Pulmonic regurgitation pathophysiology: Difference between revisions

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{{Pulmonic regurgitation}}
{{Pulmonic regurgitation}}


{{CMG}} {{AE}} {{AKI}}, {{AA}}
{{CMG}} {{AE}} {{AKI}}, {{AA}}, {{JA}}


==Overview==
==Overview==
Pathophysiologic mechanism of [[pulmonic regurgitation]] include [[right ventricular overload]] resulting in right ventricular remodelling and progressive decline in function. The rate of decline in right ventricular [[systolic function]] is affected by associated conditions such as peripheral [[pulmonary artery stenosis]] and [[pulmonary hypertension]] which further increase the severity of [[pulmonary regurgitation]].<ref name="pmid26430501">{{cite journal| author=Bigdelian H, Mardani D, Sedighi M| title=The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF). | journal=J Cardiovasc Thorac Res | year= 2015 | volume= 7 | issue= 3 | pages= 122-5 | pmid=26430501 | doi=10.15171/jcvtr.2015.26 | pmc=4586599 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26430501  }} </ref>
[[Pulmonary valve]] is located at the junction of the [[Ventricular outflow tract|right ventricular outflow tract]] and [[pulmonary artery]]. Three equal-sized, semilunar cusps or leaflets make up the [[pulmonary valve]]. [[Pulmonary valve]] opens during right ventricular [[systole]] and closes during right ventricular [[diastole]]. [[PR|Pulmonary regurgitation]] (PR) may be caused by an acquired alteration in the valvular [[morphology]], idiopathic dilatation of the [[pulmonary artery]] (IDPA), [[pulmonic valve]] ring dilatation,  congenital absence or malformation of the [[pulmonary valve|valve]], and increasing [[regurgitation]] causing [[right ventricle|right ventricular]] volume overload. The pathophysiologic mechanism of [[pulmonic regurgitation]] includes [[right ventricular overload]] resulting in the right [[ventricular remodeling]] and progressive decline in function. The rate of decline in right ventricular [[systole|systolic function]] is affected by associated conditions such as peripheral [[pulmonary artery stenosis]] and [[pulmonary hypertension]] which further increase the severity of [[pulmonary regurgitation]]. Among [[patients]] with severe [[PR]], the gene expression pattern of GRK2 and β2-[[Adrenergic receptor|adrenoceptor]] (molecular markers of [[cardiac dysfunction]]) has been reported to be altered. Isolated [[PR]] is uncommon and is usually demonstrated with other [[valve|valvular]] abnormalities or in certain conditions. Conditions associated include [[TOF]], [[rheumatic heart disease]] and [[syphilis]]. On gross pathology [[vegetation|vegetative lesions]] on the [[pulmonic valve]] leaflets may be observed among [[patient|patients]] with [[acquired]] alteration in the [[valve|valvular]] leaflet [[morphology]].


