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Aortic valve stenosis (AS) is a disease of the heart valves in which the opening of the aortic valve is narrowed.[1] The aortic valve is located between the left ventricle of the heart and the aorta; the largest artery in the body, responsible for carrying the entire output of oxygenated blood to the circulatory system.

AS is now the most common valvular heart disease in the Western World.[2] It primarily presents as calcific AS in adults of advanced age (2-7% of the population >65 years of age).[3][4]

Etiology[edit]

Aortic stenosis (AS) is most commonly caused by age-related progressive calcification of a normal (three-leafed) aortic valve (>50% of cases) with a mean age of 65 to 70 years old. Other causes of AS include calcification of a congenital bicuspid aortic valve[5] (30-40% of cases) and chronic rheumatic heart disease (less than 10% of cases).[6] Rare causes of AS include Fabry disease, systemic lupus erythematosus, Paget disease, hyperuricemia, and infection.[7]

Normal aortic valves have three leaves (tricuspid), but some individuals are born with an aortic valve that has two leaves (bicuspid). Typically, AS due to calcification of a bicuspid valve appears earlier, in the 40s or 50s,[8] whereas AS due to calcification of a normal tricuspid aortic valve appears later, usually in the 60s and 70s.

Pathophysiology[edit]

The human aortic valve has a typical orifice area of 3.0-4.0 square centimetres.[9][10] When the left ventricle (LV) contracts, it forces blood through the valve orifice into the aorta and subsequently the rest of the body. When the LV relaxes, the aortic valve closes and prevents the blood in the aorta from flowing backward into the LV. In aortic stenosis, the opening of the aortic valve becomes narrowed or constricted (stenotic), normally due to calcification.

File:Healthy and diseased aortic valves.png
Illustration depicting the difference between healthy and diseased aortic valves.


Degenerative AS, the most common variety, and bicuspid AS both begin with damage to endothelial cells from increased mechanical stress.[8][9] Inflammation is thought to be involved in the earlier stages of the pathogenesis of AS, and its associated risk factors are known to promote the deposition of LDL cholesterol and possibly a highly damaging substance known as lipoprotein (a) into the aortic valve. Over time this leads to increased inflammation and calcification resulting ultimately in significant damage and stenosis over time.[8][9]

As a consequence of stenosis, the LV must generate greater pressure with each contraction to effectively move blood through the valve and into the aorta.[2][11] Initially, the LV generates this increased pressure by thickening its muscular walls (myocardial hypertrophy). The type of hypertrophy most commonly seen in AS is known as concentric hypertrophy,[2] in which the walls of the LV are (approximately) equally thickened.

In the later stages, the LV dilates, the wall thins, and the systolic function deteriorates (resulting in impaired ability to pump blood forward).

Signs and symptoms[edit]

Symptoms related to AS depend on the degree of valve stenosis. Symptoms most often present in individuals with severe aortic stenosis, though they may occur in those with moderate aortic stenosis as well. The most common symptoms of AS are shortness of breath, angina, fatigue and syncope/presyncope, described below. Other symptoms include rapid or irregular heartbeats and palpitations.

After the onset of symptoms, patients with severe aortic stenosis have a survival rate as low as 50% at 2 years and 20% at 5 years without aortic valve replacement.[12]

File:Survival rate of patients with aortic stenosis.png
Graph showing the survival rate of patients with AS. Note the steep decline in survival following the onset of severe symptoms. This steep decline evidences that patients identified and treated before the onset of severe symptoms are more likely to survive than those who progress to severe symptoms without treatment.

The symptoms of aortic disease are commonly misinterpreted by patients as ‘normal’ signs of aging’.[13] Many patients are deemed to be asymptomatic during initial evaluations but on closer examination up to 37% exhibit indicative symptoms.[14] The European Society of Cardiology (ESC) recommend that “careful questioning, in order to check for the presence of symptoms (exertional shortness of breath, angina, dizziness or syncope), is critical for proper patient management and must take into account the possibility that patients may deny symptoms as they subconsciously reduce their activities”.[15]

ESC guidelines also suggest that exercise testing either by measuring blood pressure and assessing symptoms during treadmill exercise or “exercise stress echocardiography, may provide prognostic information in asymptomatic severe AS”.[15] As such, physicians should consider these diagnostic tools when faced with patients who they suspect may have asymptomatic severe AS.

