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Published: July 2014

Aortic Valve Disease

Gian M. Novaro

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The cardiac valves have two functions. By opening, they control the direction in which blood flows and, by closing, they allow pressure differentials to exist in a closed system. Abnormal valve function produces either pressure overloading caused by restricted opening or volume overloading caused by inadequate closure. Valvular heart disease can be approached on the basis of the pathologic lesion—aortic stenosis or aortic regurgitation—or pathophysiologically, as pressure overloading versus volume overloading.

This chapter summarizes the current approach to aortic valve disease, aortic stenosis and regurgitation, with particular emphasis on the indications for valve surgery. In general, adherence is given to the recommendations provided by the American Heart Association/American College of Cardiology (AHA/ACC) 2014 guidelines for the management of patients with valvular heart disease.1

Aortic Stenosis

Definition

Aortic stenosis typically refers to obstruction of flow at the level of the aortic valve and does not include the subvalvular and supravalvular forms of this disease. Aortic valve stenosis is usually defined by restricted systolic opening of the valve leaflets, with a mean transvalvular pressure gradient of at least 10 mm Hg. The cause of the stenosis can be further defined based on the anatomy and disease process affecting the valve.

Prevalence and Etiology

Aortic stenosis is the most common valvular heart disease in developed countries. Calcific aortic stenosis and congenital bicuspid aortic stenosis account for the overwhelming majority of aortic stenosis cases, followed by less common conditions, such as rheumatic aortic stenosis, radiation-induced aortic stenosis, and unicuspid aortic stenosis. In older adults, mild thickening, calcification, or both of a trileaflet aortic valve without restricted leaflet motion (i.e., aortic sclerosis) affects about 25% of the population older than 65 years. Calcific aortic stenosis (Fig. 1), however, affects approximately 2% to 3% of those older than 75 years. Thus, not all patients with aortic sclerosis go on to develop obstructive aortic valve disease; this occurs at a rate of about 10% within 5 years.2 Congenital bicuspid aortic stenosis is a major common cause of aortic stenosis; the approximate overall incidence of an anatomic bicuspid aortic valve is 1% to 2% of the population. Of these, about one half will develop aortic stenosis and up to one third will develop aortic regurgitation. Aortic stenosis caused by a congenital bicuspid aortic valve affects men more often than women, but later life calcific disease of a trileaflet valve involves both genders equally. Rheumatic valve disease has declined dramatically in the United States during the past 50 years, and isolated rheumatic aortic stenosis is unusual in any event. Radiation-induced aortic stenosis is a late effect of thoracic radiation exposure, causing premature valve calcification ˜15 to 20 years after initial exposure. Finally, congenital aortic stenosis usually results from failure of the valve commissures to develop fully resulting in unicuspid or dysplastic valves, and manifests with aortic stenosis in childhood or young adulthood.

The most common forms of aortic valve disease (calcific disease of a trileaflet aortic valve, calcification of a congenital bicuspid aortic valve) can be distinguished clinically by age at onset and by their characteristic echocardiographic findings. Calcific aortic stenosis, formerly referred to as "degenerative," affects trileaflet aortic valves, often in patients with other risk factors for atherosclerotic disease.3 The aortic valve leaflets undergo an active disease process, with lipid deposition, inflammation, and osteo-calcific changes. This form of aortic stenosis progresses slowly over 10 to 15 years, and patients often present between the ages of 70 and 90 years. Echocardiographic examination typically reveals varying degrees of nodular thickening and calcification of the three leaflets with restricted systolic motion. Adults with congenital bicuspid aortic valves are predominantly men, often have known of a heart murmur for many years, and usually experience the onset of symptoms between the ages of 40 and 60 years.4 Bicuspid valves (Fig. 2) usually have fusion of one of the three commissures, most commonly the left and right and, echocardiographically, can be distinguished by the presence of a raphe, leaflet doming, eccentric closure, and fish mouth orifice during systole. Congenital aortic stenosis usually presents in childhood, even in infancy, and the echocardiographic examination will show a unicuspid or bicuspid valve.