==Pathophysiology==
==Pathophysiology==
Pathophysiologic mechanism of pulmonic regurgitation may include the following steps:
===Anatomy of and physiology of [[pulmonic valve]]===
*Patients with PR develop chronic right ventricular overload resulting in right ventricular remodelling and progressive decline in function.<ref name="pmid26430501">{{cite journal| author=Bigdelian H, Mardani D, Sedighi M| title=The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF). | journal=J Cardiovasc Thorac Res | year= 2015 | volume= 7 | issue= 3 | pages= 122-5 | pmid=26430501 | doi=10.15171/jcvtr.2015.26 | pmc=4586599 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26430501 }} </ref>
*'''Location''': [[Pulmonary valve]] is located at the junction of the [[Ventricular outflow tract|right ventricular outflow tract]] and [[pulmonary artery]]. [[Pulmonic valve]] lies anterior and superior to the [[aortic valve]] at third intercostal space level. Infundibulum of the [[right ventricle]] separates it from [[tricuspid valve]].<ref name="pmid20435842">{{cite journal| author=Maganti K, Rigolin VH, Sarano ME, Bonow RO| title=Valvular heart disease: diagnosis and management. | journal=Mayo Clin Proc | year= 2010 | volume= 85 | issue= 5 | pages= 483-500 | pmid=20435842 | doi=10.4065/mcp.2009.0706 | pmc=2861980 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20435842 }} </ref>
*Progressive dilation of the right ventricle results in functional tricuspid regurgitation and increases the risk of developing arrhythmias.
[[File:Pulmonic valve anatomy.jpeg||thumb|400px|center| Cadaveric specimen of [[heart]] demonstrating [[pulmonary valve]] location between [[Ventricular outflow tract|right ventricular outflow tract]] and [[pulmonary artery]] - By Anatomist90 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20481209]]
*The rate of decline in right ventricular systolic function is affected by associated conditions such as peripheral pulmonary artery stenosis and pulmonary hypertension which further increase the severity of pulmonary regurgitation.
*'''Structure''': Three equal sized, semilunar cusps or leaflets make up the [[pulmonary valve]]. Based on the corresponding [[aortic valve]], the cusps are named right, left and anterior.<ref name="pmid10">{{cite journal |vauthors=Schmoldt A, Benthe HF, Haberland G, Felt V, Nedvídková J, Hynie S, Mosinger B, Vavrinková M, Järvisalo J, Saris NE |title=Digitoxin metabolism by rat liver microsomes |journal=Biochem. Pharmacol. |volume=24 |issue=17 |pages=1639–41 |date=September 1975 |pmid=10 |pmc=5922622 |doi=10.1016/0006-2952(75)90009-x |url=}}</ref> <ref name="pmid10">{{cite journal |vauthors=Schmoldt A, Benthe HF, Haberland G, Robinson JV, James AL, Sondén A, Rocksén D, Riddez L, Davidsson J, Persson JK, Gryth D, Bursell J, Arborelius UP, Ehrhart IC, Parker PE, Weidner WJ, Dabney JM, Scott JB, Haddy FJ, Meyer WJ, Gidwitz S, Ayers VK, Schoepp RJ, Johnston RE |title=Digitoxin metabolism by rat liver microsomes |journal=Biochem. Pharmacol. |volume=24 |issue=17 |pages=1639–41 |date=September 1975 |pmid=10 |pmc=5922622 |doi=10.1097/TA.0b013e3181a5b0e1 |url=}}</ref>
*In patients with increased pulmonary artery pressure from dysfunction of LV or residual pulmonary artery stenosis increases the severity of PR.
*The three cusps are joined by [[commissures]] and the [[Cusps of heart valves|cusps]] are thinner when compared to the aortic valve, due to a low pressure in the right ventricle.<ref name="pmid10">{{cite journal |vauthors=Schmoldt A, Benthe HF, Haberland G, Raffle A, Gray J, MacDonald HR, Flohr H, Breull W, Wiesmann UN, DiDonato S, Herschkowitz NN, Horváth I, Arányi P, Náray A, Földes I, Gyuris A |title=Digitoxin metabolism by rat liver microsomes |journal=Biochem. Pharmacol. |volume=24 |issue=17 |pages=1639–41 |date=September 1975 |pmid=10 |pmc=5922622 |doi=10.1136/bmj.1.6001.93-a |url=}}</ref>
*The severity of regurgitant jet is dependent on:<ref name="pmid26430501">{{cite journal| author=Bigdelian H, Mardani D, Sedighi M| title=The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF). | journal=J Cardiovasc Thorac Res | year= 2015 | volume= 7 | issue= 3 | pages= 122-5 | pmid=26430501 | doi=10.15171/jcvtr.2015.26 | pmc=4586599 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26430501  }} </ref>
*Histologically, the [[pulmonary valve]] consists of stratified extracellular matrix compartments. The layers constitute fibrosa, spongiosa and ventricularis.<ref name="pmid19713546">{{cite journal |vauthors=Combs MD, Yutzey KE |title=Heart valve development: regulatory networks in development and disease |journal=Circ. Res. |volume=105 |issue=5 |pages=408–21 |date=August 2009 |pmid=19713546 |pmc=2777683 |doi=10.1161/CIRCRESAHA.109.201566 |url=}}</ref>
**Size of the regurgitant orifice
*The diameter of [[pulmonic valve]] is demonstrated to be closely related to the body size. For adult men (>17 years age) mean [[pulmonary valve]] diameter is 26.2 +/- 2.3 mm and 23.9 +/- 2.2 mm  for adult women.<ref name="pmid10788818">{{cite journal |vauthors=Capps SB, Elkins RC, Fronk DM |title=Body surface area as a predictor of aortic and pulmonary valve diameter |journal=J. Thorac. Cardiovasc. Surg. |volume=119 |issue=5 |pages=975–82 |date=May 2000 |pmid=10788818 |doi=10.1016/S0022-5223(00)70092-4 |url=}}</ref>
**Afterload of the RV
*'''Physiology''': The [[right ventricle]] delivers the received blood entirely to the pulmonary circulation every beat, maintaining optimum pressure.<ref name="pmid27613549">{{cite journal |vauthors=Pinsky MR |title=The right ventricle: interaction with the pulmonary circulation |journal=Crit Care |volume=20 |issue= |pages=266 |date=September 2016 |pmid=27613549 |pmc=5018168 |doi=10.1186/s13054-016-1440-0 |url=}}</ref> [[Pulmonary valve]] opens during right ventricular [[systole]] allowing the [[deoxygenated]] blood to be delivered to the [[lungs]]. <ref name="pmid10">{{cite journal |vauthors=Schmoldt A, Benthe HF, Haberland G, Fleet GH, Phaff HJ, van Dam-Mieras MC, Slotboom AJ, Pieterson WA, de Haas GH |title=Digitoxin metabolism by rat liver microsomes |journal=Biochem. Pharmacol. |volume=24 |issue=17 |pages=1639–41 |date=September 1975 |pmid=10 |pmc=5922622 |doi=10.1016/0005-2744(75)90234-x |url=}}</ref> During the right ventricular [[diastole]] the [[pulmonary valve]]s close completely to prevent [[regurgitation]] (back flow) of the [[blood]] into the [[right ventricle]].<ref name="pmid10">{{cite journal |vauthors=Schmoldt A, Benthe HF, Haberland G, Tarentino AL, Maley F, Korelitz BI, Sommers SC, Schmoldt A, Benthe HF, Haberland G, Schmoldt A, Benthe HF, Haberland G |title=Digitoxin metabolism by rat liver microsomes |journal=Biochem. Pharmacol. |volume=24 |issue=17 |pages=1639–41 |date=September 1975 |pmid=10 |pmc=5922622 |doi=10.1016/0006-291x(75)90337-x |url=}}</ref>
**RV diastolic complaince
*The closure of the pulmonic valve contributes to the P2 component of the [[second heart sound]] ([[S2]]).
**Duration of RV diastole
===Pathogenesis===
==== According to 2014, ACC/AHA valvular heart disease guidelines the stages of severe pulmonary regurgitation are described as follows:<ref name="pmid24603191">{{cite journal| author=Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA et al.| title=2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2014 | volume= 63 | issue= 22 | pages= e57-185 | pmid=24603191 | doi=10.1016/j.jacc.2014.02.536 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24603191  }} </ref> ====
The pathogenesis of [[pulmonic regurgitation]] involves the following mechanisms:<ref>{{cite book | last = Khavandi | first = Ali | title = Essential revision notes for the cardiology KBA | publisher = Oxford University Press | location = Oxford | year = 2014 | isbn = 978-0199654901 }} </ref><ref>{{cite book | last = Khavandi | first = Ali | title = Essential revision notes for the cardiology KBA | publisher = Oxford University Press | location = Oxford | year = 2014 | isbn = 978-0199654901 }}</ref>
{| class="wikitable"
 
