Aortic regurgitation (aortic insufficiency)

I. What every physician needs to know.

In aortic regurgitation (AR), blood flows backward from the aorta into the left ventricle during diastole causing volume overload of the left ventricle (LV). In AR, the LV has to pump the regurgitant blood from the aorta and the normal preload from the left atrium. When the reflux is mild, patients may be asymptomatic for decades with little disease progression. If the chronic reflux is more severe, the rising LV end-diastolic pressure can lead to increased wall stress and compensatory myocardial hypertrophy. Eventually the ejection fraction (EF) decreases, which may precede the onset of symptoms of heart failure.

The clinical presentation is variable and depends on the acuity and severity of the lesion, the hemodynamic conditions and LV compliance. Management of chronic AR is composed of observation in mild cases to vasodilator therapy and surgical correction in more severe or symptomatic cases. Severity of AR is influenced by three factors: the size of the regurgitant orifice, the pressure gradient across the aortic valve during diastole, and the duration of diastole. It is possible to influence the pressure gradient and the duration of diastole with medications, though this ultimately a surgical disease.

Acute AR is a medical emergency and carries a grave prognosis unless promptly corrected, as the LV cannot handle the acute increase in end-diastolic pressure. As a result, pulmonary edema, hypotension and cardiogenic shock quickly develop. Chronic AR, however, is well-tolerated:10-year survival rates are 85-95% in mild disease and 50% in moderate disease. If congestive heart failure develops, the average survival decreases to less than 2 years. Avoid beta-blockers in acute AR, which prolong diastole and therefore worsen regurgitation.

II. Diagnostic Confirmation: Are you sure your patient has aortic regurgitation?

The causes of AR involve damage to aortic valve leaflets, dilation of the aortic root, or both.

Valvular causes include congenital bicuspid aortic valve, calcific or myxomatous aortic degeneration, infectious endocarditis, connective tissue diseases, or rheumatic heart disease.

An enlarged ascending aorta can stretch the aortic valve annulus leading to AR without any direct damage to the valve leaflets themselves. Causes include aortic aneurysm (inflammation as in aortitis, connective tissue disease), aortic dissection, annuloaortic ectasia, and syphilitic aortitis. Hypertension can cause dilation of the aortic root, but there is some controversy as to whether this is a true cause of AR. Chronic severe AR of any etiology may lead to dilatation of the aortic root and further worsen the AR.

In low and lower-middle income countries, the most common cause of AR is rheumatic disease, while in higher countries the most common causes are aortic root dilatation and/or bicuspid aortic valve.

Acute AR, which is much more rare than chronic AR, can be caused by aortic dissection, endocarditis, trauma, or as a result of a procedures such as transcatheter aortic valve replacement or aortic balloon dilation for aortic stenosis.

The diagnosis of AR can only be confirmed by imaging, typically with transthoracic echocardiography (TTE).

A. History Part I: Pattern Recognition:

Most patients with chronic AR are asymptomatic, and the disease may be present for years before symptoms develop. Over time, heart failure symptoms manifest: exertional dyspnea, orthopnea and paroxysmal nocturnal dyspnea.

Eventually, patients experience dyspnea at rest, reflecting severe decompensated heart failure. In addition, patients may experience angina from subendocardial ischemia related to marked ventricular hypertrophy, or reduction in coronary flow from low diastolic arterial pressure even in the absence of coronary artery disease.. Patients may note symptoms related to wide pulse pressure as well.

Signs of chronic AR are related to regurgitant flow across the aortic valve, reduced diastolic pressure, and compensatory increase in stroke volume leading to hyperdynamic pulses and a wide pulse pressure, which may exceed 80 mmHg in some cases.

Patients with acute AR are often gravely ill and hemodynamically unstable.

B. History Part 2: Prevalence:

Aortic regurgitation accounts for nearly 10% of valvular heart disease. The prevalence of chronic AR increases with age, and trace AR is common in normal patients. The Framingham Heart Study and the Strong Heart Study show that in asymptomatic patients with more than trace AR, mild AR occurs in 7-13%, moderate in approximately 2%, and severe in less than 1% of the population.

C. History Part 3: Competing diagnoses that can mimic aortic regurgitation.

The hallmark diastolic murmur and bounding peripheral pulses of chronic, severe AR can be seen in other conditions.

Diastolic murmurs heard in other diseases besides AR differ in their characteristics.

