Aortic sclerosis overview: Difference between revisions
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==Overview== | ==Overview== | ||
Aortic sclerosis commonly affects elderly population. | Aortic sclerosis commonly affects elderly population. Aortic sclerosis is defined based on [[transthoracic echocardiography|transthoracic echocardiographic]] findings which include irregular leaflet thickening and focal valve thickening with associated increase in echogenicity.<ref name="pmid15967862">{{cite journal |author=Freeman RV, Otto CM |title=Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies |journal=[[Circulation]] |volume=111 |issue=24 |pages=3316–26 |year=2005 |month=June |pmid=15967862 |doi=10.1161/CIRCULATIONAHA.104.486738 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15967862 |accessdate=2012-04-10}}</ref><ref name="pmid10403851">{{cite journal |author=Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS |title=Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly |journal=[[The New England Journal of Medicine]] |volume=341 |issue=3 |pages=142–7 |year=1999 |month=July |pmid=10403851 |doi=10.1056/NEJM199907153410302 |url=http://dx.doi.org/10.1056/NEJM199907153410302 |accessdate=2012-04-10}}</ref><ref name="pmid9060903">{{cite journal |author=Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM |title=Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study |journal=[[Journal of the American College of Cardiology]] |volume=29 |issue=3 |pages=630–4 |year=1997 |month=March |pmid=9060903 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109796005633 |accessdate=2012-04-10}}</ref><ref name="pmid21295189">{{cite journal |author=Gharacholou SM, Karon BL, Shub C, Pellikka PA |title=Aortic valve sclerosis and clinical outcomes: moving toward a definition |journal=[[The American Journal of Medicine]] |volume=124 |issue=2 |pages=103–10 |year=2011 |month=February |pmid=21295189 |doi=10.1016/j.amjmed.2010.10.012 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(10)00913-7 |accessdate=2012-04-10}}</ref> | ||
==Pathophysiology== | |||
Microscopic changes reveal lipoprotein accumulation, cellular infiltration and extracellular matrix formation that cause progressive thickening of the aortic valve.<ref name="pmid15967862">{{cite journal |author=Freeman RV, Otto CM |title=Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies |journal=[[Circulation]] |volume=111 |issue=24 |pages=3316–26 |year=2005 |month=June |pmid=15967862 |doi=10.1161/CIRCULATIONAHA.104.486738 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15967862 |accessdate=2012-04-10}}</ref> | |||
==Epidemiology== | ==Epidemiology== | ||
Aortic sclerosis is non-obstructive degeneration of the aortic valve that presents predominantly in patients over 65 years of age who have risk factors for [[coronary artery disease]]. Because aortic sclerosis is associated with coronary artery disease risk factors, it is also associated with a significant increase in the risk of cardiovascular death, [[myocardial infarction]] even in the absence of hemodynamically significant [[LVOT|left ventricular outflow tract obstruction]].<ref name="pmid8459080">{{cite journal |author=Lindroos M, Kupari M, Heikkilä J, Tilvis R |title=Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample |journal=[[Journal of the American College of Cardiology]] |volume=21 |issue=5 |pages=1220–5 |year=1993 |month=April |pmid=8459080 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0735-1097(93)90249-Z |accessdate=2012-04-10}}</ref><ref name="pmid9060903">{{cite journal |author=Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM |title=Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study |journal=[[Journal of the American College of Cardiology]] |volume=29 |issue=3 |pages=630–4 |year=1997 |month=March |pmid=9060903 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109796005633 |accessdate=2012-04-10}}</ref><ref name="pmid10403851">{{cite journal |author=Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS |title=Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly |journal=[[The New England Journal of Medicine]] |volume=341 |issue=3 |pages=142–7 |year=1999 |month=July |pmid=10403851 |doi=10.1056/NEJM199907153410302 |url=http://dx.doi.org/10.1056/NEJM199907153410302 |accessdate=2012-04-10}}</ref> | |||