!Stage
====Dynamics of regurgitation====
!Definition
*The [[Diastolic blood pressure|diastolic pressure]] difference between main [[pulmonary artery]] (MPA and [[right ventricle]] (RV) is usually very small and steers the [[pulmonic regurgitation]]. The [[right ventricle|right ventricular]] stiffness due to [[right ventricular hypertrophy]] (such as in [[Tetralogy of Fallot]] and [[fibrosis]]) increases the ventricular [[diastolic pressure]]. Increased  ventricular [[diastolic pressure]] decreases the gradient causing [[regurgitation]]. A slight increase in the intrathoracic pressure (such as among [[ventilation|ventilated]] patients) can accentuate [[PR]] considerably.<ref name="pmid17569817">{{cite journal| author=Chaturvedi RR, Redington AN| title=Pulmonary regurgitation in congenital heart disease. | journal=Heart | year= 2007 | volume= 93 | issue= 7 | pages= 880-9 | pmid=17569817 | doi=10.1136/hrt.2005.075234 | pmc=1994453 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17569817  }} </ref>
!Pulmonary Valve
*Along with [[Diastolic blood pressure|diastolic pressure]] difference between [[right ventricle]] and [[pulmonary artery]], the degree/ severity/ volume of [[Regurgitation (circulation)|regurgitant jet]] is dependent on:<ref name="pmid26430501">{{cite journal| author=Bigdelian H, Mardani D, Sedighi M| title=The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF). | journal=J Cardiovasc Thorac Res | year= 2015 | volume= 7 | issue= 3 | pages= 122-5 | pmid=26430501 | doi=10.15171/jcvtr.2015.26 | pmc=4586599 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26430501  }} </ref><ref name="pmid21251297">{{cite journal |vauthors=Geva T |title=Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support |journal=J Cardiovasc Magn Reson |volume=13 |issue= |pages=9 |date=January 2011 |pmid=21251297 |pmc=3036629 |doi=10.1186/1532-429X-13-9 |url=}}</ref>
Anatomy
**Size/ area of the [[Regurgitation (circulation)|regurgitant orifice]]
!Valve Hemodynamics
**Afterload of the [[right ventricle]]/ [[capacitance]] of [[pulmonary arteries]]
!Hemodynamic Consequences
**[[Right ventricle]] [[diastolic]] [[compliance]]
!Symptoms
**Duration of [[right ventricular]] [[diastole]]
|-
*Torricelli principle sums up some of the factors influencing [[Regurgitation (circulation)|regurgitant]] volume:<ref name="pmid21251297">{{cite journal |vauthors=Geva T |title=Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support |journal=J Cardiovasc Magn Reson |volume=13 |issue= |pages=9 |date=January 2011 |pmid=21251297 |pmc=3036629 |doi=10.1186/1532-429X-13-9 |url=}}</ref>
|C,D
PR volume = [[regurgitant orifice]] area · constant · [[diastole|diastolic]] time · mean diastolic pressure difference between the MPA and RV.(P2−P1)0.5.
|Severe PR
 
|
====Acquired alteration in the valvular morphology<ref name="CurtissMiller1983">{{cite journal|last1=Curtiss|first1=E I|last2=Miller|first2=T R|last3=Shapiro|first3=L S|title=Pulmonic regurgitation due to valvular tophi.|journal=Circulation|volume=67|issue=3|year=1983|pages=699–701|issn=0009-7322|doi=10.1161/01.CIR.67.3.699}}</ref><ref name="pmid21251297">{{cite journal |vauthors=Geva T |title=Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support |journal=J Cardiovasc Magn Reson |volume=13 |issue= |pages=9 |date=January 2011 |pmid=21251297 |pmc=3036629 |doi=10.1186/1532-429X-13-9 |url=}}</ref>====
*Distorted or absent leaflets
*The most common cause of [[PR]] is post repair of [[TOF]] to relieve [[right ventricle outflow tract]] (RVOT) obstruction. The [[valve|valvular]] lesion is thought to be due to the disruption of [[pulmonary valve]]'s morphological integrity. In a [[TOF]] patient even after the RVOT obstruction relief, the [[right ventricle]] (RV) is [[hypertrophy|hypertrophied]] and [[pulmonary artery|pulmonary arteries]] are usually [[hypoplasia|hypoplastic]], both demonstrating low compliance. Among children, [[tachycardia]] leads to shorter duration [[diastole]]s.
*Annular dilation
[[Regurgitation]] is avoided despite large [[regurgitation]] orifice due to Torricelli principle. Progressively, an increased size and [[capacitance]] of central [[pulmonary artery|pulmonary ateries]] and [[right ventricle|right ventricular]] dilatation occurs due to increased RV [[stroke volume]]. The changes described progress with age accompanied by a longer duration of [[diastole]] and decreased [[heart rate]]. This progressively leads to an increase in the degree of [[PR]].
|
*The development of [[pulmonic regurgitation]] due to [[tophus]] valvular vegetations has been reported in a case. The patient reported had long-standing cyanotic [[congenital heart disease]] and developed [[hyperuricemia]] secondary to [[polycythemia]]. The possible mechanism of development of the vegetations involved hemodynamic [[valve|valvular]] trauma in the setting of sustained [[hyperuricemia]] and subsequent [[dystrophic calcification]] at primary [[tophus]] lesion.
*Color jet fills RVOT
[[File:Factors influencing PR after TOF repair.jpg|thumb|center|400px|A few factors influencing the progression of [[PR|pulmonary regurgitation]] (PR) after TOF repair - <ref name="pmid21251297">{{cite journal |vauthors=Geva T |title=Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support |journal=J Cardiovasc Magn Reson |volume=13 |issue= |pages=9 |date=January 2011 |pmid=21251297 |pmc=3036629 |doi=10.1186/1532-429X-13-9 |url=}}</ref>]]
*CW jet density and contour: dense laminar flow with steep deceleration slope; may terminate abruptly
|
====Idiopathic dilatation of the pulmonary artery (IDPA)<ref name="pmid28228295">{{cite journal |vauthors=Malviya A, Jha PK, Kalita JP, Saikia MK, Mishra A |title=Idiopathic dilatation of pulmonary artery: A review |journal=Indian Heart J |volume=69 |issue=1 |pages=119–124 |date=2017 |pmid=28228295 |pmc=5319124 |doi=10.1016/j.ihj.2016.07.009 |url=}}</ref><ref name="pmid27891002">{{cite journal |vauthors=Sharma RK, Talwar D, Gupta SK, Bansal S |title=Idiopathic dilatation of pulmonary artery |journal=Lung India |volume=33 |issue=6 |pages=675–677 |date=2016 |pmid=27891002 |pmc=5112830 |doi=10.4103/0970-2113.192869 |url=}}</ref><ref name="SegallRitter1950">{{cite journal|last1=Segall|first1=S.|last2=Ritter|first2=I. I.|last3=Hwang|first3=W.|title=A Case of Marked Dilatation of the Pulmonary Arterial Tree Associated with Mitral Stenosis|journal=Circulation|volume=1|issue=4|year=1950|pages=777–781|issn=0009-7322|doi=10.1161/01.CIR.1.4.777}}</ref>====
*Paradoxical septal motion (volume overload pattern)
*The exact pathogenesis of dilatation of the [[pulmonary artery]] is not fully understood. The demonstration of the [[disease]] among [[child|pediatric population]] signals the [[congenital]] nature of the [[etiology]]. Main [[pulmonary artery]] and the origin of its right and left main pulmonary arteries are majorly affected. It is thought that [[pulmonary artery]] dilatation is mediated by the unequal division of truncus arteriosus communis. Other proposed mechanisms include maldevelopment of the whole [[pulmonary tree]] and the association of hypoplastic [[aorta]] with dilated.
* RV enlargement
[[File:Dilatation of pulmonary artery-image reconstrust.jpg|thumb|400px|center|3-D reconstruction of chest CT demonstrating diffuse [[aneurysm|aneurysmal]] dilatation of the pulmonary outflow tract and main pulmonary artery (right and left) - <ref name="DebZehr2005">{{cite journal|last1=Deb|first1=Subrato J.|last2=Zehr|first2=Kenton J.|last3=Shields|first3=Raymond C.|title=Idiopathic Pulmonary Artery Aneurysm|journal=The Annals of Thoracic Surgery|volume=80|issue=4|year=2005|pages=1500–1502|issn=00034975|doi=10.1016/j.athoracsur.2004.04.011}}</ref>]]
|None or variable and dependent on cause of PR and RV function
====[[Pulmonary valve]] ring dilatation<ref name="pmid3841897">{{cite journal |vauthors=Tsuneyoshi H, Hara K, Takeuchi H, Kashida M, Yamaguchi T, Toide H, Toda E, Machii K |title=[Pulmonary regurgitation with special reference to the shape of the pulmonary valve ring: a pulsed Doppler and angiographic study] |language=Japanese |journal=J Cardiogr |volume=15 |issue=4 |pages=1145–56 |date=December 1985 |pmid=3841897 |doi= |url=}}</ref>====
|}
A study utilized pulsed [[doppler echocardiography]] and [[cineangiography]] to identify the significance of [[pulmonic valve]] ring dimensions in the development of [[PR]]. It reported the ratio of [[sagittal]] to the [[transverse]] diameter of the [[pulmonic valve]] ring to be greater among patients with [[PR]]. In [[patients]] with [[PAH]] the study also demonstrated greater dilatation of the [[sagittal]] diameter of the [[pulmonic valve]] ring than pulmonary sinus diameter. In the light of the results, the etiology of [[PR]] was attributed to the distortion of [[pulmonic valve]] ring.
 