The murmur of mitral stenosis is distinct from the murmur of AR. In mitral stenosis, the low-pitched diastolic rumble most prominent at the apex is best appreciated using the bell of the stethoscope with the patient in the left lateral decubitus position. This murmur is a decrescendo rumble that ends with a late crescendo to the first heart sound. AR starts immediately after S2, whereas mitral stenosis is delayed.

A high pulmonary artery pressure may cause a diastolic pulmonary regurgitation murmur (Graham Steel). Like the diastolic murmur of AR, this murmur is high-pitched along the left sternal border. However, unlike AR, a pulmonic regurgitation (PR) murmur increases in intensity with inspiration.

Bounding pulses can be seen in other conditions causing hyperdynamic circulation such as thyrotoxicosis, pregnancy, fever, and anemia.

D. Physical Examination Findings.

Signs of chronic AR:

There may be up to three murmurs associated with chronic AR:

The diastolic, high-pitched, decrescendo murmur of AR, which starts immediately after aortic component of S2, which is typically loudest at the left upper sternal border, but can sometimes be heard radiating to the apex. This is best heard with the patient upright or leaning forward to bring the heart closer to the stethoscope. Of note, the characteristics of the diastolic murmur do not predict the severity of AR.
A systolic murmur from increased systolic flow across the valve, which may indicate severe regurgitation.
A rumbling diastolic murmur at the apex possibly related to regurgitant jet causing vibration of the anterior mitral valve leaflet (Austin-Flint).

There are several eponymous peripheral signs of chronic AR, all of which correlate with a wide pulse pressure and brisk arterial rise and fall (prominent carotid pulsation, bobbing uvula or even head, visible pulsation in capillary beds of fingernails, audible pistol shot pulse at the femoral artery). They do not correlate with disease severity, but do correlate with chronicity and are not found in acute AR.

LV enlargement may manifest as a displaced, diffuse, and hyperdynamic apical impulse.

Acute AR:

In acute AR, patients are hypotensive, diaphoretic and vasoconstricted with a rapid, thready pulse. Without time for compensatory LV mechanisms to occur, the forward cardiac flow is reduced leading to rapid development of pulmonary edema and hypotension. On cardiac exam, the rapid rise in LV diastolic pressure quickly rises above left atrial pressure, thereby prematurely closing the mitral valve. Accordingly, S1 is typically soft or absent. The diastolic murmur is lower in pitch than chronic AR, and may be absent due to an equilibration of LV and aortic pressures. The classic peripheral signs of chronic AR are also absent.

E. What diagnostic tests should be performed?

TTE is the gold standard for diagnosing AR.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory studies are not required to establish a diagnosis of AR, but may help determine an underlying etiology such as syphilitic aortitis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

TTE both establishes the diagnosis of AR and assesses severity as mild, moderate or severe (See Table I). If TTE is suboptimal, then transesophageal echocardiography or cardiac magnetic resonance imaging (MRI) can be used.

	Mild	Moderate	Severe
Regurgitant fraction (%)	<30	30-49	>50
Regurgitant volume (mL/beat)	<30	30-59	>60
Effective regurgitant orifice (mm²)	<10	10-29	>30

In patients with a bicuspid aortic valve, the morphology and size of the aortic root should also be assessed. Aortic root dilatation may itself cause AR.

Exercise stress testing may be useful in asymptomatic patients with limited physical activity to assess functional limitations under stress.

The severity of AR can be assessed during cardiac catheterization, however the grading method is subjective and correlates poorly with regurgitant volume.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

TTE may be over-utilized. The Choosing Wisely Campaign from the ABIM Foundation includes recommendations from the American Society of Echocardiography not to order follow-up echocardiograms for surveillance after a finding of trace valvular regurgitation on an initial echocardiogram.

III. Default Management.

Aortic valve replacement (AVR) is the treatment of choice for symptomatic severe AR, asymptomatic severe AR with LV systolic dysfunction due to AR, and patients undergoing other cardiac surgery. There is very little role for medical management other than relief of heart failure symptoms and as a bridge to surgical therapy. Key concept: medical therapy is not a substitute for surgery in symptomatic AR.

A. Immediate management.

Patients with AR and hypertension should be treated with vasodilators such as a dihidropyridine calcium channel blocker or angiotensin converting enzyme (ACE) inhibitor.

Patients with heart failure symptoms from chronic AR should be referred for AVR. Patients who are not surgical candidates due to comorbidities, or who are awaiting valve surgery, can be treated for systolic heart failure with diuretics, beta blockers, ACE inhibitor or angiotensin II receptor blockers (ARB), and digoxin. Some clinicians avoid beta-blockers in any form of AR due to concern for prolonging diastole and worsening regurgitation, but a retrospective study showed prolonged survival in patients with chronic severe AR on beta-blockers. While the evidence is insufficient to establish causality, the ACC/AHA guidelines include a Class IIa recommendation that “medical therapy with ACE inhibitors/ARBs and beta-blockers is reasonable in patients with severe AR who have symptoms and/or LV dysfunction when surgery is not performed because of comorbidities.”