Pathophysiology

Valvular aortic stenosis results in chronic left ventricular pressure overloading. At any stage of life, however, the natural history of aortic stenosis largely reflects the functional integrity of the mitral valve. As long as adequate mitral valve function is maintained, the pulmonary bed is protected from the systolic pressure overloading imposed by aortic stenosis. In contrast to mitral valve disease, in which the pulmonary circuit is directly involved, compensatory concentric left ventricular hypertrophy allows the pressure-overloaded ventricle to maintain stroke volume with modest increases in diastolic pressure, and patients remain asymptomatic for many years.

Eventually, however, left ventricular hypertrophy and myocardial fibrosis cause either diastolic dysfunction with the onset of congestive symptoms or myocardial oxygen needs in excess of supply with the onset of angina. Some patients might also experience exertional syncope, probably reflecting the inability to increase cardiac output and maintain blood pressure in response to vasodilation. Vasodepressor (neurocardiogenic) syncope, however, may be an operative mechanism in a portion of these syncopal episodes.

Signs and Symptoms

Most patients with calcific aortic stenosis have known of their heart murmur for many years. The critical points in defining the cardiac history in men include the results of athletic, military, insurance, or employment physical examinations. In women, pregnancy and childbearing history are important to define functional status.

Patients with typical findings of aortic stenosis should have a detailed history-taking session with inquiry about habitual activity levels and any changes in exercise tolerance. The onset of any of the classic symptoms of left ventricular outflow obstruction—angina, syncope, or heart failure—in a patient with valvular aortic stenosis indicates advanced valve disease and should be carefully and promptly evaluated.

On physical examination, the harsh systolic murmur of aortic stenosis, loudest at the base of the heart and radiating to the carotids, is often but not always prominent. Low output states, obesity, or chronic lung disease may mask the findings. The murmur may radiate toward the cardiac apex (Gallavardin phenomenon), in which case the harsh component is lost; this finding may be mistaken for a second murmur. Other hallmarks of significant aortic valve stenosis include a single (pulmonic) component of the second heart sound and a sustained left ventricular apical impulse with a fourth heart sound. The slowly rising, low-volume carotid arterial pulse of severe aortic stenosis ("pulsus parvus et tardus") may be noted in younger patients, but changes in arterial compliance often mask these findings in older adults.

Diagnosis

The electrocardiogram often shows changes of left ventricular hypertrophy. The chest radiograph is seldom helpful, although occasionally heavy calcification of the valve or ascending aortic dilation may be seen. With its widespread availability, two-dimensional and Doppler echocardiography is the test of choice in the evaluation of patients with suspected valvular disease. Echocardiography allows assessment of the valve anatomy as well as of chamber size and ventricular function. Doppler studies permit estimation of pressure gradients and estimations of aortic valve area by using the continuity equation.

With good-quality echocardiography, cardiac catheterization is usually not required to make the diagnosis of aortic stenosis. The classic catheterization laboratory studies of transvalvular gradients and cardiac output have been largely superseded by hemodynamic assessment in the echocardiography laboratory. Cardiac catheterization for the diagnosis of aortic stenosis is now only needed when then echocardiographic data are equivocal or discrepant with the clinical picture.1 Otherwise, preoperative coronary angiography is performed in patients undergoing valve surgery to exclude coronary artery disease.

Treatment

Patients with aortic stenosis fall into one of four categories of severity: mild, moderate, severe, or very severe (Table 1). Asymptomatic patients with aortic stenosis should have medical follow-up with regular inquiry about changes in exercise tolerance or other symptoms. Serial echocardiographic examinations should be based on an understanding of the natural history of the lesion. Current evidence indicates that calcific aortic stenosis progresses, on the average, at a rate of about 0.1 cm2 per year decline in valve area. Asymptomatic patients should have an echocardiographic re-evaluation every 3 years for mild aortic stenosis, every 1 to 2 years for moderate stenosis, and every 6 to 12 months for severe stenosis. Patients with moderate to severe asymptomatic aortic stenosis should avoid strenuous or competitive activity, particularly heavy postprandial exertion. Infective endocarditis precautions following the new AHA/ACC guidelines are no longer required.5

Table 1: Classification of Aortic Stenosis Severity
Severity Valve Area (cm2) Maximum Aortic Velocity (m/sec) Mean Pressure Gradient (mm Hg)
Mild 1.5-2.0 2.0-2.9 <20
Moderate 1.0-1.5 3.0-3.9 20-39
Severe 0.6-1.0 4.0-4.9 40-59
Very severe <0.6 >5.0 >60