====Congenital absence or malformation of the valve<ref name="BouzasKilner2005">{{cite journal|last1=Bouzas|first1=Beatriz|last2=Kilner|first2=Philip J.|last3=Gatzoulis|first3=Michael A.|title=Pulmonary regurgitation: not a benign lesion|journal=European Heart Journal|volume=26|issue=5|year=2005|pages=433–439|issn=0195-668X|doi=10.1093/eurheartj/ehi091}}</ref><ref name="pmid28228295">{{cite journal |vauthors=Malviya A, Jha PK, Kalita JP, Saikia MK, Mishra A |title=Idiopathic dilatation of pulmonary artery: A review |journal=Indian Heart J |volume=69 |issue=1 |pages=119–124 |date=2017 |pmid=28228295 |pmc=5319124 |doi=10.1016/j.ihj.2016.07.009 |url=}}</ref><ref name="pmid27891002">{{cite journal |vauthors=Sharma RK, Talwar D, Gupta SK, Bansal S |title=Idiopathic dilatation of pulmonary artery |journal=Lung India |volume=33 |issue=6 |pages=675–677 |date=2016 |pmid=27891002 |pmc=5112830 |doi=10.4103/0970-2113.192869 |url=}}</ref><ref name="pmid16181901">{{cite journal |vauthors=Deb SJ, Zehr KJ, Shields RC |title=Idiopathic pulmonary artery aneurysm |journal=Ann. Thorac. Surg. |volume=80 |issue=4 |pages=1500–2 |date=October 2005 |pmid=16181901 |doi=10.1016/j.athoracsur.2004.04.011 |url=}}</ref>====
*Absent [[pulmonary valve]] syndrome (APVS) is rare and involves developmental abnormality and [[dysplasia]] or absolute absence of [[pulmonary valve]] cusps. A variable degree of dilatation/[[aneurysm]] of the main [[pulmonary artery]] always accompanies the disorder.
*It is thought that the development of [[pulmonary artery]] aneurysm is mediated by either the congenital weakness or cystic [[tunica media|medial]] degeneration of the [[pulmonary artery]] walls. An association between cystic [[tunica media|medial]] degeneration and increased hemodynamic forces then leads to [[aneurysm]] formation. Pulmonary artery [[aneurysms]] have been associated with structural cardiac and vascular abnormalities, [[vasculitis]], and [[infection]] (such as [[syphilis]]).
*The pathogenesis of Fallot type (APVS) involves either [[agenesis]] of [[ductus arteriosus]] or post pulmonary stenotic dilatation due to increased [[stroke volume]].
*Quuadricuspid [[pulmonary valve]] is rare but may cause [[PR]]. Thick [[valve|valvular]] leaflets with decreased mobility without complete closure during [[diastole]] may lead to the development of [[PR]].<ref name="pmid12094521">{{cite journal |vauthors=Kotani A, Nakagawa K, Yamamoto T, Hirano Y, Kimura H, Yamada S, Ikawa H, Ishikawa K |title=[Quadricuspid pulmonary valve with valvular stenosis and regurgitation identified by transthoracic echocardiography: a case report] |language=Japanese |journal=J Cardiol |volume=39 |issue=6 |pages=313–9 |date=June 2002 |pmid=12094521 |doi= |url=}}</ref>
[[Image:Quadricuspid pulmonary valve.jpg|thumb|400px|center|Quadricuspid pulmonary valve (one of the congenital causes of [[PR]] - Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology http://www.peir.net]]
 
====Increasing regurgitation causing [[right ventricle|right ventricular]] volume overload<ref name="pmid26430501">{{cite journal| author=Bigdelian H, Mardani D, Sedighi M| title=The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF). | journal=J Cardiovasc Thorac Res | year= 2015 | volume= 7 | issue= 3 | pages= 122-5 | pmid=26430501 | doi=10.15171/jcvtr.2015.26 | pmc=4586599 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26430501  }} </ref>====
* Patients with [[pulmonic regurgitation]] (PR) develop chronic [[right ventricle|right ventricular]] overload resulting in right [[Ventricular remodeling|ventricular remodeling]] and progressive decline in function. The rate of decline in right ventricular [[systole|systolic function]] is also affected by associated conditions such as peripheral [[pulmonary artery stenosis]] and [[pulmonary hypertension]] which accentuates [[PR]]. Among [[patients]] with increased [[pulmonary artery]] pressure from dysfunction of [[left ventricle]] or residual [[pulmonary artery stenosis]] the severity of [[PR]] is increased. Progressive dilation of the [[right ventricle]] results in functional [[tricuspid regurgitation]] and increases the risk of developing [[arrhythmias]].
 