==Risk Factors== | |||
The presence of aortic sclerosis has been suggested as a marker of increased cardiovascular risk, including increased mortality. However, it remains unclear whether aortic sclerosis is independently associated with risk or merely a marker of coexistent cardiovascular risk factors.<ref name="pmid21295189">{{cite journal |author=Gharacholou SM, Karon BL, Shub C, Pellikka PA |title=Aortic valve sclerosis and clinical outcomes: moving toward a definition |journal=[[The American Journal of Medicine]] |volume=124 |issue=2 |pages=103–10 |year=2011 |month=February |pmid=21295189 |doi=10.1016/j.amjmed.2010.10.012 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(10)00913-7 |accessdate=2012-04-10}}</ref> | |||
==Natural History, Disease Progression & Prognosis== | |||
Calcification of the aortic valve is common among the elderly population and shares epidemiologic and histopathologic similarities to [[atherosclerosis]].<ref name="pmid20185020">{{cite journal |author=Owens DS, Katz R, Takasu J, Kronmal R, Budoff MJ, O'Brien KD |title=Incidence and progression of aortic valve calcium in the Multi-ethnic Study of Atherosclerosis (MESA) |journal=[[The American Journal of Cardiology]] |volume=105 |issue=5 |pages=701–8 |year=2010 |month=March |pmid=20185020 |pmc=2829478 |doi=10.1016/j.amjcard.2009.10.071 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9149(09)02766-0 |accessdate=2012-04-11}}</ref> Progressive thickening and calcification of the aortic valve subsequently causes left ventricular stiffness resulting in [[left ventricular outflow tract obstruction]], thereby leading to [[aortic stenosis]].<ref name="pmid10403851">{{cite journal |author=Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS |title=Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly |journal=[[The New England Journal of Medicine]] |volume=341 |issue=3 |pages=142–7 |year=1999 |month=July |pmid=10403851 |doi=10.1056/NEJM199907153410302 |url=http://dx.doi.org/10.1056/NEJM199907153410302 |accessdate=2012-04-11}}</ref> Prognostically, it is known that [[aortic stenosis]] is clearly associated with adverse cardiovascular outcomes; however, it is unclear whether [[aortic sclerosis]] independently increases the risk of cardiovascular events or progression of [[aortic sclerosis]] to [[aortic stenosis]] increases the risk, including mortality.<ref name="pmid10403851">{{cite journal |author=Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS |title=Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly |journal=[[The New England Journal of Medicine]] |volume=341 |issue=3 |pages=142–7 |year=1999 |month=July |pmid=10403851 |doi=10.1056/NEJM199907153410302 |url=http://dx.doi.org/10.1056/NEJM199907153410302 |accessdate=2012-04-11}}</ref> | |||
==Diagnosis== | ==Diagnosis== | ||
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===Physical Examination=== | ===Physical Examination=== | ||
While a short mid-systolic murmur may be heard in aortic sclerosis, there is no fusion of the commisures and no significant obstruction to forward flow across the aortic valve. As a result, the [[S2]] is normal in aortic sclerosis and the carotid upstroke is normal (i.e. [[pulsus parvus et tardus]]) is absent. | |||
===Echocardiography=== | ===Echocardiography=== | ||
* Focal areas of valve thickening with associated increase in echogenicity is the hallmark of aortic sclerosis,<ref name="pmid15967862">{{cite journal |author=Freeman RV, Otto CM |title=Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies |journal=[[Circulation]] |volume=111 |issue=24 |pages=3316–26 |year=2005 |month=June |pmid=15967862 |doi=10.1161/CIRCULATIONAHA.104.486738 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15967862 |accessdate=2012-04-10}}</ref><ref name="pmid10403851">{{cite journal |author=Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS |title=Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly |journal=[[The New England Journal of Medicine]] |volume=341 |issue=3 |pages=142–7 |year=1999 |month=July |pmid=10403851 |doi=10.1056/NEJM199907153410302 |url=http://dx.doi.org/10.1056/NEJM199907153410302 |accessdate=2012-04-10}}</ref><ref name="pmid9060903">{{cite journal |author=Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM |title=Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study |journal=[[Journal