To date, no medical therapy exists for the treatment of calcific aortic stenosis. The possible impact of secondary prevention measures, particularly lipid lowering with statins, on the progression of aortic stenosis has been investigated. At the moment, there is no data to support the routine use of statins for the treatment of aortic stenosis.6 However, coexisting coronary artery disease and hypercholesterolemia are common in patients with aortic stenosis, and statin therapy should be employed in accordance with primary and secondary prevention guidelines. Hypertension is common in patients with calcific aortic stenosis and should be managed appropriately, because untreated hypertension may lead to earlier onset of symptoms. Antihypertensive medications should be titrated slowly, and vasodilators should be used with caution with severe aortic stenosis.

A supervised exercise tolerance test can provide helpful objective assessment for patients with echocardiographic evidence of moderate to severe aortic stenosis who report atypical symptoms, minimal complaints, or are sedentary and do not experience exercise intolerance. Stress testing performed with caution and under physician supervision can be done with relative safety in those with aortic stenosis. Functional limitation with an inability to exercise to an average predicted level of metabolic equivalents or a blunted blood pressure response (<20 mm Hg) may be viewed as a "symptom." Nevertheless, encountering truly asymptomatic individuals with very severe aortic stenosis is uncommon, and in the presence of symptoms, stress testing for severe aortic stenosis should not be performed.

Symptomatic patients (i.e., those with angina, syncope, or dyspnea) with severe aortic stenosis should undergo valve replacement (Class I recommendation).1 Additional recommendations for aortic valve surgery include patients with severe (Class I) and moderate (Class IIa) aortic stenosis undergoing coronary artery bypass grafting or surgery on the aorta or other heart valves; patients with severe aortic stenosis and left ventricular ejection fraction less than 0.50 (Class I); patients with severe aortic stenosis who exhibit an abnormal response to treadmill exercise such as a drop in blood pressure or decreased functional capacity (Class IIa); and patients with very severe aortic stenosis and low surgical risk (Class IIa).

The preoperative evaluation should address any major comorbid conditions and optimize their management. A carotid duplex examination should be performed, because distinguishing a carotid bruit from a radiating murmur is difficult clinically. Coronary angiography is indicated to evaluate the need for coronary revascularization, because at least one half of patents will have significant coronary disease as indicated by the preoperative angiogram. Smoking cessation is strongly encouraged, and diabetic control to achieve hemoglobin A1c levels below 7% may reduce postoperative infection risk. Thyroid disease and the need for thyroid hormone replacement should be assessed. Dental care should be completed before surgery.

A multidisciplinary Heart Valve Team including the cardiologist and cardiac surgeon should be involved in the discussion of timing and choice of intervention during heart valve surgery. Some of these discussions revolve around the choice of prosthesis and the advantages and drawbacks of mechanical versus bioprosthetic valves (Fig. 3). Often, the choice of prosthesis is straightforward, but younger patients in particular may have special needs, which should be addressed. Bioprosthetic valves offer the advantage of not requiring long-term oral anticoagulation, but have the drawback of relatively limited durability (on average 15-20 years). In contrast, mechanical valves offer greater long-term durability but require lifelong warfarin therapy. The generally accepted risk of serious bleeding with warfarin is about 1% to 2% per year. Childbearing age (in women) and engaging in high intensity sports activities are factors that are relative contraindications to chronic oral anticoagulation with warfarin and may influence the choice of valves. In general, bioprosthetic valves are favored in patients older than 60 years and mechanical valves in those younger than 50 years. Homograft aortic valve replacement with a cryopreserved cadaveric valve may offer specific advantages for patients with infective endocarditis or diseases of the aortic root. Another option is now available for patients with symptomatic severe aortic stenosis who are unable to have aortic valve replacement surgery because of prohibitive surgical risk (predicted surgical morbidity and mortality ≥50%), or when the predicted surgical risk is deemed too high (predicted 30-day mortality ≥15%). For these patients, transcatheter aortic valve replacement is now considered a viable alternative (Fig. 4). In the inoperable patients with prohibitive surgical risk, transcatheter aortic valve replacement is recommended to improve survival and ameliorate symptoms.7 The treatment decisions in these very high risk patients are complicated, and necessitate input from the Heart Valve Team, particularly the cardiac surgeon and the interventional cardiologist.