===Genetics===
*ADAMTS19 has been identified as a novel causative gene for [[autosomal recessive]] cardiac [[valve]] disease. ADAMTS is a [[disintegrin]] and [[metalloproteinase]] with [[thrombospondin]] motifs [[protein]] family. All [[patients]] demonstrated anomalies of the [[aortic valve|aortic]] and/or [[pulmonary valve|pulmonary]] heart [[valves]], such as thickening of [[valve]] leaflets, [[stenosis]] and insufficiency.<ref name="WünnemannTa-Shma2019">{{cite journal|last1=Wünnemann|first1=Florian|last2=Ta-Shma|first2=Asaf|last3=Preuss|first3=Christoph|last4=Leclerc|first4=Severine|last5=van Vliet|first5=Patrick Piet|last6=Oneglia|first6=Andrea|last7=Thibeault|first7=Maryse|last8=Nordquist|first8=Emily|last9=Lincoln|first9=Joy|last10=Scharfenberg|first10=Franka|last11=Becker-Pauly|first11=Christoph|last12=Hofmann|first12=Philipp|last13=Hoff|first13=Kirstin|last14=Audain|first14=Enrique|last15=Kramer|first15=Hans-Heiner|last16=Makalowski|first16=Wojciech|last17=Nir|first17=Amiram|last18=Gerety|first18=Sebastian S.|last19=Hurles|first19=Matthew|last20=Comes|first20=Johanna|last21=Fournier|first21=Anne|last22=Osinska|first22=Hanna|last23=Robins|first23=Jeffrey|last24=Pucéat|first24=Michel|last25=Elpeleg|first25=Orly|last26=Hitz|first26=Marc-Phillip|last27=Andelfinger|first27=Gregor|title=Loss of ADAMTS19 causes progressive non-syndromic heart valve disease|journal=Nature Genetics|volume=52|issue=1|year=2019|pages=40–47|issn=1061-4036|doi=10.1038/s41588-019-0536-2}}</ref><ref name="MassadehAlhashem2020">{{cite journal|last1=Massadeh|first1=Salam|last2=Alhashem|first2=Amal|last3=Laar|first3=Ingrid M.B.H.|last4=Alhabshan|first4=Fahad|last5=Ordonez|first5=Natalia|last6=Alawbathani|first6=Salem|last7=Khan|first7=Suliman|last8=Kabbani|first8=Mohamed S.|last9=Chaikhouni|first9=Farah|last10=Sheereen|first10=Atia|last11=Almohammed|first11=Iman|last12=Alghamdi|first12=Bader|last13=Frohn‐Mulder|first13=Ingrid|last14=Ahmad|first14=Salim|last15=Beetz|first15=Christian|last16=Bauer|first16=Peter|last17=Wessels|first17=Marja W.|last18=Alaamery|first18=Manal|last19=Bertoli‐Avella|first19=Aida M.|title=
           
              ADAMTS19
           
            ‐associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype
          |journal=Clinical Genetics|volume=98|issue=1|year=2020|pages=56–63|issn=0009-9163|doi=10.1111/cge.13760}}</ref>
*Among [[patients]] with severe [[PR|pulmonary regurgitation]] (PR), the gene expression pattern of GRK2 and β2-[[Adrenergic receptor|adrenoceptor]] ( molecular markers of [[cardiac dysfunction]]) has been reported to be altered. The [[lymphocyte]] expression of described [[Adrenergic receptor|adrenoceptors]] and [[kinase]]s demonstrates [[neurohormone|neurohumoral]] changes in [[heart failure]].<ref name="pmid30104167">{{cite journal |vauthors=Rodríguez-Serrano M, Rueda Soriano J, Buendía Fuentes F, Osa Sáez AM, Montó Guillot F, D'Ocon Navaza P, Aguero J, Oliver E, Serrano F, Martínez-Dolz L |title=Changes in Adrenoceptor and GRK Expression in Patients With Chronic Pulmonary Regurgitation |journal=Rev Esp Cardiol (Engl Ed) |volume=72 |issue=7 |pages=569–576 |date=July 2019 |pmid=30104167 |doi=10.1016/j.rec.2018.05.030 |url=}}</ref>
*25% cases of absent [[pulmonary valve]] syndrome (APVS) are associated with [[Chromosome abnormality|chromosomal anomalies]] such as [[Trisomy 21]], [[Trisomy 13]], [[chromosome]] 6 and 7 deletions.<ref name="pmid24843213">{{cite journal |vauthors=Grewal DS, Chamoli SC, Saxena S |title=Absent pulmonary valve syndrome - Antenatal diagnosis |journal=Med J Armed Forces India |volume=70 |issue=2 |pages=198–200 |date=April 2014 |pmid=24843213 |pmc=4017172 |doi=10.1016/j.mjafi.2013.07.002 |url=}}</ref>
*22q11 micro-deletion has been shown to be associated with 25% cases of APVS.<ref name="pmid15386602">{{cite journal |vauthors=Volpe P, Paladini D, Marasini M, Buonadonna AL, Russo MG, Caruso G, Marzullo A, Arciprete P, Martinelli P, Gentile M |title=Characteristics, associations and outcome of absent pulmonary valve syndrome in the fetus |journal=Ultrasound Obstet Gynecol |volume=24 |issue=6 |pages=623–8 |date=November 2004 |pmid=15386602 |doi=10.1002/uog.1729 |url=}}</ref>
 