Angina[edit]

Angina in the setting of heart failure also increases the risk of death.

Angina in the setting of AS is secondary to left ventricular hypertrophy (LVH) that is caused by the constant production of increased pressure required to overcome the pressure gradient caused by AS. While the myocardium (heart muscle) of the LV gets thicker, the arteries that supply the muscle do not get significantly longer or bigger, so the muscle may become ischemic (does not receive an adequate blood supply).

The ischemia may first be evident during exercise, when the heart muscle requires increased blood supply to compensate for the increased workload. The individual may complain of exertional angina. At this stage, a stress test with imaging may be suggestive of ischemia.

Eventually, the muscle will require more blood supply at rest than can be provided by the coronary arteries. At this point there may be signs of ventricular strain pattern (ST segment depression and T wave inversion) on the electrocardiogram (ECG), suggesting subendocardial ischemia. The subendocardium is the region that becomes ischemic because it is the furthest from the main epicardial coronary arteries.

Syncope[edit]

Syncope (fainting spells) from AS is usually associated with exercise or exertion.[2][16] In the setting of heart failure it increases the risk of death. In patients with syncope, the 3-year mortality rate is 50%, if the aortic valve is not replaced.

It is unclear why AS causes syncope. One popular theory is that severe AS produces a nearly fixed cardiac output. When the patient exercises, their peripheral vascular resistance will decrease as the blood vessels of the skeletal muscles dilate to allow the muscles to receive more blood. This decrease in peripheral vascular resistance is normally compensated for by an increase in the cardiac output. Since patients with severe AS cannot increase their cardiac output, the blood pressure falls, and patients experience syncope due to decreased blood perfusion to the brain.

A second theory as to why syncope may occur in AS is that during exercise, the high pressures generated in the hypertrophied LV cause a vasodepressor response, which causes a secondary peripheral vasodilation that, in turn, causes decreased blood flow to the brain resulting in loss of consciousness. Indeed, in AS, because of the fixed obstruction to blood flow out from the heart, it may be impossible for the heart to increase its output to offset peripheral vasodilation.

A third mechanism may sometimes be operative. Due to the hypertrophy of the LV in aortic stenosis, including the consequent inability of the coronary arteries to adequately supply blood to the myocardium (see "Angina" above), arrhythmias may develop. These can lead to syncope.

Finally, in calcific aortic stenosis[8][16] at least, the calcification in and around the aortic valve can progress and extend to involve the electrical conduction system of the heart. If that occurs, the result may be heart block - a potentially lethal condition of which syncope may be a symptom.

Congestive heart failure[edit]

Congestive heart failure (CHF) carries a grave prognosis in patients with AS. Patients with CHF that is attributed to AS have a 2-year mortality rate of 50%, if the aortic valve is not replaced.

CHF in the setting of AS is due to a combination of LVH with fibrosis, systolic dysfunction (a decrease in the ejection fraction) and diastolic dysfunction (elevated filling pressure of the LV).[2]

Associated symptoms[edit]

In Heyde's syndrome, aortic stenosis is associated with gastrointestinal bleeding due to angiodysplasia of the colon.[17] Recent research has shown that the stenosis causes a form of von Willebrand disease by breaking down its associated coagulation factor (factor VIII-associated antigen, also called von Willebrand factor), due to increased turbulence around the stenosed valve.

Complications[edit]

Since the stenosed aortic valve may limit the heart's output, people with AS are at risk of syncope and dangerously low blood pressure should they use any of a number of medications for cardiovascular diseases that often co-exist with aortic stenosis. Examples include nitroglycerin, nitrates, terazosin (Hytrin), and hydralazine. Note that all of these substances lead to peripheral vasodilation. Under normal circumstances, in the absence of AS, the heart is able to increase its output and thereby offset the effect of the dilated blood vessels. In some cases of AS, however, due to the obstruction of blood flow out of the heart caused by the stenosed aortic valve, [[cardiac output]] cannot be increased. Low blood pressure or syncope may ensue.

