COVID-19-associated heart failure: Difference between revisions
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==Classification== | ==Classification== | ||
*Heart Failure in COVID-19 may be classified similarly to heart failure from other causes. | *[[Heart Failure]] ([[(HF)]] in [[COVID-19]] may be classified similarly to [[heart failure]] from other causes. | ||
* In general, | * In general, [[heart failure]] can be classified based on: | ||
**The pathophysiology of heart failure: | **'''The pathophysiology of heart failure''': | ||
***systolic vs diastolic | ***[[systolic HF]] vs [[diastolic HF]] | ||
***left-sided vs right-sided | ***[[left-sided HF]] vs [[right-sided HF]] | ||
**The duration of symptoms: | **'''The duration of symptoms''': | ||
***acute vs chronic | ***acute HF [[(AHF)]] vs chronic HF [[(CHF)]] | ||
**The underlying physiology based on left ventricular ejection fraction (LVEF): | **'''The underlying physiology based on [[left ventricular ejection fraction (LVEF)]]:''' | ||
***Heart failure with reduced ejection fraction (HFrEF) vs heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) | ***[[Heart failure with reduced ejection fraction]] [[(HFrEF)]] vs [[heart failure with mid-range ejection fraction]] [[(HFmrEF)]] and [[heart failure with preserved ejection fraction]] [[(HFpEF)]] | ||
**The severity of heart failure (i.e., the New York Heart Association Class I-IV) | **'''The severity of [[heart failure]]''' (i.e., the [[New York Heart Association Class]] I-IV) | ||
**The stage of congestive heart failure (i.e., AHA Class A, B, C, D) | **'''The stage of congestive heart failure''' (i.e., [[AHA Class A, B, C, D]]) | ||
*Acute heart failure has two forms: | *[[Acute heart failure]] has two forms: | ||
**Newly-arisen (“de novo”) acute heart failure | **Newly-arisen (“de novo”) acute heart failure | ||
**Acutely decompensated chronic heart failure (ADCHF) | **Acutely decompensated chronic heart failure (ADCHF) | ||
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==Pathophysiology== | ==Pathophysiology== | ||
*Presumed pathophysiologic mechanisms for the development of new or decompensated heart failure in patients with COVID-19 include:<ref name="pmid32219357">{{ | *Presumed pathophysiologic mechanisms for the development of new or decompensated heart failure in patients with [[COVID-19]] include:<ref name="pmid32219357">{{Cite pmid|32219357}}</ref> <ref name="pmid32360242">{{Cite pmid|32360242}}</ref> <ref name="pmid32186331">{{Cite pmid|32186331}}</ref> <ref name="pmid30625066">{{Cite pmid|30625066}}</ref> <ref name="pmid32140732">{{Cite pmid|32140732}}</ref> | ||
**Acute exacerbation of [[chronic heart failure]] caused by precipitating factors | **Acute exacerbation of [[chronic heart failure]] caused by precipitating factors | ||
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==Causes== | ==Causes== | ||
*Acute myocardial injury | *[[Acute myocardial injury]] | ||
*Acute coronary syndromes | *[[Acute coronary syndromes]] | ||
*Myocarditis | *[[Myocarditis]] | ||
*Hypertensive crisis | *[[Hypertensive crisis]] | ||
*Arrhythmias: Tachycardia or severe bradycardia | *[[Arrhythmias]]: Tachycardia or severe bradycardia | ||
*Stress-induced cardiomyopathy | *[[Stress-induced cardiomyopathy]] | ||
*Circulatory failure: | *Circulatory failure: | ||
**Acute pulmonary embolism | **[[Acute pulmonary embolism]] | ||
**Pericardial tamponade | **[[Pericardial tamponade]] | ||
*Iatrogenic | *Iatrogenic | ||
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==Differentiating ((COVID-19 associated heart failure)) from other Diseases== | ==Differentiating ((COVID-19 associated heart failure)) from other Diseases== | ||
In patients with COVID-19 infection, acute heart failure should be differentiated from other diseases presenting with dyspnea and/or tachypnea. | In patients with [[COVID-19]] infection, [[acute heart failure]] should be differentiated from other diseases presenting with [[dyspnea]] and/or [[tachypnea]]. | ||
The differentials include the following: | The differentials include the following: | ||
*Pneumonia | *[[Pneumonia]] | ||
*ARDS | *[[ARDS]] | ||
*Myocarditis/pericarditis | *[[Myocarditis]]/[[pericarditis]] | ||
*Acute pulmonary embolism | *[[Acute pulmonary embolism]] | ||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