===Associated conditions===
Isolated [[PR]] is uncommon and is usually demonstrated with other [[valve|valvular]] abnormalities or in certain conditions. The most important conditions/[[diseases]] associated with [[PR]] include:
*'''[[TOF]]''': Surgical repair of [[pulmonic stenosis]] associated with [[TOF]] may lead to [[PR]]. Post [[TOF]] repair, [[PR]] is a common complication.
*'''[[Marfan syndrome]]''': Dilatation of [[pulmonary artery]] root is one of the established diagnostic criteria of [[Marfan syndrome]].<ref name="pmid11997425">{{cite journal |vauthors=Nollen GJ, van Schijndel KE, Timmermans J, Groenink M, Barentsz JO, van der Wall EE, Stoker J, Mulder BJ |title=Pulmonary artery root dilatation in Marfan syndrome: quantitative assessment of an unknown criterion |journal=Heart |volume=87 |issue=5 |pages=470–1 |date=May 2002 |pmid=11997425 |pmc=1767105 |doi=10.1136/heart.87.5.470 |url=}}</ref> Although other valvular [[regurgitations]] are common in [[Marfan syndrome]], pulmonic [[regurgitation]] is also possible.
*'''[[Rheumatic heart disease]]''': The [[disease]] is uncommon among developed countries but developing countries still share the burden of the [[disease]].<ref name="pmid8432279">{{cite journal |vauthors=Eisenberg MJ |title=Rheumatic heart disease in the developing world: prevalence, prevention, and control |journal=Eur. Heart J. |volume=14 |issue=1 |pages=122–8 |date=January 1993 |pmid=8432279 |doi=10.1093/eurheartj/14.1.122 |url=}}</ref><ref name="prasadKumar2017">{{cite journal|last1=prasad|first1=Arun|last2=Kumar|first2=Sanjeev |last3=Kr Singh|first3= Birendra |last4=Kumari|first4=Neelam |title=Mortality Due to Rheumatic Heart Disease in Developing World: A Preventable Problem|journal=Journal of Clinical & Experimental Cardiology|volume=08|issue=03|year=2017|issn=21559880|doi=10.4172/2155-9880.1000503}}</ref>
*'''[[Syphilis]]''': Although a rare cause, [[pulmonary artery]] dilatation and [[PAH]] may be caused by [[tertiary syphilis]]. Given the prognostic implications and available [[treatments]], early detection of [[PAH]].<ref name="pmid25406836">{{cite journal |vauthors=Raymond TE, Khabbaza JE, Yadav R, Tonelli AR |title=Significance of main pulmonary artery dilation on imaging studies |journal=Ann Am Thorac Soc |volume=11 |issue=10 |pages=1623–32 |date=December 2014 |pmid=25406836 |pmc=4298979 |doi=10.1513/AnnalsATS.201406-253PP |url=}}</ref> Being a [[sexually transmitted disease]] (STD), it is important to screen the [[patient]] for other [[sexually transmitted disease|STDs]].
 
===Gross pathology===
*On gross pathology vegetative lesions on the [[pulmonic valve]] leaflets may be observed among [[patient]]<nowiki/>s with [[acquired]] alteration in the [[valve|valvular]] leaflet [[morphology]].<ref name="CurtissMiller1983">{{cite journal|last1=Curtiss|first1=E I|last2=Miller|first2=T R|last3=Shapiro|first3=L S|title=Pulmonic regurgitation due to valvular tophi.|journal=Circulation|volume=67|issue=3|year=1983|pages=699–701|issn=0009-7322|doi=10.1161/01.CIR.67.3.699}}</ref>
===Microscopic pathology===
*On polarized light microscopy of the material taken from the [[pulmonic valve]], [[Gout diagnostic study of choice|negatively birefringent crystals]] may be observed in [[acquired]] alteration in the [[valve|valvular]] leaflet [[morphology]].<ref name="CurtissMiller1983">{{cite journal|last1=Curtiss|first1=E I|last2=Miller|first2=T R|last3=Shapiro|first3=L S|title=Pulmonic regurgitation due to valvular tophi.|journal=Circulation|volume=67|issue=3|year=1983|pages=699–701|issn=0009-7322|doi=10.1161/01.CIR.67.3.699}}</ref>
 
 


==References==
==References==
{{Reflist}}
{{Reflist|2}}


==See Also==
==See Also==

Latest revision as of 16:40, 5 August 2020

Pulmonic regurgitation Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2], Aysha Anwar, M.B.B.S[3], Javaria Anwer M.D.[4]

Overview

Pulmonary valve is located at the junction of the right ventricular outflow tract and pulmonary artery. Three equal-sized, semilunar cusps or leaflets make up the pulmonary valve. Pulmonary valve opens during right ventricular systole and closes during right ventricular diastole. Pulmonary regurgitation (PR) may be caused by an acquired alteration in the valvular morphology, idiopathic dilatation of the pulmonary artery (IDPA), pulmonic valve ring dilatation, congenital absence or malformation of the valve, and increasing regurgitation causing right ventricular volume overload. The pathophysiologic mechanism of pulmonic regurgitation includes right ventricular overload resulting in the right ventricular remodeling and progressive decline in function. The rate of decline in right ventricular systolic function is affected by associated conditions such as peripheral pulmonary artery stenosis and pulmonary hypertension which further increase the severity of pulmonary regurgitation. Among patients with severe PR, the gene expression pattern of GRK2 and β2-adrenoceptor (molecular markers of cardiac dysfunction) has been reported to be altered. Isolated PR is uncommon and is usually demonstrated with other valvular abnormalities or in certain conditions. Conditions associated include TOF, rheumatic heart disease and syphilis. On gross pathology vegetative lesions on the pulmonic valve leaflets may be observed among patients with acquired alteration in the valvular leaflet morphology.

