Aortic stenosis pathophysiology: Difference between revisions
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==Left Ventricular Hypertrophy== | ==Left Ventricular Hypertrophy== | ||
Long-standing [[aortic stenosis]] exposes the left ventricle to a sustained prolonged pressure overload state which may lead to [[LVOT|outflow tract obstruction]]. Over the years, this sustained increase in systolic pressure generated by the [[left ventricle]], results in [[left ventricular hypertrophy|concentric hypertrophy]] of the [[myocardium]] with subsequent thickening of the left ventricular wall; however, the chamber volume remains within normal limits.<ref name="pmid129304">{{cite journal |author=Sasayama S, Ross J, Franklin D, Bloor CM, Bishop S, Dilley RB |title=Adaptations of the left ventricle to chronic pressure overload |journal=[[Circulation Research]] |volume=38 |issue=3 |pages=172–8 |year=1976 |month=March |pmid=129304 |doi= |url=http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=129304 |accessdate=2012-04-10}}</ref><ref name="pmid155986">{{cite journal |author=Gaasch WH |title=Left ventricular radius to wall thickness ratio |journal=[[The American Journal of Cardiology]] |volume=43 |issue=6 |pages=1189–94 |year=1979 |month=June |pmid=155986 |doi= |url= |accessdate=2012-04-10}}</ref><ref name="pmid6446989">{{cite journal |author=Spann JF, Bove AA, Natarajan G, Kreulen T |title=Ventricular performance, pump function and compensatory mechanisms in patients with aortic stenosis |journal=[[Circulation]] |volume=62 |issue=3 |pages=576–82 |year=1980 |month=September |pmid=6446989 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=6446989 |accessdate=2012-04-10}}</ref> Although, this massive concentric hypertrophy characterized by a reduced diastolic radius-to-wall thickness ratio has shown to initially counter balance the increased systolic left ventricular pressure, if this process continued, an inverse relationship has been observed between [[ejection fraction]] and left ventricular mass.<ref name="pmid2969811">{{cite journal |author=Krayenbuehl HP, Hess OM, Ritter M, Monrad ES, Hoppeler H |title=Left ventricular systolic function in aortic stenosis |journal=[[European Heart Journal]] |volume=9 Suppl E |issue= |pages=19–23 |year=1988 |month=April |pmid=2969811 |doi= |url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2969811 |accessdate=2012-04-10}}</ref> | Long-standing [[aortic stenosis]] exposes the left ventricle to a sustained prolonged pressure overload state which may lead to [[LVOT|outflow tract obstruction]]. Over the years, this sustained increase in systolic pressure generated by the [[left ventricle]], results in [[left ventricular hypertrophy|concentric hypertrophy]] of the [[myocardium]] with subsequent thickening of the left ventricular wall; however, the chamber volume remains within normal limits.<ref name="pmid129304">{{cite journal |author=Sasayama S, Ross J, Franklin D, Bloor CM, Bishop S, Dilley RB |title=Adaptations of the left ventricle to chronic pressure overload |journal=[[Circulation Research]] |volume=38 |issue=3 |pages=172–8 |year=1976 |month=March |pmid=129304 |doi= |url=http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=129304 |accessdate=2012-04-10}}</ref><ref name="pmid155986">{{cite journal |author=Gaasch WH |title=Left ventricular radius to wall thickness ratio |journal=[[The American Journal of Cardiology]] |volume=43 |issue=6 |pages=1189–94 |year=1979 |month=June |pmid=155986 |doi= |url= |accessdate=2012-04-10}}</ref><ref name="pmid6446989">{{cite journal |author=Spann JF, Bove AA, Natarajan G, Kreulen T |title=Ventricular performance, pump function and compensatory mechanisms in patients with aortic stenosis |journal=[[Circulation]] |volume=62 |issue=3 |pages=576–82 |year=1980 |month=September |pmid=6446989 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=6446989 |accessdate=2012-04-10}}</ref> The left ventricular wall increases in thickness (i.e. [[concentric hypertrophy]] occurs) as a results of a parallel replication of the [[sarcomeres]]. During the period of [[concentric hypertrophy]], the left ventricle is not dilated and there is preservation of left ventricular systolic function, but diastolic function may be reduced due to a reduction in diastolic compliance. | ||
Although, this massive concentric hypertrophy characterized by a reduced diastolic radius-to-wall thickness ratio has shown to initially counter balance the increased systolic left ventricular pressure, if this process continued, an inverse relationship has been observed between [[ejection fraction]] and left ventricular mass.<ref name="pmid2969811">{{cite journal |author=Krayenbuehl HP, Hess OM, Ritter M, Monrad ES, Hoppeler H |title=Left ventricular systolic function in aortic stenosis |journal=[[European Heart Journal]] |volume=9 Suppl E |issue= |pages=19–23 |year=1988 |month=April |pmid=2969811 |doi= |url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2969811 |accessdate=2012-04-10}}</ref> | |||