*In one study, acute heart failure was seen in 4.1% of patients with acute cardiac injury. | *Data on incidence on acute heart failure in COVID-19 patients is limited. | ||
*In a retrospective study on | *In one study, [[acute heart failure]] was seen in 4.1% of patients with [[acute cardiac injury]]. | ||
*In a retrospective study on 191 [[COVID-19]] patients in Wuhan, China, the incidence of heart failure was 23% (52% in non-survivors vs 12% in survivors). | |||
==Risk Factors== | ==Risk Factors== | ||
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==Natural History, Complications, and Prognosis== | ==Natural History, Complications, and Prognosis== | ||
*COVID-19 patients with chronic heart failure are more likely to develop severe forms of the disease. | *[[COVID-19]] patients with [[chronic heart failure]] are more likely to develop severe forms of the disease. | ||
*COVID-19 patients who develop acute heart failure (either de novo AHF or ADHF) have worse outcomes. | *[[COVID-19]] patients who develop [[acute heart failure]] (either de novo AHF or ADHF) have worse outcomes. | ||
*Acute heart failure in COVID-19 may progress to cardiogenic shock. | *[[Acute heart failure]] in [[COVID-19]] may progress to [[cardiogenic shock]]. | ||
==Diagnosis== | ==Diagnosis== | ||
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===History and Symptoms=== | ===History and Symptoms=== | ||
*The most common symptoms of acute heart failure in COVID-19 patients are: | *The most common symptoms of [[acute heart failure]] in [[COVID-19]] patients are: | ||
**New or worsening dyspnea: may overlap with dyspnea caused by concomitant respiratory involvement and ARDS due to COVID-19 | **New or worsening [[dyspnea]]: may overlap with dyspnea caused by concomitant respiratory involvement and [[ARDS]] due to [[COVID-19]] | ||
**Peripheral edema | **[[Peripheral edema]] | ||
**Confusion and altered mentation | **Confusion and altered mentation | ||
**Orthopnea | **[[Orthopnea]] | ||
**Palpitations | **[[Palpitations]] | ||
**Paroxysmal nocturnal dyspnea | *Less common symptoms include: | ||
**[[Paroxysmal nocturnal dyspnea]] | |||
**Cool extremities | **Cool extremities | ||
**Cyanosis | **[[Cyanosis ]] | ||
**Dizziness | **[[Dizziness]] | ||
**Syncope | **[[Syncope]] | ||
**Fatigue | **Fatigue | ||
**Hemoptysis | **[[Hemoptysis]] | ||
===Physical Examination=== | ===Physical Examination=== | ||
*Physical examination of patients with acute heart failure is usually remarkable for: | *Physical examination of patients with [[acute heart failure]] is usually remarkable for: | ||
**Crackles on auscultation | **[[Crackles]] on auscultation | ||
**Distended jugular veins | **[[Distended jugular veins]] | ||
**Lower extremity edema | **Lower extremity edema | ||
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*Cardiac Troponins: | *Cardiac Troponins: | ||
**Elevated | **Elevated [[cardiac troponin]] levels suggest the presence of myocardial cell injury or death. | ||
**Cardiac troponin levels may increase in patients with chronic or acute decompensated | **Cardiac troponin levels may increase in patients with chronic or acute decompensated heart failure.<ref name="pmid20863950">{{Cite pmid|20863950}}</ref> | ||
*Natriuretic Peptides: | *Natriuretic Peptides: | ||
**[[Natriuretic peptides]] (BNP/NT-proBNP) are released from the heart in response to increased myocardial stress and are quantitative markers of increased intracardiac filling pressure.<ref name="pmid28062628">{{Cite pmid|28062628}}</ref> | **[[Natriuretic peptides]] (BNP/NT-proBNP) are released from the heart in response to increased [[myocardial stress]] and are quantitative markers of increased [[intracardiac filling pressure]].<ref name="pmid28062628">{{Cite pmid|28062628}}</ref> | ||
**Elevated [[BNP]] and [[NT-proBNP]] are of both diagnostic and prognostic significance in patients with heart failure. | **Elevated [[BNP]] and [[NT-proBNP]] are of both diagnostic and prognostic significance in patients with [[heart failure]]. | ||
**Increased BNP or NT-proBNP levels have been demonstrated in COVID-19 patients. | **Increased [[BNP]] or [[NT-proBNP]] levels have been demonstrated in COVID-19 patients. | ||
**Increased NT-proBNP level was associated with worse clinical outcomes in patients with severe COVID-19.