of the American College of Cardiology]] |volume=29 |issue=3 |pages=630–4 |year=1997 |month=March |pmid=9060903 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109796005633 |accessdate=2012-04-10}}</ref><ref name="pmid21295189">{{cite journal |author=Gharacholou SM, Karon BL, Shub C, Pellikka PA |title=Aortic valve sclerosis and clinical outcomes: moving toward a definition |journal=[[The American Journal of Medicine]] |volume=124 |issue=2 |pages=103–10 |year=2011 |month=February |pmid=21295189 |doi=10.1016/j.amjmed.2010.10.012 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(10)00913-7 |accessdate=2012-04-10}}</ref> as opposed to the diffuse thickening observed as a part of normal aging | * Focal areas of valve thickening with associated increase in echogenicity is the hallmark of aortic sclerosis,<ref name="pmid15967862">{{cite journal |author=Freeman RV, Otto CM |title=Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies |journal=[[Circulation]] |volume=111 |issue=24 |pages=3316–26 |year=2005 |month=June |pmid=15967862 |doi=10.1161/CIRCULATIONAHA.104.486738 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15967862 |accessdate=2012-04-10}}</ref><ref name="pmid10403851">{{cite journal |author=Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS |title=Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly |journal=[[The New England Journal of Medicine]] |volume=341 |issue=3 |pages=142–7 |year=1999 |month=July |pmid=10403851 |doi=10.1056/NEJM199907153410302 |url=http://dx.doi.org/10.1056/NEJM199907153410302 |accessdate=2012-04-10}}</ref><ref name="pmid9060903">{{cite journal |author=Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM |title=Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study |journal=[[Journal of the American College of Cardiology]] |volume=29 |issue=3 |pages=630–4 |year=1997 |month=March |pmid=9060903 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109796005633 |accessdate=2012-04-10}}</ref><ref name="pmid21295189">{{cite journal |author=Gharacholou SM, Karon BL, Shub C, Pellikka PA |title=Aortic valve sclerosis and clinical outcomes: moving toward a definition |journal=[[The American Journal of Medicine]] |volume=124 |issue=2 |pages=103–10 |year=2011 |month=February |pmid=21295189 |doi=10.1016/j.amjmed.2010.10.012 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9343(10)00913-7 |accessdate=2012-04-10}}</ref> as opposed to the diffuse thickening observed as a part of normal aging | ||
* Aortic side of the valve in the center of the valve cusp is commonly affected | |||
* Commissural areas are spared | * Commissural areas are spared | ||
* Irregular leaflet thickening | |||
* Leaflet mobility is normal | * Leaflet mobility is normal | ||
* Valvular hemodynamic parameters are normal with a jet velocity of less than 2.5 m per sec across the valve | * Valvular hemodynamic parameters are normal with a jet flow velocity of less than 2.5 m per sec across the valve | ||
==Treatment== | |||
*[[Aortic sclerosis]] has been suggested as a marker of increased cardiovascular risk, including increased mortality.<ref name="pmid15967862">{{cite journal |author=Freeman RV, Otto CM |title=Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies |journal=[[Circulation]] |volume=111 |issue=24 |pages=3316–26 |year=2005 |month=June |pmid=15967862 |doi=10.1161/CIRCULATIONAHA.104.486738 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15967862 |accessdate=2012-04-10}}</ref><ref name="pmid11527641">{{cite journal |author=Agmon Y, Khandheria BK, Meissner I, Sicks JR, O'Fallon WM, Wiebers DO, Whisnant JP, Seward JB, Tajik AJ |title=Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study |journal=[[Journal of the American College of Cardiology]] |volume=38 |issue=3 |pages=827–34 |year=2001 |month=September |pmid=11527641 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S073510970101422X |accessdate=2012-04-10}}</ref> Therefore, '''''risk factor reduction''''' among this patient population is reasonable although no definitive study has demonstrated reduction in [[aortic sclerosis]] progression achieved with aggressive management of [[hypertension]] and [[dyslipidemia]] | |||