Another factor that may contribute to reduced ventricular function is [[dyssynchronous contraction]] subsequent to regional wall motion abnormalities, [[fibrosis]] or [[ischemia]].<ref name="pmid9014797">{{cite journal |author=Jin XY, Pepper JR, Gibson DG |title=Effects of incoordination on left ventricular force-velocity relation in aortic stenosis |journal=[[Heart (British Cardiac Society)]]|volume=76 |issue=6 |pages=495–501 |year=1996 |month=December |pmid=9014797|pmc=484601 |doi= |url=http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=9014797|accessdate=2012-04-10}}</ref> | Another factor that may contribute to reduced ventricular function is [[dyssynchronous contraction]] subsequent to regional wall motion abnormalities, [[fibrosis]] or [[ischemia]].<ref name="pmid9014797">{{cite journal |author=Jin XY, Pepper JR, Gibson DG |title=Effects of incoordination on left ventricular force-velocity relation in aortic stenosis |journal=[[Heart (British Cardiac Society)]]|volume=76 |issue=6 |pages=495–501 |year=1996 |month=December |pmid=9014797|pmc=484601 |doi= |url=http://heart.bmj.com/cgi/pmidlookup?view=long&pmid=9014797|accessdate=2012-04-10}}</ref> | ||
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An increase in left ventricular end-diastolic pressure without chamber dilatation is observed subsequently to the increased left ventricular wall thickness, depressed volume/mass ratio and reduced chamber compliance <ref name="pmid136186">{{cite journal |author=Gaasch WH, Levine HJ, Quinones MA, Alexander JK |title=Left ventricular compliance: mechanisms and clinical implications |journal=[[The American Journal of Cardiology]] |volume=38 |issue=5 |pages=645–53 |year=1976 |month=November |pmid=136186 |doi= |url= |accessdate=2012-04-10}}</ref><ref name="pmid">{{cite journal |author=Murakami T, Hess OM, Gage JE, Grimm J, Krayenbuehl HP |title= |journal=[[]] |volume= |issue= |pages= |year= |month=June |pmid= |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=2938847 |accessdate=2012-04-10}}</ref><ref name="pmid">{{cite journal |author=Hess OM, Ritter M, Schneider J, Grimm J, Turina M, Krayenbuehl HP |title=Diastolic stiffness and myocardial structure in aortic valve disease before and after valve replacement |journal=[[]] |volume= |issue= |pages=855–65 |year=1984 |month=May |pmid= |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=6231136 |accessdate=2012-04-10}}</ref> thereby reflecting [[diastolic dysfunction]]<ref name="pmid8151903">{{cite journal |author=Gaasch WH |title=Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction |journal=[[JAMA : the Journal of the American Medical Association]] |volume=271 |issue=16 |pages=1276–80 |year=1994 |month=April |pmid=8151903 |doi= |url= |accessdate=2012-04-10}}</ref> | An increase in left ventricular end-diastolic pressure without chamber dilatation is observed subsequently to the increased left ventricular wall thickness, depressed volume/mass ratio and reduced chamber compliance <ref name="pmid136186">{{cite journal |author=Gaasch WH, Levine HJ, Quinones MA, Alexander JK |title=Left ventricular compliance: mechanisms and clinical implications |journal=[[The American Journal of Cardiology]] |volume=38 |issue=5 |pages=645–53 |year=1976 |month=November |pmid=136186 |doi= |url= |accessdate=2012-04-10}}</ref><ref name="pmid">{{cite journal |author=Murakami T, Hess OM, Gage JE, Grimm J, Krayenbuehl HP |title= |journal=[[]] |volume= |issue= |pages= |year= |month=June |pmid= |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=2938847 |accessdate=2012-04-10}}</ref><ref name="pmid">{{cite journal |author=Hess OM, Ritter M, Schneider J, Grimm J, Turina M, Krayenbuehl HP |title=Diastolic stiffness and myocardial structure in aortic valve disease before and after valve replacement |journal=[[]] |volume= |issue= |pages=855–65 |year=1984 |month=May |pmid= |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=6231136 |accessdate=2012-04-10}}</ref> thereby reflecting [[diastolic dysfunction]]<ref name="pmid8151903">{{cite journal |author=Gaasch WH |title=Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction |journal=[[JAMA : the Journal of the American Medical Association]] |volume=271 |issue=16 |pages=1276–80 |year=1994 |month=April |pmid=8151903 |doi= |url= |accessdate=2012-04-10}}</ref> | ||