<ref name="pmid32293449">{{Cite pmid|32293449}}</ref> <ref name="pmid32232979">{{Cite pmid|32232979}}</ref> | **Increased [[NT-proBNP]] level was associated with worse clinical outcomes in patients with severe COVID-19.<ref name="pmid32293449">{{Cite pmid|32293449}}</ref> <ref name="pmid32232979">{{Cite pmid|32232979}}</ref> | ||
**However, increased natriuretic peptide levels are frequently seen among patients with severe inflammatory or respiratory diseases.<ref name="pmid18298480">{{Cite pmid|18298480}}</ref> <ref name="pmid16442916">{{Cite pmid|16442916}}</ref> <ref name="pmid28322314">{{Cite pmid|28322314}}</ref> <ref name="pmid23837838">{{Cite pmid|23837838}}</ref> <ref name="pmid21478812">{{Cite pmid|21478812}}</ref> | **However, increased [[natriuretic peptide]] levels are frequently seen among patients with severe inflammatory or respiratory diseases.<ref name="pmid18298480">{{Cite pmid|18298480}}</ref> <ref name="pmid16442916">{{Cite pmid|16442916}}</ref> <ref name="pmid28322314">{{Cite pmid|28322314}}</ref> <ref name="pmid23837838">{{Cite pmid|23837838}}</ref> <ref name="pmid21478812">{{Cite pmid|21478812}}</ref> | ||
**Therefore, routine measurement of BNP/NT-proBNP has not been recommended in COVID-19 patients, unless there is a high suspicion of | **Therefore, routine measurement of [[BNP]]/[[NT-proBNP]] has not been recommended in [[COVID-19 patients]], unless there is a high suspicion of [[heart failure]] based on clinical grounds. | ||
===Electrocardiogram=== | ===Electrocardiogram=== | ||
*There is no specific electrocardiographic finding for [[acute heart failure]] in COVID-19 patients. | *There is no specific electrocardiographic finding for [[acute heart failure]] in [[COVID-19 patients]]. | ||
*The ECG may help in identifying preexisting cardiac abnormalities and precipitating factors, such as [[ischemia]], [[myocarditis]], and [[arrhythmias]]. | *The ECG may help in identifying preexisting cardiac abnormalities and precipitating factors, such as [[ischemia]], [[myocarditis]], and [[arrhythmias]]. | ||
*These ECG findings may include: | *These ECG findings may include: | ||
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===X-ray=== | ===X-ray=== | ||
* | *A [[Chest x-ray]] may be helpful in the diagnosis of [[heart failure]]. Findings on [[chest X-ray]] suggestive of [[heart failure]] include: | ||
**[[Cardiomegaly]] | **[[Cardiomegaly]] | ||
**Pulmonary congestion | **[[Pulmonary congestion]] | ||
**Increased pulmonary vascular markings. | **Increased pulmonary vascular markings. | ||
*However, signs of [[pulmonary edema]] may be obscured by underlying respiratory involvement and ARDS due to COVID-19. | *However, signs of [[pulmonary edema]] may be obscured by underlying respiratory involvement and [[ARDS]] due to [[COVID-19]]. | ||
===Echocardiography or Ultrasound=== | ===Echocardiography or Ultrasound=== | ||
*A complete standard [[transthoracicechocardiography]] (TTE) has not been recommended in COVID-19 patients considering the limited personal protective equipment (PPE) and the risk of exposure of additional health care personnel.<ref name="pmid32391912">{{Cite pmid|32391912}}</ref> | *A complete standard [[transthoracicechocardiography]] [[(TTE)]] has not been recommended in [[COVID-19]] patients considering the limited [[personal protective equipment (PPE)]] and the risk of exposure of additional health care personnel.<ref name="pmid32391912">{{Cite pmid|32391912}}</ref> | ||
*To deal with limited resources (both personal protective equipment and personnel) and reducing the exposure time of personnel, a focused TTE to find gross abnormalities in cardiac structure/function seems satisfactory. | *To deal with limited resources (both personal protective equipment and personnel) and reducing the exposure time of personnel, a focused TTE to find gross abnormalities in cardiac structure/function seems satisfactory. | ||
*In addition, bedside options, which may be performed by the trained personnel who might already be in the room with these patients, might also be considered. These include: | *In addition, bedside options, which may be performed by the trained personnel who might already be in the room with these patients, might also be considered. These include: | ||