Risk factors[edit]

Risk factors known to influence disease progression of AS include lifestyle habits similar to those of coronary artery disease such as hypertension, advanced age, being male, hyperlipidemia, diabetes mellitus, cigarette smoking, metabolic syndrome, and end-stage renal disease.[2][7][8]

Diagnosis[edit]

AS is a progressive disease that ranges from asymptomatic to severe. The ESC has published criteria for the definition of severe valve stenosis based on ECG, seen below:

File:Echocardiographic criteria for the definition of severe valve stenosis.png
Echocardiographic criteria for the definition of severe valve stenosis: an integrative approach. Taken from Guidelines on the management of valvular heart disease (version 2012)[15]

AS is more frequently diagnosed when it is severe, often due to more obvious symptoms. However, data suggests that up to 37% of patients deemed to be asymptomatic during initial evaluations are found to exhibit indicative symptoms on closer examination.[14] This suggests that AS may be under-diagnosed and opportunities to improve diagnosis and subsequent management may exist.

In primary care, shortness of breath or a serendipitous murmur heard during auscultation are commonly recognised presentations, leading to closer assessment and subsequent diagnosis.

Good evidence exists to demonstrate that certain characteristics of the peripheral pulse can rule in the diagnosis.[18] In particular, there may be a slow and/or sustained upstroke of the arterial pulse, and the pulse may be of low volume. This is sometimes referred to as pulsus ''parvus et tardus''.[6][16] There may also be a noticeable delay between the first heart sound (on auscultation) and the corresponding pulse in the carotid artery (so-called 'apical-carotid delay'). In similar manner, there may be a delay between the appearance of each pulse in the brachial artery (in the arm) and the radial artery (in the wrist).

The first heart sound may be followed by a sharp ejection sound ("ejection click") best heard at the lower left sternal border and the apex, and, thus, appear to be "split". The ejection sound, caused by the impact of LV outflow against the partially fused aortic valve leaflets, is more commonly associated with a mobile bicuspid aortic valve than an immobile calcified aortic valve. The intensity of this sound does not vary with respiration, which helps distinguish it from the ejection click produced by a stenotic pulmonary valve, which will diminish slightly in intensity during inspiration.[19] Clinical signs can however me misleading especially in the elderly.

An easily heard systolic, crescendo-decrescendo ('ejection') murmur is heard loudest at the upper right sternal border, at the 2nd right intercostal space,[6] and radiates to the carotid arteries bilaterally.[2][16] The murmur increases with squatting, decreases with standing and isometric muscular contraction such as the Valsalva maneuver, which helps distinguish it from hypertrophic obstructive cardiomyopathy (HOCM). The murmur is louder during expiration, but is also easily heard during inspiration. The more severe the degree of the stenosis, the later the peak occurs in the crescendo-decrescendo of the murmur.

The second heart sound (A2) tends to become decreased and softer as the aortic stenosis becomes more severe.[6] This is a result of the increasing calcification of the valve preventing it from "snapping" shut and producing a sharp, loud sound. Due to increases in left ventricular pressure from the stenotic aortic valve, over time the ventricle may hypertrophy, resulting in a diastolic dysfunction. As a result, one may hear a fourth heart sound due to the stiff ventricle.[16] With continued increases in ventricular pressure, dilatation of the ventricle will occur, and a third heart sound may be manifest.

Finally, AS often co-exists with some degree of aortic insufficiency (aortic regurgitation). Hence, the physical exam for AS may also reveal signs of the latter, for example an early diastolic decrescendo murmur. Indeed, when both valve abnormalities are present, the expected findings of either may be modified or may not even be present. Rather, new signs that reflect the presence of simultaneous aortic stenosis and insufficiency, e.g. pulsus bisferiens, emerge.

According to a meta analysis, the most useful findings for diagnosing AS in the clinical setting were slow rate of rise of the carotid pulse (positive likelihood ratioranged 2.8-130 across studies), mid to late peak intensity of the murmur (positive likelihood ratio, 8.0-101), and decreased intensity of the second heart sound (positive likelihood ratio, 3.1-50).[18] Patients where heart murmurs of any severity are detected should be routinely referred to a cardiologist.

