerov A, et al. COVID-19 and the Heart Circ Res 2020
- Bansai M. Cardiovascular disease and COVID-19. Diabetes Metabl Syndrome 2020
- Madjid M. Potential Mechanisms for Acute Effect of Viral Infection on CV System. JAMA Cardiology 2020
- Li J-W, et al. The Impact of 2019 Novel Coronavirus on Heart Injury: A Systemic Review and Meta- analysis. Prog Cardiovasc Dis. 2020
- Huang, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
- Wang D, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020
- Shi S, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA 2020
- Zhou F, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054-1062.
- Kochi AN; et al. Cardiac and arrhythmic complications in Covid-19 patients. Journal of Cardiovascular Electrophysiology.2020
- Peng QY, et al. Using echocardiography to guide the treatment of novel coronavirus pneumonia. Crit Care 2020
- Klok FA, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Apr 10. pii: S0 049-3848(20)30120-1
- Arachchillage D, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. doi.org/10.1111/jth.14820
- Zeng JH, et al. First Case of COVID-19 Infection with Fulminant Myocarditis Complication: Case Report and Insights. Preprints 2020, 2020030180 10.20944/preprints202003.0180.v1
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