Patients and physicians should bear in mind that valve replacement is palliative, not curative. A prosthetic heart valve commits a patient to continued infective endocarditis prophylaxis, regular cardiac follow-up, and often continued medical therapy, including anticoagulation with warfarin for those with mechanical prostheses. Reoperation may be required for malfunction of the prosthetic valve. In addition, a small but not insignificant subset of patients may require implantation of a permanent pacemaker after aortic valve surgery. Patients should clearly indicate their willingness to accept the limitations that valve replacement imposes before surgery. In addition, patients must understand that surgical risks include wound infection and stroke, as well as perioperative mortality.

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Aortic Regurgitation

Definition

Aortic regurgitation is defined by incompetence of the aortic valve, in which a portion of the left ventricular forward stroke volume returns to the chamber during diastole. The cause of the regurgitation, as for aortic stenosis, can be further defined based on the anatomy of the valve and aortic root and the disease process affecting the valve.

Causes and Pathophysiology

Aortic regurgitation can occur because of leaflet pathology or aortic root disease.8, 9 As an isolated lesion, aortic regurgitation usually occurs because of a congenital bicuspid aortic valve, often resulting from leaflet prolapse, and from calcific aortic valve disease. Infective endocarditis involving the aortic valve may result in aortic regurgitation because of loss of coaptation, leaflet retraction, or perforation (Fig. 5). Although uncommon in the United States, aortic regurgitation due to rheumatic heart disease is still common in developing countries. Additionally, any pathologic process that results in aortic root dilation and loss of leaflet coaptation can also result in aortic regurgitation. Examples include diseases of the aortic root, such as Marfan syndrome (Fig. 6), annuloaortic ectasia, long standing hypertension, and familial aortic aneurysmal disease. Additionally, ascending aortic dissections and congenital diseases, such as ventricular septal defects as seen in tetralogy of Fallot, can lead to aortic regurgitation. Other less common conditions which can affect both the aortic valve and the aortic root include radiation heart disease, Ehlers-Danlos syndrome, and inflammatory aortitis and/or aortic valvulitis caused by giant cell aortitis, reactive arthritis, syphilitic aortitis, ankylosing spondylitis, and rheumatoid arthritis.

Regardless of cause, chronic aortic regurgitation results in volume overloading of the left ventricle and, in contrast to mitral regurgitation, also causes a component of pressure overload. The volume overload usually is well tolerated for long periods, possibly even decades. The sequelae of aortic regurgitation reflect the severity of the diastolic leak; these include left ventricular dilation and eccentric hypertrophy, with remodeling of the left ventricle to a more spherical shape. The ejection fraction usually is preserved until the late stages of the disease.

Because patients may tolerate severe aortic regurgitation with minimal symptoms, management should include careful monitoring of left ventricular dimensions and systolic function. In addition, because aortic root and proximal ascending aortic dilation can coexist, careful monitoring of aortic enlargement is warranted in these patients. Surgical intervention is indicated, even in asymptomatic individuals, when left ventricular dilation reaches critical dimensions or ventricular dysfunction occurs.1

Signs and Symptoms

Patients with chronic aortic regurgitation caused by congenital bicuspid valve, hypertension, or annuloaortic ectasia often have little clinical history other than a known cardiac murmur noted on routine auscultation. In contrast, patients with aortic regurgitation caused by infective endocarditis or certain aortic root diseases, may recount rather dramatic illness or systemic complaints. Nonetheless, cardiac complaints are unusual until the later stages of volume overloading, when effort intolerance becomes a problem. Symptoms of aortic regurgitation often begin with nonspecific fatigue. Patients might relate that their ability to get through a day's work is maintained, but they are exhausted after returning home. Palpitation, or awareness of a forceful heartbeat, is an early complaint, sometimes noted by spouses. With further progression, typical heart failure symptoms follow. Angina pectoris and syncope are much less common with aortic regurgitation than with aortic stenosis. In contrast, palpitation and ventricular premature beats are more frequent, and nonsustained ventricular tachycardia has often been reported. Overt heart failure and cardiac chest pain are infrequent but, if present, may reflect a more acute process.