Other peripheral signs include:

Electrocardiogram[edit]

Although AS does not lead to any specific findings on the ECG, it still often leads to a number of ECG abnormalities. ECG manifestations of LVH are common in AS[8][16] and arise as a result of the stenosis having placed a chronically high pressure load on the LV (with LVH being the expected response to chronic pressure loads on the left ventricle no matter what the cause).

As noted above, the calcification process that occurs in AS can progress to extend beyond the aortic valve and into the electrical conduction system of the heart. Evidence of this phenomenon may rarely include ECG patterns characteristic of certain types of heart block such as Left bundle branch block.[8]

Heart catheterisation[edit]

Cardiac chamber catheterisation provides an alternative route to diagnosis, indicating severe stenosis in valve area of <1.0 cm2 (normally about 3 cm2).[20] It can directly measure the pressure on both sides of the aortic valve. The pressure gradient may be used as a decision point for treatment. It may be useful in symptomatic patients before surgery where non-invasive tests have failed to provide the diagnosis. There are various technical reasons why the severity of AS may be underestimated at catheterisation and surprisingly low gradients should always be treated with caution.[16] Cardiac catheterisation is not recommended to assess the severity of aortic stenosis when non-invasive testing is sufficient to make the diagnosis.[8]

Echocardiogram[edit]

Severity of aortic stenosis[6]
Degree of aortic stenosis Mean gradient (mmHg) Aortic valve area (cm2)
Mild aortic stenosis <25 >1.5
Moderate aortic stenosis 25 - 40 1.0 - 1.5
Severe aortic stenosis >40 <1.0
Critical aortic stenosis >70 <0.6

Echocardiogram (heart ultrasound) is the best non-invasive tool to evaluate the aortic valve anatomy and function.

The aortic valve area can be calculated non-invasively using echocardiographic flow velocities at the narrowest portion of the valve and in the sub valvular region where the dimensions can be measured using the continuity equation. Using the velocity of the blood through the valve, the pressure gradient across the valve can be calculated by the continuity equation or using the modified Bernoulli's equation:

Gradient = 4(velocity)2 mmHg

A normal aortic valve has a gradient of only a few mmHg. A decreased valvular area causes increased pressure gradient, and these parameters are used to classify and grade AS as mild, moderate or severe. The pressure gradient can be abnormally low in the presence of mitral stenosis, heart failure, co-existent aortic regurgitation and also ischaemic heart disease (disease related to decreased blood supply and oxygen causing ischaemia).

Echocardiogram may also show LVH, thickened and immobile aortic valve and dilated aortic root.[2] However, it may appear deceptively normal in acute cases.[17]

Chest X-ray[edit]

Chest X-ray can also assist in the diagnosis, showing calcific aortic valve, and, in longstanding disease, enlarged LV[6][16] and atrium.[16]

Management[edit]

AS is a progressive condition which requires different management approaches depending on the severity of disease and the specific profile of the individual patient. The ESC publishes a guideline document summarising best practice management for AS http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/valvular-heart-disease.aspx. In patients with severe AS, aortic valve replacement (AVR) is the definitive therapy.[15]

File:ESC guidelines on the management of severe AS.png
ESC guidelines on the management of severe AS.

Medical management[edit]

The use of medical therapies in the treatment of AS is contentious. There are currently no studies that conclusively illustrate a benefit of medical therapies, however some therapies may be useful for the management of common comorbidities associated with AS.

Statins[edit]

Statins do not effect the progression of advanced AS. The latest trials do not show any benefit in slowing AS progression,[8] but did demonstrate a decrease in ischaemic cardiovascular events.[2]

In general, medical therapy has relatively poor efficacy in treating AS.[16] However, it may be useful to manage commonly coexisting conditions that correlate with AS:

Since calcific AS shares many pathological features and risk factors with atherosclerosis, and since atherosclerosis may be prevented and/or reversed by cholesterol lowering, there has been interest in attempting to modify the course of calcific AS by lowering cholesterol levels with statin drugs. Although a number of small, observational studies demonstrated an association between lowered cholesterol and decreased progression, and even regression, of calcific AS, a recent, large randomised clinical trial, published in 2005, failed to find any predictable effect of cholesterol lowering on calcific AS. A 2007 study did demonstrate a slowing of AS with the statin rosuvastatin.[22] However, a large randomised controlled trial published in the New England Journal of Medicine in 2008 failed to find any beneficial effect of intensive cholesterol lowering on the course of AS.[8]

In summary, medical therapies have failed to consistently show any benefit in the treatment of AS and should not be considered an alternative to continuous monitoring and aortic valve replacement (AVR).