In acute AR, immediate surgical intervention with aortic valve replacement is required. Aortic balloon counterpulsation will worsen the AR and therefore is contraindicated. Intravenous blood pressure support with the use of dopamine, dobutamine or vasoconstrictors may be required to stabilize the patient prior to surgery. Avoid beta-blockers in acute AR as the effect of prolonging diastole and blocking the compensatory tachycardia may cause or worsen hypotension.

B. Physical Examination Tips to Guide Management.

Daily assessment of the patient’s volume status is required during ongoing diuresis. Accordingly, a thorough lung exam is required to evaluate for pulmonary edema, as is an evaluation of the legs and sacrum for signs of peripheral edema.

The cardiac exam may not acutely change during diuresis.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients treated with diuretics, ACE inhibitors, ARBs require monitoring of creatinine and electrolytes.

D. Long-term management.

Patients with asymptomatic AR should have surveillance TTE performed every 3-5 years for mild AR, every 1-2 years for moderate AR, and every 6-12 months for severe AR. Any patient with previously asymptomatic AR who develops symptoms requires a TTE to evaluate for disease progression. Overall, patients with asymptomatic moderate to severe AR and normal LV function require aortic valve replacement at an annual rate of 4%.

Vasodilator therapy decreases the systolic blood pressure, allowing for increased cardiac output in AR, but has not been proven to alter the disease course. As such, routine use of vasodilators is not recommended in asymptomatic patients with normal LV systolic function and normal blood pressure. Nifedipine, ACE inhibitors, and ARBs have been studied with conflicting results. Current guidelines recommend use of vasodilators in patients with asymptomatic chronic AR and hypertension, asymptomatic chronic AR and LV dysfunction, and symptomatic patients who either are not surgical candidates or are awaiting surgery.

Timing of AVR in asymptomatic patients weighs risks of surgery against risk of disease progression. AVR surgery is associated with a mortality of ~4%; it is generally lower in high-volume centers, if patients have mild or no symptoms, or a better preoperative EF. In asymptomatic patients, surgery is advised if the EF is less than 55% or if the LV end-systolic diameter is greater than 55 mm. These thresholds are called the “55 rule.”

The optimal surgical approach to aortic valve correction is uncertain. Surgical valve repair, pulmonary autografts and standard valve replacement with mechanical or bioprosthetic valves have all been used. The usual operation is AVR with a mechanical valve in young patients and with a bioprosthesis in older patients or those unable to tolerate anticoagulation (bioprosthetic valves don’t last as long as mechanical valves, but don’t require anticoagulation). Transcatheter AVR (TAVR) is not currently approved for AR in the United States, although there are some small international studies supporting its use.

Patients with a mechanical aortic valve require long-term anticoagulation with a goal INR between 2.5-3.5. Aortic valve repair is performed in certain instances of bicuspid aortic valve with eccentric jets, but the long-term outcomes are less favorable than with mitral valve repair.

E. Common Pitfalls and Side-Effects of Management

As mentioned, beta-blockers may be unnecessarily avoided in patients with symptomatic chronic AR who are not surgical candidates or are awaiting surgery. In acute AR, beta-blockers may lead to acute hypotension and should be avoided or used with caution.

IV. Management with Co-Morbidities

A. Pregnancy

Pregnant patients with AR who are asymptomatic generally tolerate the pregnancy without complications or need for medications.

Symptomatic patients may be treated with diuretics and nifedipine. ACE inhibitors are contraindicated due to the risk of fetal harm.

If symptoms progress to being present with minimal exertion or at rest, these patients may require aortic valve replacement during their pregnancy. The surgery is delayed as long as possible until the fetus is viable, and then a cesarean section may be performed at the same time.

B. Renal Insufficiency.

Patients with renal insufficiency may be more resistant to the effects of loop diuretics. The starting dose may need to be higher than the typical low dose used in patients with normal kidney function.

C. Liver Insufficiency.

No change in standard management.

D. Systolic and Diastolic Heart Failure

Patients with systolic heart failure and AR who are not being treated with valve replacement should be on medications that are otherwise used for heart failure as mentioned above.

