Tricuspid regurgitation differential diagnosis: Difference between revisions

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*Severe TR has been documented to mimic some hemodynamic findings in [[constrictive pericarditis]], with [[right heart catheterization]] demonstrating a constrictive physiology. [[Echocardiography]], CT thorax, and [[cardiac MRI]] are useful for ruling out [[pericardium|pericardial]] pathology.
*Severe TR has been documented to mimic some hemodynamic findings in [[constrictive pericarditis]], with [[right heart catheterization]] demonstrating a constrictive physiology. [[Echocardiography]], CT thorax, and [[cardiac MRI]] are useful for ruling out [[pericardium|pericardial]] pathology.
|}<br />
{| class="wikitable"
! rowspan="2" |Diseases
! rowspan="2" |History
! rowspan="2" |Symptoms
! rowspan="2" |Physical Examination
! rowspan="2" |Murmur
! colspan="4" |Diagnosis
! rowspan="2" |Other Findings
|- style="background: #DCDCDC; padding: 5px; text-align: center;"
!ECG
!CXR
!Echocardiogram
!Cardiac Catheterization
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Mitral Stenosis]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Age ( Mitral annular calcification in older patients)
*[[Rheumatic fever]]
*[[Endocarditis]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[Dyspnea on exertion]]
*[[Paroxysmal nocturnal dyspnea]]
*[[Orthopnea]]
*New onset [[atrial fibrillation]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Mitral facies
*Heart murmur
*[[JVD|Jugular vein distension]]
*Apical impulse displaced laterally or not palpable
*Diastolic thrill  at the apex
*Signs of heart failure in severe cases
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Diastolic murmur
*Low pitched
*Opening snap  followed by decrescendo-crescendo rumbling murmur
*Best heard with the bell of the stethoscope at apex at end-expiration in left lateral decubitus position
*Intensity increases after a [[valsalva maneuver]], after exercise and after increased after load (eg., squatting, isometric hand grip)
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[P mitrale]]
*[[Atrial  fibrillation]]: No P waves and irregularly irregular rhythm
*[[Right axis deviation]]
*Right ventricular hypertropy: Dominant R wave in V1 and V2
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Straightening of the left border of the heart suggestive of enlargement of the [[left atrium]]
*Double right heart border (Enlarged left atrium and normal right atrium)
*Prominent left atrial appendage
*Splaying of [[Carina|subcarinal angle]] (>120 degrees)
*Calcification of [[mitral valve]]
*[[Kerley B lines]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Reduced valve leaflet mobility
*Valve calcification
*Doming of mitral valve
*Valve thickening
*Enlargement of left atrium
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Right heart catheterization:'''
*[[Pulmonary capillary wedge pressure]] (left atrial pressure)
'''Left heart catheterization:'''
*Pressures in left ventricle
*Determines the gradient between the left and right atrium during ventricular diastole (marker of the severity of mitral stenosis)
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[Hemoptysis]] ([[heart failure]])
*[[Ortner's syndrome]]
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |[[Mitral Regurgitation]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[CAD]]
*[[MI]]
*[[Rheumatic fever]]
*[[Endocarditis]]
*[[Mitral valve prolapse]]
*[[Cardiomyopathy]]
*[[Radiation therapy]]
*Trauma
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[Palpitations]]
*Symptoms of heart failure in severe cases
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Palpation'''
*Brisk carotid upstroke and hyperdymanic carotid impulse on palpation
*Apical impulse is displaced to left
*S3 and a palpable thrill
'''Auscultation'''
*Murmur
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[Holosystolic murmur]]
*High pitched, blowing
*Radiates to axilla
*Best heard with the diaphragm of the stethoscope at apex in left lateral [[decubitus]] position
*Intensity increases with hand grip or squatting
*Decrease in intensity on standing or [[valsalva maneuver]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[P mitrale]] in lead II
*Increased QRS voltage
*[[Right axis deviation]]
*[[Atrial fibrillation]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Acute MR'''
*[[Kerley B lines]]
*No enlargement of cardiac silhouette
'''Chronic MR'''
*Enlarged cardiac silhouette
*Straightening of left heart border
*Splaying of subcarinal angle
*Calcification of mitral annulus
*Double right heart border
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Enlargement of left atrium and ventricle
*Identify valve abnormality
*Valve calcification
*Severity of regurgitation
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Grading of MR is done with left ventriculography
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Decompensated and acute MR may lead to [[heart failure]]
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |[[Atrial septal defect]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Frequent respiratory or lung infections
*[[Dyspnea]]
*Tiring when feeding (Infants)
*Shortness of breath on exertion
*[[Palpitations]]
*Swelling of feet
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[Shortness of breath]]
*[[Fatigue]]
*[[Failure to thrive]]
*Swelling of feet and abdomen ([[Right heart failure]])
*[[Palpitations]]
*Respiratory infections
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Inspection'''
*Precordial bulge
*Precordial lift
'''Palpation'''
*Right ventricular impulse
*Pulmonary artery pulsations
*Thrill
'''Auscultation'''
*Murmur
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Midsystolic (ejection systolic) murmur
*Widely split, fixed S2
*Upper left sternal border
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Normal
*Prolonged PR interval
*[[Right bundle branch block]]
*ECG findings varies according to the underlying type of ASD
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Increased pulmonary markings
*[[Cardiomegaly]]
*Triangular appearance of heart
*Schimitar sign
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Gold standard test for diagnosis of atrial septal defect  (for more information click [[Atrial septal defect echocardiography]])
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Defect size
*Pulmonary venous return
*[[Pulmonary vascular resistance]]
*[[Pulmonary artery hypertension]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Asymptomatic until later part of their life
*May be associated with [[migraine with aura]]
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |[[Atrial myxoma|Left Atrial Myxoma]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*[[Dyspnea]]