*Patients with isolated aortic valve disease rarely experience embolic events, therefore, according to the 2008 ACCP guidelines '''''no antithrombotic therapy''''' is required for the prevention of calcific microemboli.<ref name="pmid18574274">{{cite journal |author=Salem DN, O'Gara PT, Madias C, Pauker SG |title=Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) |journal=[[Chest]] |volume=133 |issue=6 Suppl |pages=593S–629S |year=2008 |month=June |pmid=18574274 |doi=10.1378/chest.08-0724 |url=http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=18574274 |accessdate=2012-04-10}}</ref> | |||
*According to the 2008 ACC/AHA guidelines,<ref name="pmid18820172">{{cite journal |author=Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O'Gara PT, O'Rourke RA, Otto CM, Shah PM, Shanewise JS |title=2008 Focused update incorporated into the ACC/AHA 2006 guidelines 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 (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons |journal=[[Circulation]] |volume=118 |issue=15 |pages=e523–661 |year=2008 |month=October |pmid=18820172 |doi=10.1161/CIRCULATIONAHA.108.190748 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=18820172 |accessdate=2012-04-10}}</ref> '''''no antibiotic prophylaxis''''' is recommended for patients with [[aortic sclerosis]]. | |||
==References== | ==References== | ||
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{{WH}} | {{WH}} | ||
{{WS}} | {{WS}} | ||
[[CME Category::Cardiology]] | |||
[[Category:Disease]] | [[Category:Disease]] | ||
[[Category:Cardiology]] | [[Category:Cardiology]] | ||
Latest revision as of 23:02, 14 March 2016
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Aortic sclerosisMicrochapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Aortic sclerosis overview On the Web |
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American Roentgen Ray Society Images of Aortic sclerosis overview |
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Risk calculators and risk factors for Aortic sclerosis overview |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]
Overview
Aortic sclerosis commonly affects elderly population. Aortic sclerosis is defined based on transthoracic echocardiographic findings which include irregular leaflet thickening and focal valve thickening with associated increase in echogenicity.[1][2][3][4]
Pathophysiology
Microscopic changes reveal lipoprotein accumulation, cellular infiltration and extracellular matrix formation that cause progressive thickening of the aortic valve.[1]
Epidemiology
Aortic sclerosis is non-obstructive degeneration of the aortic valve that presents predominantly in patients over 65 years of age who have risk factors for coronary artery disease. Because aortic sclerosis is associated with coronary artery disease risk factors, it is also associated with a significant increase in the risk of cardiovascular death, myocardial infarction even in the absence of hemodynamically significant left ventricular outflow tract obstruction.[5][3][2]
Risk Factors
The presence of aortic sclerosis has been suggested as a marker of increased cardiovascular risk, including increased mortality. However, it remains unclear whether aortic sclerosis is independently associated with risk or merely a marker of coexistent cardiovascular risk factors.[4]
Natural History, Disease Progression & Prognosis
Calcification of the aortic valve is common among the elderly population and shares epidemiologic and histopathologic similarities to atherosclerosis.[6] Progressive thickening and calcification of the aortic valve subsequently causes left ventricular stiffness resulting in left ventricular outflow tract obstruction, thereby leading to aortic stenosis.[2] Prognostically, it is known that aortic stenosis is clearly associated with adverse cardiovascular outcomes; however, it is unclear whether aortic sclerosis independently increases the risk of cardiovascular events or progression of aortic sclerosis to aortic stenosis increases the risk, including mortality.[2]
Diagnosis
History and Symptoms
- Mostly asymptomatic
- Aortic sclerosis is an incidental echocardiographic finding
Physical Examination
While a short mid-systolic murmur may be heard in aortic sclerosis, there is no fusion of the commisures and no significant obstruction to forward flow across the aortic valve. As a result, the S2 is normal in aortic sclerosis and the carotid upstroke is normal (i.e. pulsus parvus et tardus) is absent.