The hypertrophied left ventricle may have reduced coronary blood flow even in the absence of obstructive epicardial stenoses due to compression of the capillary network. This may lead to subendocardial [[ischemia]] during stress or exercise.<ref name="pmid6215582">{{cite journal| author=Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL| title=Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries. | journal=N Engl J Med | year= 1982 | volume= 307 | issue= 22 | pages= 1362-6 | pmid=6215582 | doi=10.1056/NEJM198211253072202 | pmc= | url= }} </ref><ref name="pmid11870246">{{cite journal| author=Carabello BA| title=Clinical practice. Aortic stenosis. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 9 | pages= 677-82 | pmid=11870246 | doi=10.1056/NEJMcp010846 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11870246 }} </ref>. | The hypertrophied left ventricle may have reduced coronary blood flow even in the absence of obstructive epicardial stenoses due to compression of the capillary network. This may lead to subendocardial [[ischemia]] during stress or exercise.<ref name="pmid6215582">{{cite journal| author=Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL| title=Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries. | journal=N Engl J Med | year= 1982 | volume= 307 | issue= 22 | pages= 1362-6 | pmid=6215582 | doi=10.1056/NEJM198211253072202 | pmc= | url= }} </ref><ref name="pmid11870246">{{cite journal| author=Carabello BA| title=Clinical practice. Aortic stenosis. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 9 | pages= 677-82 | pmid=11870246 | doi=10.1056/NEJMcp010846 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11870246 }} </ref>. | ||
==Pressure Gradient & Valve Area== | ==Pressure Gradient & Valve Area== | ||
Revision as of 00:00, 14 April 2012
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Aortic Stenosis Microchapters |
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Diagnosis |
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Treatment |
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Percutaneous Aortic Balloon Valvotomy (PABV) or Aortic Valvuloplasty |
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Transcatheter Aortic Valve Replacement (TAVR) |
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Case Studies |
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Aortic stenosis pathophysiology On the Web |
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American Roentgen Ray Society Images of Aortic stenosis pathophysiology |
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Directions to Hospitals Treating Aortic stenosis pathophysiology |
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Risk calculators and risk factors for Aortic stenosis pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Mohammed A. Sbeih, M.D. [2], Lakshmi Gopalakrishnan, M.B.B.S. [3] Assistant Editor-In-Chief: Kristin Feeney, B.S. [4]
Overview
The impedance to antegrade blood flow as a result of aortic stenosis results in chronic pressure overload of the left ventricle. The most common complication of aortic stenosis is left ventricular hypertrophy. The obstruction of flow in aortic stenosis can obviously occur at the level of the aortic valve itself, but can also occur at the subvalvular (below the aortic valve) or supravalvular (above the aortic valve) level as well.
Left Ventricular Hypertrophy
Long-standing aortic stenosis exposes the left ventricle to a sustained prolonged pressure overload state which may lead to outflow tract obstruction. Over the years, this sustained increase in systolic pressure generated by the left ventricle, results in concentric hypertrophy of the myocardium with subsequent thickening of the left ventricular wall; however, the chamber volume remains within normal limits.[1][2][3] The left ventricular wall increases in thickness (i.e. concentric hypertrophy occurs) as a results of a parallel replication of the sarcomeres. During the period of concentric hypertrophy, the left ventricle is not dilated and there is preservation of left ventricular systolic function, but diastolic function may be reduced due to a reduction in diastolic compliance.
Although, this massive concentric hypertrophy characterized by a reduced diastolic radius-to-wall thickness ratio has shown to initially counter balance the increased systolic left ventricular pressure, if this process continued, an inverse relationship has been observed between ejection fraction and left ventricular mass.[4]
Another factor that may contribute to reduced ventricular function is dyssynchronous contraction subsequent to regional wall motion abnormalities, fibrosis or ischemia.[5]
Therefore, as a result of inadequate degree of hypertrophy with disproportional wall thickness an increase in systolic wall stress ensues[4][6][7] which when coupled with reduced left ventricular contractility[8] leads to significant reduction in the ejection fraction. Furthermore, among such patients with low ejection fraction secondary to increase afterload, Carabello et al demonstrated the lack of benefit of corrective surgery.[6]
An increase in left ventricular end-diastolic pressure without chamber dilatation is observed subsequently to the increased left ventricular wall thickness, depressed volume/mass ratio and reduced chamber compliance [9][6][6] thereby reflecting diastolic dysfunction[10]
The hypertrophied left ventricle may have reduced coronary blood flow even in the absence of obstructive epicardial stenoses due to compression of the capillary network. This may lead to subendocardial ischemia during stress or exercise.[11][12].