Careful physical examination may yield a host of eponymous signs (e.g., Hill's sign, Corrigan's pulse), almost all of which reflect a high stroke volume and wide pulse pressure. The wide pulse pressure, bounding arterial pulses, and hyperdynamic circulation of chronic moderately severe aortic regurgitation are easily noted. In contrast, the soft, blowing, diastolic murmur may be subtle, requiring careful auscultation, with the patient sitting forward in fully held expiration. The murmur is almost always best heard using the diaphragm of the stethoscope applied firmly to the upper right parasternal area of the anterior chest. A systolic murmur may be audible because of increased stroke volume. The duration of the diastolic murmur should be noted, because this reflects the severity of the leak until the late stages of disease, when the left ventricular diastolic pressure increases and shortens the diastolic murmur. An Austin-Flint apical diastolic murmur may also be present. This mid-diastolic murmur, best heard at the apex and often preceded by an S3 heart sound, occurs in the absence of organic mitral valve disease. It is likely the result of an antegrade flow across an incompletely opened mitral valve caused by the aortic regurgitant jet's effect on the anterior mitral leaflet. An Austin-Flint murmur usually indicates significant aortic regurgitation.

Diagnosis

The electrocardiogram of patients with aortic regurgitation commonly demonstrates voltage consistent with left ventricular hypertrophy, but often without the ST segment depressions and T inversion of the strain pattern. The generous voltage and upright T waves in the lateral chest leads have been referred to as "volume overload left ventricular hypertrophy." In addition, premature ventricular contractions may be present.

Echocardiography will, in almost all cases, define the functional anatomy of the valve and aortic root, and Doppler imaging will help assess the severity of the diastolic leak (Fig. 6). In addition, the echocardiogram documents left ventricular dimensions, ejection fraction, and wall thickness. If transthoracic echocardiographic imaging is not adequate to define the pathoanatomy, transesophageal echocardiography should be performed. The anatomic consequences of aortic regurgitation include, as noted above, both left ventricular hypertrophy and dilation. Serial echocardiographic measurements of left ventricular systolic function, and end-diastolic and end-systolic dimensions provide excellent objective parameters for long-term follow-up of asymptomatic patients.

Cardiac catheterization is no longer used as the primary diagnostic imaging modality for aortic regurgitation. Angiographic assessment of regurgitant valve lesion severity is subjective and dependent on technical factors, such as catheter position and the rate and volume of contrast injection. Diagnostic coronary angiography should be performed as part of the presurgical evaluation when valve repair or replacement is planned.

Treatment

In theory, patients with aortic regurgitation should benefit from long-term administration of a direct-acting vasodilator in order to augment forward cardiac output. These agents have been studied and found not to significantly change the natural history of the asymptomatic patient with chronic severe aortic regurgitation and normal ventricular function. Such agents (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) however may be considered for long-term therapy in symptomatic patients with severe aortic regurgitation who are not considered surgical candidates (Class IIa recommendation).10 In addition, although beta blockers theoretically prolong diastole and worsen aortic insufficiency, many clinicians use modest doses of beta blockers because of the known association between aortic regurgitation and aneurysmal diseases of the aorta.

Patients with aortic regurgitation should have detailed counseling about physical activity. Isometric exercise, weight lifting, and heavy exertional activities, which involve strenuous arm work, should be specifically prohibited because of the reflex increase in peripheral vascular resistance that occurs with arm exercise. In contrast, rhythmic, low-resistance, large muscle group exercise such as bicycling reduces peripheral resistance, and should be encouraged for fitness and a sense of well-being. Infective endocarditis prophylaxis is no longer required based on the new AHA/ACC guidelines.5

As noted earlier, most patients with chronic aortic regurgitation have a protracted clinical course, despite evidence of severe regurgitation. Nevertheless, long-term care of the asymptomatic individual with aortic regurgitation consists of carefully monitoring for the onset of symptoms or, more often, of left ventricular dysfunction and/or dilation. Asymptomatic patients with chronic severe aortic regurgitation and normal left ventricular systolic function should be assessed clinically and echocardiographically approximately every 6 to 12 months. Current guidelines suggest aortic valve surgery for chronic severe aortic regurgitation for patients with symptom onset (Class I recommendation), asymptomatic patients with left ventricular ejection fraction lower than 0.50 (Class I), patients undergoing coronary artery bypass grafting or surgery on the aorta or other heart valves (Class I), and patients with preserved ventricular function but left ventricular end-systolic dimension >50 mm (Class IIa) or end-diastolic dimension >65 mm with low surgical risk (Class IIb). Aortic valve surgery is also considered in asymptomatic patients with moderate aortic regurgitation undergoing coronary artery bypass grafting or surgery on the aorta or other heart valves (Class IIa).1