*[[Orthopnea]]
*[[Pulmonary edema]]
*Hyperpigmentation of skin and endocrine activity
*Cerebral [[embolism]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Symptoms may mimic mitral stenosis
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Skin'''
*Signs of an embolic phenomenon
*[[Raynaud's phenomenon]]
*Swelling
*Clubbing
'''Auscultation:'''
*Lung: Fine crepitations
*Heart: Characteristic "tumor plop"
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Early diastolic sound as "tumor plop"
*Low frequency diastolic murmur may be heard if the tumor obstructing mitral valve
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Often normal
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Often normal
'''Rare findings:'''
*[[cardiomegaly]]
*Left atrial enlargement
*tumor calcification etc.,
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Initial and most useful diagnostic study
*For more information click [[Myxoma echocardiography or ultrasound]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Useful to detect vascular supply of the tumor by the coronary arteries
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Associated with Carney complex (genetic predisposition)
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |Prosthetic Valve Obstruction
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*History of valve replacement
*Systemic embolism
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Shortness of breath
*Fatigue
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Ausculation'''
Muffling of murmur
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Muffling or disappearance of prosthetic sounds
*Appearance of new regurgitant or obstructive murmur
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Degree of stenosis
*Assess thrombus size and location
*Differentiate between thrombus, [[pannus]] and vegetations
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |Causes:
*Thrombus
*Pannus formation
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |[[Cor Triatriatum]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Dyspnea on exertion
*Recent onset of [[congestive heart failure]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Dsypnea on exertion
*Orthopnea
*Tachypnea
*Palpitations
*Growth failure
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Auscultation'''
*Murmur
'''Other findings'''
*Signs of heart failure
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Diastolic murmur with loud P2
*No opening snap or a loud S1
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |Non specific but may have
*[[Right axis deviation]]
*Right atrial enlargement
*[[Right ventricular hypertrophy]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Normal cardiac silhouette
*Hemodynamic changes similar to mitral stenosis (non specific findings)
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Direct visualization of membrane through the atrium
*+/- visualization of accessory chamber
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Normal left ventricular hemodynamic profile with a trans atrial gradient
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |Types
*Cor triatriatum sinistrum
*Cor triatriatum dextrum
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |Congenital Mitral Stenosis
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Respiratory distress shortly after birth
*Recurrent severe pulmonary infections
*Other associated congenital cardiovascular anamolies
*[[Atrial fibrillation]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Infants:'''
*Exhaustion and sweating on feeding
*Rapid breathing
*[[Failure to thrive]]
*Pulmonary infections
*Chronic cough
'''Older patients:'''
*Dyspnea
*Orthopnea
*Paroxysmal nocturnal dyspnea
*Peripheral edema
*Fatigue
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Auscultation'''
*Murmur
'''Other findings'''
*Signs of heart failure
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Mild-Moderate'''
*Loud S1
*Loud P2
*Low frequency diastolic murmur best heard at the apex
'''Severe'''
*Soft S1
*Loud pulmonic component of S2 with minimal respiratory splitting of S2
*Holodiastolic murmur with presystolic accentuation best heard at the apex
*Early diastolic murmur of pulmonic valve regurgitation
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Sharp P waves in leads I and II
*Inversion of P wave in lead III
*Marked Q waves in leads II and III
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Left atrial dilation
*Moderate enlargement of right heart
*Pulmonary venous congestion
*Esophageal compression
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Reduced valve leaflet mobility
*Left atrial size
*Severity of mitral stenosis
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |Very rare condition
|-
| colspan="10" |
|-
| style="vertical-align: top;background: #DCDCDC; padding: 5px; text-align: center;" |Supravalvular Ring Mitral Stenosis
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Other associated congenital heart defects
*Fatigue
*Frequent respiratory infections
*Failure to thrive
*Poor feeding
*Precocious congestive heart failure
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Shortness of breath
*Tachypnea
*Dyspnea
*Nocturnal cough
*Heamoptysis
*[[Syncope]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Auscultation:'''
Lungs: Fine, crepitant rales and rhonchi or wheezes may be present
Heart: Murmur
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*An apical mid diastolic murmur with presystolic accentuation
*No opening snap
*The murmur is more prominent if associated with [[VSD]] or [[PDA]]
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Left atrial and ventricular enlargement
*Alveolar edema
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Supramitral ring''':
*Associated with normal mitral valve apparatus
'''Intramitral ring:'''
*Hypomobility of the posterior leaflet
*Reduced interpapillary muscle distance
*Reduced chordal length
*Dominant papillary muscle
*Hypoplastic mitral annulus
(Difficult to visualize membrane <1mm in size)
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |
*Persistently elevated pulmonary venous pressures
*Increased pulmonary artery pressure
| style="vertical-align: top;background: #F5F5F5; padding: 5px;" |'''Types'''
*Supramitral
*Intramitral
It is attached between the opening of the atrial appendage and the mitral annulus which helps in differentiating with Cor triatriatum sinister.
*Intramitral type is associated with shone complex
|}
|}
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Revision as of 18:55, 17 January 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]