Pathophysiology

Anatomy of and physiology of pulmonic valve

Cadaveric specimen of heart demonstrating pulmonary valve location between right ventricular outflow tract and pulmonary artery - By Anatomist90 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20481209
  • Structure: Three equal sized, semilunar cusps or leaflets make up the pulmonary valve. Based on the corresponding aortic valve, the cusps are named right, left and anterior.[2] [2]
  • The three cusps are joined by commissures and the cusps are thinner when compared to the aortic valve, due to a low pressure in the right ventricle.[2]
  • Histologically, the pulmonary valve consists of stratified extracellular matrix compartments. The layers constitute fibrosa, spongiosa and ventricularis.[3]
  • The diameter of pulmonic valve is demonstrated to be closely related to the body size. For adult men (>17 years age) mean pulmonary valve diameter is 26.2 +/- 2.3 mm and 23.9 +/- 2.2 mm for adult women.[4]
  • Physiology: The right ventricle delivers the received blood entirely to the pulmonary circulation every beat, maintaining optimum pressure.[5] Pulmonary valve opens during right ventricular systole allowing the deoxygenated blood to be delivered to the lungs. [2] During the right ventricular diastole the pulmonary valves close completely to prevent regurgitation (back flow) of the blood into the right ventricle.[2]
  • The closure of the pulmonic valve contributes to the P2 component of the second heart sound (S2).

Pathogenesis

The pathogenesis of pulmonic regurgitation involves the following mechanisms:[6][7]

Dynamics of regurgitation

PR volume = regurgitant orifice area · constant · diastolic time · mean diastolic pressure difference between the MPA and RV.(P2−P1)0.5.

Acquired alteration in the valvular morphology[11][10]

Regurgitation is avoided despite large regurgitation orifice due to Torricelli principle. Progressively, an increased size and capacitance of central pulmonary ateries and right ventricular dilatation occurs due to increased RV stroke volume. The changes described progress with age accompanied by a longer duration of diastole and decreased heart rate. This progressively leads to an increase in the degree of PR.

A few factors influencing the progression of pulmonary regurgitation (PR) after TOF repair - [10]

Idiopathic dilatation of the pulmonary artery (IDPA)[12][13][14]

3-D reconstruction of chest CT demonstrating diffuse aneurysmal dilatation of the pulmonary outflow tract and main pulmonary artery (right and left) - [15]

Pulmonary valve ring dilatation[16]

A study utilized pulsed doppler echocardiography and cineangiography to identify the significance of pulmonic valve ring dimensions in the development of PR. It reported the ratio of sagittal to the transverse diameter of the pulmonic valve ring to be greater among patients with PR. In patients with PAH the study also demonstrated greater dilatation of the sagittal diameter of the pulmonic valve ring than pulmonary sinus diameter. In the light of the results, the etiology of PR was attributed to the distortion of pulmonic valve ring.

Congenital absence or malformation of the valve[17][12][13][18]

Quadricuspid pulmonary valve (one of the congenital causes of PR - Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology http://www.peir.net

Increasing regurgitation causing right ventricular volume overload[9]

Genetics

Associated conditions

Isolated PR is uncommon and is usually demonstrated with other valvular abnormalities or in certain conditions. The most important conditions/diseases associated with PR include:

Gross pathology

Microscopic pathology


References

  1. ↑ Maganti K, Rigolin VH, Sarano ME, Bonow RO (2010). "Valvular heart disease: diagnosis and management". Mayo Clin Proc. 85 (5): 483–500. doi:10.4065/mcp.2009.0706. PMC 2861980. PMID 20435842.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Schmoldt A, Benthe HF, Haberland G, Felt V, Nedvídková J, Hynie S, Mosinger B, Vavrinková M, Järvisalo J, Saris NE (September 1975). "Digitoxin metabolism by rat liver microsomes". Biochem. Pharmacol. 24 (17): 1639–41. doi:10.1016/0006-2952(75)90009-x. PMC 5922622. PMID 10.
  3. ↑ Combs MD, Yutzey KE (August 2009). "Heart valve development: regulatory networks in development and disease". Circ. Res. 105 (5): 408–21. doi:10.1161/CIRCRESAHA.109.201566. PMC 2777683. PMID 19713546.
  4. ↑ Capps SB, Elkins RC, Fronk DM (May 2000). "Body surface area as a predictor of aortic and pulmonary valve diameter". J. Thorac. Cardiovasc. Surg. 119 (5): 975–82. doi:10.1016/S0022-5223(00)70092-4. PMID 10788818.
  5. ↑ Pinsky MR (September 2016). "The right ventricle: interaction with the pulmonary circulation". Crit Care. 20: 266. doi:10.1186/s13054-016-1440-0. PMC 5018168. PMID 27613549.
  6. ↑ Khavandi, Ali (2014). Essential revision notes for the cardiology KBA. Oxford: Oxford University Press. ISBN 978-0199654901.
  7. ↑ Khavandi, Ali (2014). Essential revision notes for the cardiology KBA. Oxford: Oxford University Press. ISBN 978-0199654901.
  8. ↑ Chaturvedi RR, Redington AN (2007). "Pulmonary regurgitation in congenital heart disease". Heart. 93 (7): 880–9. doi:10.1136/hrt.2005.075234. PMC 1994453. PMID 17569817.
  9. ↑ 9.0 9.1 Bigdelian H, Mardani D, Sedighi M (2015). "The Effect of Pulmonary Valve Replacement (PVR) Surgery on Hemodynamics of Patients Who Underwent Repair of Tetralogy of Fallot (TOF)". J Cardiovasc Thorac Res. 7 (3): 122–5. doi:10.15171/jcvtr.2015.26. PMC 4586599. PMID 26430501.
  10. ↑ 10.0 10.1 10.2 10.3 Geva T (January 2011). "Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support". J Cardiovasc Magn Reson. 13: 9. doi:10.1186/1532-429X-13-9. PMC 3036629. PMID 21251297.
  11. ↑ 11.0 11.1 11.2 Curtiss, E I; Miller, T R; Shapiro, L S (1983). "Pulmonic regurgitation due to valvular tophi". Circulation. 67 (3): 699–701. doi:10.1161/01.CIR.67.3.699. ISSN 0009-7322.
  12. ↑ 12.0 12.1 Malviya A, Jha PK, Kalita JP, Saikia MK, Mishra A (2017). "Idiopathic dilatation of pulmonary artery: A review". Indian Heart J. 69 (1): 119–124. doi:10.1016/j.ihj.2016.07.009. PMC 5319124. PMID 28228295.
  13. ↑ 13.0 13.1 Sharma RK, Talwar D, Gupta SK, Bansal S (2016). "Idiopathic dilatation of pulmonary artery". Lung India. 33 (6): 675–677. doi:10.4103/0970-2113.192869. PMC 5112830. PMID 27891002.
  14. ↑ Segall, S.; Ritter, I. I.; Hwang, W. (1950). "A Case of Marked Dilatation of the Pulmonary Arterial Tree Associated with Mitral Stenosis". Circulation. 1 (4): 777–781. doi:10.1161/01.CIR.1.4.777. ISSN 0009-7322.
  15. ↑ Deb, Subrato J.; Zehr, Kenton J.; Shields, Raymond C. (2005). "Idiopathic Pulmonary Artery Aneurysm". The Annals of Thoracic Surgery. 80 (4): 1500–1502. doi:10.1016/j.athoracsur.2004.04.011. ISSN 0003-4975.
  16. ↑ Tsuneyoshi H, Hara K, Takeuchi H, Kashida M, Yamaguchi T, Toide H, Toda E, Machii K (December 1985). "[Pulmonary regurgitation with special reference to the shape of the pulmonary valve ring: a pulsed Doppler and angiographic study]". J Cardiogr (in Japanese). 15 (4): 1145–56. PMID 3841897.
  17. ↑ Bouzas, Beatriz; Kilner, Philip J.; Gatzoulis, Michael A. (2005). "Pulmonary regurgitation: not a benign lesion". European Heart Journal. 26 (5): 433–439. doi:10.1093/eurheartj/ehi091. ISSN 0195-668X.
  18. ↑ Deb SJ, Zehr KJ, Shields RC (October 2005). "Idiopathic pulmonary artery aneurysm". Ann. Thorac. Surg. 80 (4): 1500–2. doi:10.1016/j.athoracsur.2004.04.011. PMID 16181901.
  19. ↑ Kotani A, Nakagawa K, Yamamoto T, Hirano Y, Kimura H, Yamada S, Ikawa H, Ishikawa K (June 2002). "[Quadricuspid pulmonary valve with valvular stenosis and regurgitation identified by transthoracic echocardiography: a case report]". J Cardiol (in Japanese). 39 (6): 313–9. PMID 12094521.
  20. ↑ Wünnemann, Florian; Ta-Shma, Asaf; Preuss, Christoph; Leclerc, Severine; van Vliet, Patrick Piet; Oneglia, Andrea; Thibeault, Maryse; Nordquist, Emily; Lincoln, Joy; Scharfenberg, Franka; Becker-Pauly, Christoph; Hofmann, Philipp; Hoff, Kirstin; Audain, Enrique; Kramer, Hans-Heiner; Makalowski, Wojciech; Nir, Amiram; Gerety, Sebastian S.; Hurles, Matthew; Comes, Johanna; Fournier, Anne; Osinska, Hanna; Robins, Jeffrey; Pucéat, Michel; Elpeleg, Orly; Hitz, Marc-Phillip; Andelfinger, Gregor (2019). "Loss of ADAMTS19 causes progressive non-syndromic heart valve disease". Nature Genetics. 52 (1): 40–47. doi:10.1038/s41588-019-0536-2. ISSN 1061-4036.
  21. ↑ Massadeh, Salam; Alhashem, Amal; Laar, Ingrid M.B.H.; Alhabshan, Fahad; Ordonez, Natalia; Alawbathani, Salem; Khan, Suliman; Kabbani, Mohamed S.; Chaikhouni, Farah; Sheereen, Atia; Almohammed, Iman; Alghamdi, Bader; Frohn‐Mulder, Ingrid; Ahmad, Salim; Beetz, Christian; Bauer, Peter; Wessels, Marja W.; Alaamery, Manal; Bertoli‐Avella, Aida M. (2020). "ADAMTS19 ‐associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype". Clinical Genetics. 98 (1): 56–63. doi:10.1111/cge.13760. ISSN 0009-9163. line feed character in |title= at position 9 (help)
  22. ↑ Rodríguez-Serrano M, Rueda Soriano J, Buendía Fuentes F, Osa Sáez AM, Montó Guillot F, D'Ocon Navaza P, Aguero J, Oliver E, Serrano F, Martínez-Dolz L (July 2019). "Changes in Adrenoceptor and GRK Expression in Patients With Chronic Pulmonary Regurgitation". Rev Esp Cardiol (Engl Ed). 72 (7): 569–576. doi:10.1016/j.rec.2018.05.030. PMID 30104167.
  23. ↑ Grewal DS, Chamoli SC, Saxena S (April 2014). "Absent pulmonary valve syndrome - Antenatal diagnosis". Med J Armed Forces India. 70 (2): 198–200. doi:10.1016/j.mjafi.2013.07.002. PMC 4017172. PMID 24843213.
  24. ↑ Volpe P, Paladini D, Marasini M, Buonadonna AL, Russo MG, Caruso G, Marzullo A, Arciprete P, Martinelli P, Gentile M (November 2004). "Characteristics, associations and outcome of absent pulmonary valve syndrome in the fetus". Ultrasound Obstet Gynecol. 24 (6): 623–8. doi:10.1002/uog.1729. PMID 15386602.
  25. ↑ Nollen GJ, van Schijndel KE, Timmermans J, Groenink M, Barentsz JO, van der Wall EE, Stoker J, Mulder BJ (May 2002). "Pulmonary artery root dilatation in Marfan syndrome: quantitative assessment of an unknown criterion". Heart. 87 (5): 470–1. doi:10.1136/heart.87.5.470. PMC 1767105. PMID 11997425.
  26. ↑ Eisenberg MJ (January 1993). "Rheumatic heart disease in the developing world: prevalence, prevention, and control". Eur. Heart J. 14 (1): 122–8. doi:10.1093/eurheartj/14.1.122. PMID 8432279.
  27. ↑ prasad, Arun; Kumar, Sanjeev; Kr Singh, Birendra; Kumari, Neelam (2017). "Mortality Due to Rheumatic Heart Disease in Developing World: A Preventable Problem". Journal of Clinical & Experimental Cardiology. 08 (03). doi:10.4172/2155-9880.1000503. ISSN 2155-9880.
  28. ↑ Raymond TE, Khabbaza JE, Yadav R, Tonelli AR (December 2014). "Significance of main pulmonary artery dilation on imaging studies". Ann Am Thorac Soc. 11 (10): 1623–32. doi:10.1513/AnnalsATS.201406-253PP. PMC 4298979. PMID 25406836.

See Also

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