Aortic valve replacement (AVR)[edit]

Main article: aortic valve replacement

The ESC states that: “Early valve replacement should be strongly recommended in all symptomatic patients with severe AS who are otherwise candidates for surgery.”[15]

While AVR has been the standard of care for AS for several decades, currently AVR approaches include open-heart surgery, minimally invasive cardiac surgery (MICS) and minimally invasive catheter-based (percutaneous) implant.

It is recommended that antibiotic prophylaxis be limited only to those with prosthetic heart valves, those with previous episode(s) of endocarditis, and those with certain types of congenital heart disease.[citation needed]

File:Aortic Valve Replacement Examples.png
Examples of replacement valves.

Surgical valve replacement[edit]

A diseased aortic valve is most commonly replaced using a surgical procedure with either a mechanical or a tissue valve. The procedure is done either in an open-heart surgical procedure or, in a smaller but growing number of cases, a minimally invasive cardiac surgery (MICS) procedure.

Percutaneous (transcatheter) aortic valve replacement[edit]

For patients who are not candidates for surgical valve replacement, transcatheter valve replacement may be a suitable alternative. When selecting the optimal therapy for individual patients, the percutaneous (transcatheter) approach must be carefully weighed against the excellent results achieved with conventional surgery.

The ESC states that “TAVI is indicated in patients with severe symptomatic AS who are not suitable for AVR as assessed by a ‘heart team’ and who are likely to gain improvement in their quality of life and to have a life expectancy of more than 1 year after consideration of their comorbidities”, and furthermore, that “TAVI should be considered in high-risk patients with severe symptomatic AS who may still be suitable for surgery, but in whom TAVI is favoured by a ‘heart team’ based on the individual risk profile and anatomic suitability.”[15]

Non-replacement treatments[edit]

Treatment options exist which do not involve replacing the diseased valve.

Apicoaortic conduit[edit]

Apicoaortic conduit (AAC), or aortic valve bypass (AVB), has been shown to be an effective treatment for AS.[23] There is long-term stability of the left ventricular haemodynamics after AVB, with no further biologic progression of native aortic valve stenosis. Once the pressure gradient across the native valve is substantially reduced, the narrowing and calcification of the native valve halts.

Balloon valvuloplasty[edit]

For infants and children, balloon valvuloplasty, where a balloon is inflated to stretch the valve and allow greater flow, may also be effective. In adults, however, it is generally ineffective, as the valve tends to return to a stenosed state. The surgeon will make a small incision at the top of the patient's leg and proceed to insert the balloon into the artery and then inflate it to get a better flow of blood around the patient's body.[24]

Prognosis[edit]

If untreated, severe symptomatic AS carries a poor prognosis with a 2-year mortality rate of 50-60% and a 3-year survival rate of less than 30%.[25]

Epidemiology[edit]

Approximately 2% of people over the age of 65, 3% of people over 75[2], and 4% percent of people over 85 have AS.[26] The prevalence is increasing with the aging population in North America and Europe.[27]

History[edit]

Aortic stenosis was first described by French physician Lazare Rivière in 1663.[10]

References[edit]