Overview

The blowing holosystolic murmur of tricuspid regurgitation must be distinguished from the murmur of mitral regurgitation and a ventricular septal defect.

Differentiating Tricuspid regurgitation from other Diseases

Tricuspid Regurgitation Mitral Regurgitation VSD Constrictive Pericarditis[1]
  • The holosystolic murmur can be best heard over the left third and fourth intercostal spaces and along the sternal border.
  • When the shunt becomes reversed (Eisenmenger's syndrome), the murmur may be absent and S2 can become markedly accentuated and single.
Tricuspid Regurgitation Mitral Regurgitation VSD Constrictive Pericarditis[1]
  • The holosystolic murmur can be best heard over the left third and fourth intercostal spaces and along the sternal border.
  • When the shunt becomes reversed (Eisenmenger's syndrome), the murmur may be absent and S2 can become markedly accentuated and single.


Diseases History Symptoms Physical Examination Murmur Diagnosis Other Findings
ECG CXR Echocardiogram Cardiac Catheterization
Mitral Stenosis
  • Age ( Mitral annular calcification in older patients)
  • Mitral facies
  • Heart murmur
  • Apical impulse displaced laterally or not palpable
  • Diastolic thrill at the apex
  • Signs of heart failure in severe cases
  • Diastolic murmur
  • Low pitched
  • Opening snap followed by decrescendo-crescendo rumbling murmur
  • Best heard with the bell of the stethoscope at apex at end-expiration in left lateral decubitus position
  • Intensity increases after a valsalva maneuver, after exercise and after increased after load (eg., squatting, isometric hand grip)
  • Right ventricular hypertropy: Dominant R wave in V1 and V2
  • Straightening of the left border of the heart suggestive of enlargement of the left atrium
  • Double right heart border (Enlarged left atrium and normal right atrium)
  • Prominent left atrial appendage
  • Reduced valve leaflet mobility
  • Valve calcification
  • Doming of mitral valve
  • Valve thickening
  • Enlargement of left atrium
Right heart catheterization:

Left heart catheterization:

  • Pressures in left ventricle
  • Determines the gradient between the left and right atrium during ventricular diastole (marker of the severity of mitral stenosis)
Mitral Regurgitation
  • Trauma
  • Symptoms of heart failure in severe cases
Palpation
  • Brisk carotid upstroke and hyperdymanic carotid impulse on palpation
  • Apical impulse is displaced to left
  • S3 and a palpable thrill

Auscultation

  • Murmur
  • High pitched, blowing
  • Radiates to axilla
  • Best heard with the diaphragm of the stethoscope at apex in left lateral decubitus position
  • Intensity increases with hand grip or squatting
Acute MR

Chronic MR

  • Enlarged cardiac silhouette
  • Straightening of left heart border
  • Splaying of subcarinal angle
  • Calcification of mitral annulus
  • Double right heart border
  • Enlargement of left atrium and ventricle
  • Identify valve abnormality
  • Valve calcification
  • Severity of regurgitation
  • Grading of MR is done with left ventriculography
Atrial septal defect
  • Frequent respiratory or lung infections
  • Dyspnea
  • Tiring when feeding (Infants)
  • Shortness of breath on exertion
  • Palpitations
  • Swelling of feet
Inspection
  • Precordial bulge
  • Precordial lift