When concerns arise about the physiologic significance of aortic regurgitation and possible indications for surgery, maximal cardiopulmonary exercise testing and stress echocardiography may be useful. Patients who can achieve high levels of activity with evidence of good contractile reserve can generally be managed conservatively. Impaired functional capacity under stress should prompt consideration of valve surgery.

The issues involved in the choice of a prosthetic valve and in postsurgical care are similar for patients with aortic regurgitation, as described earlier for aortic stenosis. A notable distinction is the select group of patients with pliable congenital bicuspid aortic valves and aortic regurgitation, for whom valve repair may be a viable option. Notably, clinicians should remember the association between ascending aortic disease (i.e., aneurysm formation and risk of dissection) in patients with bicuspid aortic valve or connective tissue diseases. In the setting of a bicuspid aortic valve, concomitant aortic repair should be performed at the time of valve surgery when the aortic size reaches >4.5 cm.

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Summary

  • Calcific aortic stenosis and congenital bicuspid aortic valve stenosis account for most aortic stenosis cases.
  • Two-dimensional and Doppler echocardiography represent the gold standard in the evaluation of patients with suspected aortic valvular disease.
  • Symptomatic patients with severe aortic stenosis should undergo valve replacement, as well as those with severe aortic stenosis undergoing other cardiac surgery, severe aortic stenosis and left ventricular dysfunction, and moderate aortic stenosis undergoing other cardiac surgery.
  • Chronic aortic regurgitation may be caused by leaflet pathology, such as a congenital bicuspid aortic valve, or may be related to any pathologic process that results in aortic root dilation.
  • Aortic valve surgery for chronic severe aortic regurgitation is indicated for those with symptom onset, asymptomatic patients with left ventricular dysfunction, patients undergoing other cardiac surgery, and patients with preserved ventricular function but a left ventricular end-systolic dimension more than 50 mm or end-diastolic dimension more than 65 mm.

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References

  1. Nishimura RA, Otto CM, Bonow RO, et al. 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 [published online ahead of print March 3, 2014]. J Am Coll Cardiol 2014; 63:e57–e185. doi:10.1016/j.jacc.2014.02.536.
  2. Novaro GM, Katz R, Aviles RJ, et al. Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study [published online ahead of print October 29, 2007]. J Am Coll Cardiol 2007; 50:1992–1998. doi:10.1016/j.jacc.2007.07.064.
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  4. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation [published online ahead of print February 14, 2005]. Circulation 2005; 111:920–925. doi:10.1161/01.CIR.0000155623.48408.C5.
  5. Gopalakrishnan PP, Shukla SK, Tak T. Infective endocarditis: rationale for revised guidelines for antibiotic prophylaxis [published online ahead of print July 16, 2009]. Clin Med Res 2009; 7:63–68. doi:10.3121/cmr.2009.848.
  6. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J; ASTRONOMER Investigators. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial [published online ahead of print January 4, 2010]. Circulation 2010; 121:306–314. doi:10.1161/CIRCULATIONAHA.109.900027.
  7. Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery [published online ahead of print September 22, 2010]. N Engl J Med 2010; 363:1597–1607. doi:10.1056/NEJMoa1008232.
  8. Enriquez-Sarano M, Tajik AJ. Aortic regurgitation. N Engl J Med 2004; 351:1539–1546.
  9. Bekeredjian R, Grayburn PA. Valvular heart disease: aortic regurgitation [erratum appears in Circulation 2005; 112:e124]. Circulation 2005; 112:125–134.
  10. Elder DH, Wei L, Szwejkowski BR, et al. The impact of renin-angiotensin-aldosterone system blockade on heart failure outcomes and mortality in patients identified to have aortic regurgitation: a large population cohort study. J Am Coll Cardiol 2011; 58:2084–2091.

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