Echocardiography
- Focal areas of valve thickening with associated increase in echogenicity is the hallmark of aortic sclerosis,[1][2][3][4] as opposed to the diffuse thickening observed as a part of normal aging
- Aortic side of the valve in the center of the valve cusp is commonly affected
- Commissural areas are spared
- Irregular leaflet thickening
- Leaflet mobility is normal
- Valvular hemodynamic parameters are normal with a jet flow velocity of less than 2.5 m per sec across the valve
Treatment
- Aortic sclerosis has been suggested as a marker of increased cardiovascular risk, including increased mortality.[1][7] Therefore, risk factor reduction among this patient population is reasonable although no definitive study has demonstrated reduction in aortic sclerosis progression achieved with aggressive management of hypertension and dyslipidemia
- Patients with isolated aortic valve disease rarely experience embolic events, therefore, according to the 2008 ACCP guidelines no antithrombotic therapy is required for the prevention of calcific microemboli.[8]
- According to the 2008 ACC/AHA guidelines,[9] no antibiotic prophylaxis is recommended for patients with aortic sclerosis.
References
- ↑ 1.0 1.1 1.2 1.3 Freeman RV, Otto CM (2005). "Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies". Circulation. 111 (24): 3316–26. doi:10.1161/CIRCULATIONAHA.104.486738. PMID 15967862. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ 2.0 2.1 2.2 2.3 2.4 Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS (1999). "Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly". The New England Journal of Medicine. 341 (3): 142–7. doi:10.1056/NEJM199907153410302. PMID 10403851. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 3.2 Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM (1997). "Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study". Journal of the American College of Cardiology. 29 (3): 630–4. PMID 9060903. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ 4.0 4.1 4.2 Gharacholou SM, Karon BL, Shub C, Pellikka PA (2011). "Aortic valve sclerosis and clinical outcomes: moving toward a definition". The American Journal of Medicine. 124 (2): 103–10. doi:10.1016/j.amjmed.2010.10.012. PMID 21295189. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Lindroos M, Kupari M, Heikkilä J, Tilvis R (1993). "Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample". Journal of the American College of Cardiology. 21 (5): 1220–5. PMID 8459080. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Owens DS, Katz R, Takasu J, Kronmal R, Budoff MJ, O'Brien KD (2010). "Incidence and progression of aortic valve calcium in the Multi-ethnic Study of Atherosclerosis (MESA)". The American Journal of Cardiology. 105 (5): 701–8. doi:10.1016/j.amjcard.2009.10.071. PMC 2829478. PMID 20185020. Retrieved 2012-04-11. Unknown parameter
|month=ignored (help) - ↑ Agmon Y, Khandheria BK, Meissner I, Sicks JR, O'Fallon WM, Wiebers DO, Whisnant JP, Seward JB, Tajik AJ (2001). "Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study". Journal of the American College of Cardiology. 38 (3): 827–34. PMID 11527641. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Salem DN, O'Gara PT, Madias C, Pauker SG (2008). "Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 593S–629S. doi:10.1378/chest.08-0724. PMID 18574274. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O'Gara PT, O'Rourke RA, Otto CM, Shah PM, Shanewise JS (2008). "2008 Focused update incorporated into the ACC/AHA 2006 guidelines 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 (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons". Circulation. 118 (15): e523–661. doi:10.1161/CIRCULATIONAHA.108.190748. PMID 18820172. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help)