Pressure Gradient & Valve Area
When the aortic valve becomes stenosed, it can result in the formation of a pressure gradient between the left ventricle (LV) and the aorta [13]. The more constricted the valve, the bigger the gradient between the LV and the aorta.
For instance, in patient with mild AS, the gradient may be 20 mmHg. This means that, at peak systole, while the LV may generate a pressure of 140 mmHg, the pressure that is transmitted into the aorta will only be 120 mmHg. So, while a blood pressure cuff may measure a normal systolic blood pressure the actual pressure generated by and inside the LV would be considerably higher. As the left ventricle fails, however, it may no longer be able to mount the contractility necessary to generate a large gradient across the aortic valve.
Therefore, absence of a large gradient across the aortic valve does not exclude the presence of critical aortic stenosis. The presence of a low gradient and low ejection results in low flow aortic stenosis. It is for this reason that the best measure of the severity of aortic stenosis is the aortic valve area, not the aortic valve gradient.
Aortic valve area
Aortic valve area calculation
Subvalvular Gradients in AS in the Absence of Anatomic Obstruction
Fluid dynamic mediated subvalvular pressure gradients are often present in patients with severe aortic stenosis in the absence of an anatomic subvalvular obstruction and constitute ~50% of the total measured transvalvular gradient. The extent of increase in cardiac output during exercise is inversely related to the magnitude of subvalvular gradient.[14]
Flow Velocity
If the left ventricular function and contractility is preserved, a flow velocity across the stenosed valve of at least 2.6 m/sec is deemed consistent with aortic stenosis. This is based upon echocardiographic estimation of the aortic jet velocity, aortic valve area and the mean transvalvular gradient. In aortic valve sclerosis (not stenosis); the aortic valve becomes calcified but the aortic jet velocity is ≤ 2.5 m/sec (without a significant gradient). Aortic valve sclerosis is commonly defined as a focal thickening of the aortic cusps with calcific nodules generally at the base of leaflets and transvalvular velocity at Doppler still in the normal range (Vmax <2 m/s). Until few years ago, it was considered a physiologic process related to aging without clinical relevance. However, aortic valve sclerosis is not observed in about 50% of people over 80 years old. Furthermore, several experimental and clinical studies have demonstrated that it could represent an active phenomenon, significantly related to risk factors for atherosclerosis and cardiovascular morbidity and mortality [15]. [16].
Low Flow, Low Gradient, Low Ejection Fraction Aortic Stenosis
If there is a decline in left ventricular function due to systolic dysfunction, there may be only a moderate transvalvular gradient or low flow aortic stenosis. If there is fibrosis of the left ventricle, there may be incomplete recovery after aortic valve replacement. This scenario can also occur among patients in whom there is a history of myocardial infarction: there is insufficient contractility to mount an aortic gradient.
Definition
- An aortic valve areas < 1.0 cm2
- A left ventricular ejection fraction < 40%
- A mean pressure difference or gradient across the aortic valve of < 30 mm Hg
Assessment
- Echocardiography is fairly accurate to assess the severity of aortic stenosis in patients with normal or near normal cardiac output. However, in patients with low output aortic stenosis, dobutamine stress echocardiography or cardiac catheterization may be required to accurately assess the severity of aortic stenosis.
- With a dobutamine infusion, the aortic valve area should increase to > 1.2 cm2, and the mean pressure gradient should rise above 30 mm Hg. If there is a failure to acheive these improvements, early surgical mortality is 32-33%, but it is only 5–7% in those patients who can augment their contractility and gradient. Survival at five years was 88% after surgery if the patient can augment their contractility, but only 10–25% if the patient cannot augment their contractility.
ACC/AHA Guidelines- Recommendation [17]
| “ |
Class IIa1. Dobutamine stress echocardiography is reasonable to evaluate patients with low-flow/low-gradient aortic stenosis and left ventricular dysfunction. (Level of Evidence: B) 2. Cardiac catheterization for hemodynamic measurements with infusion of dobutamine can be useful for evaluation of patients with low-flow/low-gradient aortic stenosis and left ventricular dysfunction. (Level of Evidence: C) |
” |
Relationship of Hemodynamic Severity to Symptoms of Aortic Stenosis
- In general, aortic stenosis patients with normal left ventricular systolic function become symptomatic, usually when:
- Valve area is less than 1.0 cm2.
- Jet velocity is over 4.0 m/sec.
- Mean transvalvular pressure gradient exceeds 40 mm Hg.