**[[Cardiac point-of-care ultrasound]] (POCUS) | **[[Cardiac point-of-care ultrasound]] [[(POCUS)]] | ||
**Focused cardiac ultrasound study (FoCUS) | **[[Focused cardiac ultrasound study]] [[(FoCUS)]] | ||
**Critical care echocardiography | **Critical care echocardiography | ||
*Cardiac ultrasound can help in assessing the following parameters: | *Cardiac ultrasound can help in assessing the following parameters: | ||
**Left ventricular systolic function (ejection fraction) to distinguish systolic dysfunction with a reduced ejection fraction (<40%) from diastolic dysfunction with a preserved ejection fraction | **[[Left ventricular systolic function]] [[(left ventricular ejection fraction, LVEF)]] to distinguish [[systolic dysfunction]] with a [[reduced ejection fraction]] (LVEF<40%) from [[diastolic dysfunction]] with a preserved ejection fraction (LVEF>40%) | ||
**Left ventricular diastolic function | **Left ventricular [[diastolic function]] | ||
**Left ventricular structural abnormalities, including | **Left ventricular structural abnormalities, including [[left ventricular size]] and [[left ventricular wall thickness]] | ||
**Left atrial size | **Left atrial size | ||
**Right ventricular size and function | **Right ventricular size and function | ||
**Detection and quantification of valvular abnormalities | **Detection and quantification of [[valvular abnormalities]] | ||
**Measurement of systolic pulmonary artery pressure | **Measurement of [[systolic pulmonary artery pressure]] | ||
**Detection and quantification of pericardial effusion | **Detection and quantification of [[pericardial effusion]] | ||
**Detection of [[regional wall motion abnormalities]]/reduced [[strain]] that would suggest underlying [[ischemia]]. | **Detection of [[regional wall motion abnormalities]]/reduced [[strain]] that would suggest underlying [[ischemia]]. | ||
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===Medical Therapy=== | ===Medical Therapy=== | ||
*Acute heart failure in the setting of COVID-19 is generally treated similarly to acute heart failure in other settings. These may include: | *[[Acute heart failure]] in the setting of [[COVID-19]] is generally treated similarly to [[acute heart failure]] in other settings. These may include: | ||
**Fluid restriction | **[[Fluid restriction]] | ||
**Diuretic therapy | **[[Diuretic]] therapy | ||
**[[Vasopressors]] and/or [[inotropes]] | **[[Vasopressors]] and/or [[inotropes]] | ||
**[[Ventricular assisted devices]] and [[extracorporeal membrane oxygenation (ECMO)]] | **[[Ventricular assisted devices]] and [[extracorporeal membrane oxygenation (ECMO)]] | ||
*[[Beta-blockers]] should not be initiated during the acute stage due to their negative inotropic effects.<ref name="pmid24251454">{{Cite pmid|24251454}}</ref> | *[[Beta-blockers]] should not be initiated during the acute stage due to their [[negative inotropic effects]].<ref name="pmid24251454">{{Cite pmid|24251454}}</ref> | ||
*[[Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)]] should be used with caution in patients with acute heart failure due to their effect on fluid and sodium retention.<ref name="pmid12656651">{{Cite pmid|12656651}}</ref> | *[[Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)]] should be used with caution in patients with [[acute heart failure]] due to their effect on fluid and sodium retention.<ref name="pmid12656651">{{Cite pmid|12656651}}</ref> | ||
*Patients with chronic heart failure are recommended to continue their previous guideline-directed medical therapy, including [[beta-blockers]], [[ | *Patients with [[chronic heart failure]] are recommended to continue their previous guideline-directed medical therapy, including [[beta-blockers]], [[ACE inhibitors]] or [[Angiotensin II receptor blockers]], and [[mineralocorticoid receptor antagonists]]. <ref name="pmid31129923">{{Cite pmid|31129923}}</ref> | ||
==References== | ==References== | ||
Revision as of 21:56, 29 June 2020
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]Mandana Chitsazan, M.D. [3]
Synonyms and keywords: coronavirus disease-19, coronavirus disease 2019, SARS-CoV-2, COVID-19, 2019-nCoV, 2019 novel coronavirus, acute heart failure, de novo acute heart failure, chronic heart failure, acute decompensated heart failure, HFrEF, HFpEF, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction
Overview
- Both de novo acute heart failure and acute decompensation of chronic heart failure can occur in patients with COVID-19.