  1. ^ Aortic stenosis at Mount Sinai Hospital
  2. ^ a b c d e f g h i j Manning, WJ (October 2013). "Asymptomatic aortic stenosis in the elderly: a clinical review". JAMA 310 (14): 1490–1497.doi:10.1001/jama.2013.279194. PMID 24104373.
  3. ^ Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Ba ̈rwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231–1243.
  4. ^ Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–1011.
  5. ^ Ricardo Zalaquett, Cristóbal Camplá, et al. (2005). "Cirugía reparadora de la válvula aórtica bicúspide insuficiente". Rev Méd Chile, 133(3): pp. 279-86. ISSN 0034-9887.
  6. ^ a b c d e f g h VOC=VITIUM ORGANICUM CORDIS, a compendium of the Department of Cardiology at Uppsala Academic Hospital. By Per Kvidal September 1999, with revision by Erik Björklund May 2008
  7. ^ a b Olszowska, M (November 2011). "Pathogenesis and pathophysiology of aortic valve stenosis in adults". Polskie Archiwum Medcyny Wewnetrznej 121 (11): 409–413. PMID 22129836.
  8. ^ a b c d e f g h i j Rogers, FJ (November 2013). "Aortic stenosis: new thoughts on a cardiac disease of older people". Journal of the American Osteopathic Association 113(11): 820–828. doi:10.7556/jaoa.2013.057. PMID 24174503
  9. ^ a b c d Olszowska, M (November 2011). "Pathogenesis and pathophysiology of aortic valve stenosis in adults". Polskie Archiwum Medcyny Wewnetrznej 121 (11): 409–413. PMID 22129836.
  10. ^ a b Leopold, JA (August 2012). "Cellular mechanisms of aortic valve calcification".Circulation. Cardiovascular Interventions 5 (4): 605–614.doi:10.1161/CIRCINTERVENTIONS.112.971028. PMC 3427002. PMID 22896576.
  11. ^ Lilly LS (editor) (2003). Pathophysiology of Heart Disease (3rd ed.). Lippincott Williams & Wilkins. ISBN 0-7817-4027-4.
  12. ^ Otto CM. Timing of aortic valve surgery. Heart. 2000;84:211-21.
  13. ^ Alliance for Aging Research. Aortic Stenosis: Under-Diagnosed and Under-Treated. 2010.
  14. ^ a b Das P. Exercise testing to stratify risk in aortic stenosis. European Heart Journal. 2005;26:1309-1313
  15. ^ a b c d e f European Heart Journal (2012) 33, 2451–2496.
  16. ^ a b c d e f g h i j k l Chapter 1: Diseases of the Cardiovascular system > Section: Valvular Heart Disease in: Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7153-6.
  17. ^ a b Figuinha, FC; Spina, GS; Tarasoutchi, F (March 2011). "Heyde's syndrome: case report and literature review". Arquivos Brasileiros de Cardiologia 96 (3): e42–e45. PMID 21484065.
  18. ^ a b Etchells E, Bell C, Robb K (February 1997). "Does this patient have an abnormal systolic murmur?". JAMA 277 (7):564–71. doi:10.1001/jama.277.7.564. PMID 9032164.
  19. ^ Lilly, editor, Leonard S. (2007). Pathophysiology of heart disease : a collaborative project of medical students and faculty (4th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 36. ISBN 978-0-7817-6321-9.
  20. ^ Yale atlas of echocardiography
  21. ^ Rutherford SD, Braunwald E. Chronic ischaemic heart disease. In: Braunwald E, ed. Heart disease: A textbook of cardiovascular medicine. 4th ed. Philadelphia: WB Saunders, 1992:1292-1364.
  22. ^ Moura LM, Ramos SF, Zamorano JL et al. (2007). "Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis". Journal of the American College of Cardiology 49 (5): 554–561. doi:10.1016/j.jacc.2006.07.072. PMID 17276178.
  23. ^ Vliek CJ, Balaras E, Li S, Lin JY, Young CA, DeFillippi CR, Griffith BP, Gammie JS,Early and Midterm Hemodynamics After Aortic Valve Bypass (Apicoaortic Conduit) Surgery, Ann Thorac Surg 2010;90:136–43.
  24. ^ Mayo Clinic > Aortic valve stenosis > Treatments and drugs Retrieved September 2010
  25. ^ Spaccarotella, C; Mongiardo, A; Indolfi, C (2011). "Pathophysiology of aortic stenosis and approach to treatment with percutaneous valve implantation". Circulation Journal: Official Journal of the Japanese Circulation Society 75 (1): 11–19. doi:10.1253/circj.CJ-10-1105. PMID 21178291.
  26. ^ Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997; 29: 630-634.
  27. ^ Clinical Anesthesiology by Edward Morgan
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