- However, many patients develop symptoms only when more severe valve obstruction is present, other patients become symptomatic at less severe degree of stenosis, particularly if there is coexisting aortic regurgitation.
ACC/AHA Guidelines- Severity Classification [17]
Indicator Mild Moderate Severe Jet velocity (m per s) Less than 3.0 3.0–4.0 Greater than 4.0 Mean gradient (mm Hg)† Less than 25 25–40 Greater than 40 Valve area (cm2) Greater than 1.5 1.0–1.5 Less than 1.0 Valve area index (cm2 per m2) Less than 0.6
† Valve gradients are flow dependent and when used as estimates of severity of valve stenosis should be assessed with knowledge of cardiac output or forward flow across the valve.
Microscopic Pathology
Pathological Findings
Aortic Stenosis Autopsy Report
Guideline Resources
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[17]
References
- ↑ Sasayama S, Ross J, Franklin D, Bloor CM, Bishop S, Dilley RB (1976). "Adaptations of the left ventricle to chronic pressure overload". Circulation Research. 38 (3): 172–8. PMID 129304. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Gaasch WH (1979). "Left ventricular radius to wall thickness ratio". The American Journal of Cardiology. 43 (6): 1189–94. PMID 155986. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help) - ↑ Spann JF, Bove AA, Natarajan G, Kreulen T (1980). "Ventricular performance, pump function and compensatory mechanisms in patients with aortic stenosis". Circulation. 62 (3): 576–82. PMID 6446989. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ 4.0 4.1 Krayenbuehl HP, Hess OM, Ritter M, Monrad ES, Hoppeler H (1988). "Left ventricular systolic function in aortic stenosis". European Heart Journal. 9 Suppl E: 19–23. PMID 2969811. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Jin XY, Pepper JR, Gibson DG (1996). "Effects of incoordination on left ventricular force-velocity relation in aortic stenosis". Heart (British Cardiac Society). 76 (6): 495–501. PMC 484601. PMID 9014797. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ 6.0 6.1 6.2 6.3 Ross J (1976). "Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function". Progress in Cardiovascular Diseases. 18 (4): 255–64. Retrieved 2012-04-10.
- ↑ Gunther S, Grossman W (1979). "Determinants of ventricular function in pressure-overload hypertrophy in man". Circulation. 59 (4): 679–88. PMID 154367. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Huber D, Grimm J, Koch R, Krayenbuehl HP (1981). "Determinants of ejection performance in aortic stenosis". Circulation. 64 (1): 126–34. PMID 7237709. Retrieved 2012-04-10. Unknown parameter
|month=ignored (help) - ↑ Gaasch WH, Levine HJ, Quinones MA, Alexander JK (1976). "Left ventricular compliance: mechanisms and clinical implications". The American Journal of Cardiology. 38 (5): 645–53. PMID 136186. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help) - ↑ Gaasch WH (1994). "Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction". JAMA : the Journal of the American Medical Association. 271 (16): 1276–80. PMID 8151903. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help) - ↑ Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL (1982). "Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries". N Engl J Med. 307 (22): 1362–6. doi:10.1056/NEJM198211253072202. PMID 6215582.
- ↑ Carabello BA (2002). "Clinical practice. Aortic stenosis". N Engl J Med. 346 (9): 677–82. doi:10.1056/NEJMcp010846. PMID 11870246.
- ↑ Lilly LS (editor) (2003). Pathophysiology of Heart Disease (3rd ed. ed.). Lippincott Williams & Wilkins. ISBN 0-7817-4027-4.
- ↑ Laskey WK, Kussmaul WG (2001). "Subvalvular gradients in patients with valvular aortic stenosis: prevalence, magnitude, and physiological importance". Circulation. 104 (9): 1019–22. PMID 11524395. Retrieved 2012-04-12. Unknown parameter
|month=ignored (help) - ↑ Branch KR, O'Brien KD, Otto CM (2002). "Aortic valve sclerosis as a marker of active atherosclerosis". Curr Cardiol Rep. 4 (2): 111–7. PMID 11827633.
- ↑ {{Faggiano P, D'Aloia A, Antonini-Canterin F, Pinamonti B, DiLenarda A, Brentana L, Metra M, Nodari S, Dei Cas L. Usefulness of cardiac calcification on two-dimensional echocardiography for distinguishing ischemic from nonischemic dilated cardiomyopathy: a preliminary report. J Cardiovasc Med. 2006.}}
- ↑ 17.0 17.1 17.2 Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Faxon DP, Freed MD; et al. (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". J Am Coll Cardiol. 52 (13): e1–142. doi:10.1016/j.jacc.2008.05.007. PMID 18848134.
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