- Patients with chronic heart failure may be at higher risk of developing severe COVID-19 infection due to the advanced age and the presence of multiple comorbidities.
Historical perspective
Classification
- Heart Failure ((HF) in COVID-19 may be classified similarly to heart failure from other causes.
- In general, heart failure can be classified based on:
- The pathophysiology of heart failure:
- The duration of symptoms:
- The underlying physiology based on left ventricular ejection fraction (LVEF):
- The severity of heart failure (i.e., the New York Heart Association Class I-IV)
- The stage of congestive heart failure (i.e., AHA Class A, B, C, D)
- Acute heart failure has two forms:
- Newly-arisen (“de novo”) acute heart failure
- Acutely decompensated chronic heart failure (ADCHF)
Pathophysiology
- Presumed pathophysiologic mechanisms for the development of new or decompensated heart failure in patients with COVID-19 include:[1] [2] [3] [4] [5]
- Acute exacerbation of chronic heart failure caused by precipitating factors
- Acute myocardial injury (which in turn can be caused by several mechanisms)
- Stress cardiomyopathy (i.e., Takotsubo cardiomyopathy)
- Impaired myocardial relaxation resulting in diastolic dysfunction [i.e., Heart failure with preserved ejection fraction (HFpEF) ]
- Right-sided heart failure, secondary to pulmonary hypertension caused by hypoxia and acute respiratory distress syndrome (ARDS)
Causes
- Acute myocardial injury
- Acute coronary syndromes
- Myocarditis
- Hypertensive crisis
- Arrhythmias: Tachycardia or severe bradycardia
- Stress-induced cardiomyopathy
- Circulatory failure:
- Iatrogenic
Differentiating ((COVID-19 associated heart failure)) from other Diseases
In patients with COVID-19 infection, acute heart failure should be differentiated from other diseases presenting with dyspnea and/or tachypnea. The differentials include the following:
Epidemiology and Demographics
- Data on incidence on acute heart failure in COVID-19 patients is limited.
- In one study, acute heart failure was seen in 4.1% of patients with acute cardiac injury.
- In a retrospective study on 191 COVID-19 patients in Wuhan, China, the incidence of heart failure was 23% (52% in non-survivors vs 12% in survivors).
Risk Factors
Screening
- There is insufficient evidence to recommend routine screening for heart failure in COVID-19 patients.
- Routine measurement of natriuretic peptides and/or cardiac troponins have not been recommended in the absence of a high index of suspicion for HF on the clinical grounds.
Natural History, Complications, and Prognosis
- COVID-19 patients with chronic heart failure are more likely to develop severe forms of the disease.
- COVID-19 patients who develop acute heart failure (either de novo AHF or ADHF) have worse outcomes.
- Acute heart failure in COVID-19 may progress to cardiogenic shock.
Diagnosis
Diagnostic Study of Choice
History and Symptoms
- The most common symptoms of acute heart failure in COVID-19 patients are:
- New or worsening dyspnea: may overlap with dyspnea caused by concomitant respiratory involvement and ARDS due to COVID-19
- Peripheral edema
- Confusion and altered mentation
- Orthopnea
- Palpitations
- Less common symptoms include:
- Paroxysmal nocturnal dyspnea
- Cool extremities
- Cyanosis
- Dizziness
- Syncope
- Fatigue
- Hemoptysis
Physical Examination
- Physical examination of patients with acute heart failure is usually remarkable for:
- Crackles on auscultation
- Distended jugular veins
- Lower extremity edema
Laboratory Findings
- Cardiac Troponins:
- Elevated cardiac troponin levels suggest the presence of myocardial cell injury or death.