Palpation

  • Right ventricular impulse
  • Pulmonary artery pulsations
  • Thrill

Auscultation

  • Murmur
  • Midsystolic (ejection systolic) murmur
  • Widely split, fixed S2
  • Upper left sternal border
  • Increased pulmonary markings
  • Cardiomegaly
  • Triangular appearance of heart
  • Schimitar sign
Left Atrial Myxoma
  • Symptoms may mimic mitral stenosis
Skin

Auscultation:

  • Lung: Fine crepitations
  • Heart: Characteristic "tumor plop"
  • Early diastolic sound as "tumor plop"
  • Low frequency diastolic murmur may be heard if the tumor obstructing mitral valve
  • Often normal
  • Often normal

Rare findings:

  • cardiomegaly
  • Left atrial enlargement
  • tumor calcification etc.,
  • Useful to detect vascular supply of the tumor by the coronary arteries
  • Associated with Carney complex (genetic predisposition)
Prosthetic Valve Obstruction
  • History of valve replacement
  • Systemic embolism
  • Shortness of breath
  • Fatigue
Ausculation

Muffling of murmur

  • Muffling or disappearance of prosthetic sounds
  • Appearance of new regurgitant or obstructive murmur
  • Degree of stenosis
  • Assess thrombus size and location
  • Differentiate between thrombus, pannus and vegetations
Causes:
  • Thrombus
  • Pannus formation
Cor Triatriatum
  • Dsypnea on exertion
  • Orthopnea
  • Tachypnea
  • Palpitations
  • Growth failure
Auscultation
  • Murmur

Other findings

  • Signs of heart failure
  • Diastolic murmur with loud P2
  • No opening snap or a loud S1
Non specific but may have
  • Normal cardiac silhouette
  • Hemodynamic changes similar to mitral stenosis (non specific findings)
  • Direct visualization of membrane through the atrium
  • +/- visualization of accessory chamber
  • Normal left ventricular hemodynamic profile with a trans atrial gradient
Types
  • Cor triatriatum sinistrum
  • Cor triatriatum dextrum
Congenital Mitral Stenosis
  • Respiratory distress shortly after birth
  • Recurrent severe pulmonary infections
  • Other associated congenital cardiovascular anamolies
  • Atrial fibrillation
Infants:
  • Exhaustion and sweating on feeding
  • Rapid breathing
  • Failure to thrive
  • Pulmonary infections
  • Chronic cough

Older patients:

  • Dyspnea
  • Orthopnea
  • Paroxysmal nocturnal dyspnea
  • Peripheral edema
  • Fatigue
Auscultation
  • Murmur

Other findings

  • Signs of heart failure
Mild-Moderate
  • Loud S1
  • Loud P2
  • Low frequency diastolic murmur best heard at the apex

Severe

  • Soft S1
  • Loud pulmonic component of S2 with minimal respiratory splitting of S2
  • Holodiastolic murmur with presystolic accentuation best heard at the apex
  • Early diastolic murmur of pulmonic valve regurgitation
  • Sharp P waves in leads I and II
  • Inversion of P wave in lead III
  • Marked Q waves in leads II and III
  • Left atrial dilation
  • Moderate enlargement of right heart
  • Pulmonary venous congestion
  • Esophageal compression
  • Reduced valve leaflet mobility
  • Left atrial size
  • Severity of mitral stenosis
Very rare condition
Supravalvular Ring Mitral Stenosis
  • Other associated congenital heart defects
  • Fatigue
  • Frequent respiratory infections
  • Failure to thrive
  • Poor feeding
  • Precocious congestive heart failure
  • Shortness of breath
  • Tachypnea
  • Dyspnea
  • Nocturnal cough
  • Heamoptysis
  • Syncope
Auscultation:

Lungs: Fine, crepitant rales and rhonchi or wheezes may be present

Heart: Murmur

  • An apical mid diastolic murmur with presystolic accentuation
  • No opening snap
  • The murmur is more prominent if associated with VSD or PDA
  • Left atrial and ventricular enlargement
  • Alveolar edema
Supramitral ring:
  • Associated with normal mitral valve apparatus

Intramitral ring:

  • Hypomobility of the posterior leaflet
  • Reduced interpapillary muscle distance
  • Reduced chordal length
  • Dominant papillary muscle
  • Hypoplastic mitral annulus

(Difficult to visualize membrane <1mm in size)

  • Persistently elevated pulmonary venous pressures
  • Increased pulmonary artery pressure
Types
  • Supramitral
  • Intramitral

It is attached between the opening of the atrial appendage and the mitral annulus which helps in differentiating with Cor triatriatum sinister.

  • Intramitral type is associated with shone complex

References

  1. 1.0 1.1 Ozpelit E, Akdeniz B, Ozpelit ME, Göldeli O (2014). "Severe tricuspid regurgitation mimicking constrictive pericarditis". Am J Case Rep. 15: 271–4. doi:10.12659/AJCR.890092. PMC 4079647. PMID 24995118.

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