- Cardiac troponin levels may increase in patients with chronic or acute decompensated heart failure.[6]
- Natriuretic Peptides:
- Natriuretic peptides (BNP/NT-proBNP) are released from the heart in response to increased myocardial stress and are quantitative markers of increased intracardiac filling pressure.[7]
- Elevated BNP and NT-proBNP are of both diagnostic and prognostic significance in patients with heart failure.
- Increased BNP or NT-proBNP levels have been demonstrated in COVID-19 patients.
- Increased NT-proBNP level was associated with worse clinical outcomes in patients with severe COVID-19.[8] [9]
- However, increased natriuretic peptide levels are frequently seen among patients with severe inflammatory or respiratory diseases.[10] [11] [12] [13] [14]
- Therefore, routine measurement of BNP/NT-proBNP has not been recommended in COVID-19 patients, unless there is a high suspicion of heart failure based on clinical grounds.
Electrocardiogram
- There is no specific electrocardiographic finding for acute heart failure in COVID-19 patients.
- The ECG may help in identifying preexisting cardiac abnormalities and precipitating factors, such as ischemia, myocarditis, and arrhythmias.
- These ECG findings may include:
- Low QRS Voltage
- Left ventricular hypertrophy
- Left atrial enlargement
- Left bundle branch block
- Poor R progression
- ST-T changes
X-ray
- A Chest x-ray may be helpful in the diagnosis of heart failure. Findings on chest X-ray suggestive of heart failure include:
- Cardiomegaly
- Pulmonary congestion
- Increased pulmonary vascular markings.
- However, signs of pulmonary edema may be obscured by underlying respiratory involvement and ARDS due to COVID-19.
Echocardiography or Ultrasound
- A complete standard transthoracicechocardiography (TTE) has not been recommended in COVID-19 patients considering the limited personal protective equipment (PPE) and the risk of exposure of additional health care personnel.[15]
- To deal with limited resources (both personal protective equipment and personnel) and reducing the exposure time of personnel, a focused TTE to find gross abnormalities in cardiac structure/function seems satisfactory.
- In addition, bedside options, which may be performed by the trained personnel who might already be in the room with these patients, might also be considered. These include:
- Cardiac point-of-care ultrasound (POCUS)
- Focused cardiac ultrasound study (FoCUS)
- Critical care echocardiography
- Cardiac ultrasound can help in assessing the following parameters:
- Left ventricular systolic function (left ventricular ejection fraction, LVEF) to distinguish systolic dysfunction with a reduced ejection fraction (LVEF<40%) from diastolic dysfunction with a preserved ejection fraction (LVEF>40%)
- Left ventricular diastolic function
- Left ventricular structural abnormalities, including left ventricular size and left ventricular wall thickness
- Left atrial size
- Right ventricular size and function
- Detection and quantification of valvular abnormalities
- Measurement of systolic pulmonary artery pressure
- Detection and quantification of pericardial effusion
- Detection of regional wall motion abnormalities/reduced strain that would suggest underlying ischemia.
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
- Acute heart failure in the setting of COVID-19 is generally treated similarly to acute heart failure in other settings. These may include:
- Beta-blockers should not be initiated during the acute stage due to their negative inotropic effects.[16]
- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) should be used with caution in patients with acute heart failure due to their effect on fluid and sodium retention.[17]
- Patients with chronic heart failure are recommended to continue their previous guideline-directed medical therapy, including beta-blockers, ACE inhibitors or Angiotensin II receptor blockers, and mineralocorticoid receptor antagonists. [18]
References
- ↑ PMID 32219357 (PMID 32219357)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 32360242 (PMID 32360242)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 32186331 (PMID 32186331)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 30625066 (PMID 30625066)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 32140732 (PMID 32140732)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 20863950 (PMID 20863950)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 28062628 (PMID 28062628)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 32293449 (PMID 32293449)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 32232979 (PMID 32232979)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 18298480 (PMID 18298480)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 16442916 (PMID 16442916)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 28322314 (PMID 28322314)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 23837838 (PMID 23837838)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 21478812 (PMID 21478812)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 32391912 (PMID 32391912)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 24251454 (PMID 24251454)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 12656651 (PMID 12656651)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand - ↑ PMID 31129923 (PMID 31129923)
Citation will be completed automatically in a few minutes. Jump the queue or expand by hand