E. Coronary Artery Disease or Peripheral Vascular Disease

Patients with known coronary artery disease or those at high enough risk (men over the age of 35, postmenopausal women) being evaluated for aortic valve surgery should undergo preoperative coronary angiography. The angiography will provide an assessment of the coronary atherosclerotic burden; coronary bypass may be required at the time of valve surgery.

Patients with hypertension and any degree of AR may benefit from vasodilator therapy to help lower the arterial pressure and decrease the systolic wall stress.

F. Diabetes or other Endocrine issues

No change in standard management.

G. Malignancy

No change in standard management.

H. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

I. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

J. Gastrointestinal or Nutrition Issues

No change in standard management.

K. Hematologic or Coagulation Issues

No change in standard management.

L. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out Considerations While Hospitalized.

If called for worsening shortness of breath, evaluate volume status and hemodynamics. In patients with acute AR, worsening clinical status will require rapid surgical intervention. Patients with chronic AR and worsening clinical status should have a recent TTE to evaluate current cardiac function and careful administration of vasodilators and diuretics while undergoing preoperative risk assessment.

B. Anticipated Length of Stay.

Length of stay will be determined by the patient’s response to therapy and any scheduled inpatient invasive procedures. Hospitalization may be as short as 1-2 days, or up to a week or more.

C. When is the Patient Ready for Discharge.

Symptomatic patients with AR are ready for discharge when they are no longer symptomatic at rest and can ambulate at baseline without dyspnea. If surgery is required during the hospitalization, discharge timing will be determined by cardiac surgery.

D. Arranging for Clinic Follow-up

Patients with symptomatic AR require close follow-up with a cardiologist and/or a cardiac surgeon.

1. When should clinic follow up be arranged and with whom?

Symptomatic patients with AR should be seen in clinic within 2 weeks of discharge to provide prompt evaluation for symptom recurrence. This appointment may be handled by the internist, unless the patient has an earlier appointment with a cardiologist.

All patients with symptomatic AR should be followed by a cardiologist as an outpatient. Many will require aortic valve surgery (if not already performed during the hospitalization); after discussion with the cardiologist, a timely outpatient appointment with a cardiac surgeon may also be necessary.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

An echocardiogram will typically be required at some point during the hospitalization to provide the outpatient physicians a current, accurate assessment of the AR.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

If a diuretic or ACE inhibitor was started or a dose adjustment was made, a chemistry panel should be obtained prior to the clinic visit to evaluate the potassium and creatinine levels.

Typically, postoperative patients from aortic valve surgery require an echocardiogram prior to their first surgical clinic visit.

E. Placement Considerations.

Upon improvement of symptoms, most patients with AR will be able to return home. If the functional mobility of the patient is limited at baseline, assessment by occupational and physical therapy at least 1 day prior to discharge may outline the patient’s home skilled needs.

If surgery was performed on the aortic valve, a physical therapy consult to assess rehabilitation needs may be required. Such patients may require a brief stay in an acute or subacute rehabilitation facility.

F. Prognosis and Patient Counseling.

Prognosis

The long-term prognosis of chronic AR depends on the severity of the regurgitation and the presence of left ventricular dysfunction.

In asymptomatic patients with a normal LV function, the annual rate of progression to symptoms and/or LV dysfunction is less than 6%. Therefore, 10 years after the diagnosis of severe AR, approximately half of these patients develop LV dysfunction.

Asymptomatic patients with LV systolic dysfunction carry an annual rate of progression to symptoms of greater than 25%.

Survival

Patients with mild symptoms (dyspnea or angina with moderate exertion) have an annual mortality rate of 6.3%. Patients with severe symptoms such as dyspnea or angina at rest or mild exertion not treated with surgery carry an annual mortality of 25%.

The 10-year survival rate post aortic valve replacement depends on the LVEF: if the EF is less than 35%, the survival is 41%, for EF between 35-49%, it rises to 56%; patients with an EF of 50% or more have a 10-year survival of 70%.

Restrictions

Patients with mild to moderate AR and normal LV size and function have no restrictions to play competitive sports. In cases where the AR is severe, or the LV size and function are abnormal, participation in competitive sports should be restricted.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Typically, patients recovering from dyspnea from pulmonary edema require outpatient follow-up within 2 weeks to prevent readmission from reaccumulation of fluid. Patients should be advised to weigh themselves daily and report increases in weight to their outpatient-treating physician.

Antibiotic prophylaxis prior to dental procedures is no longer indicated for AR itself. Prophylaxis should be given to patients with prior heart valve replacement or who have previously had endocarditis.

VII. What's the evidence?

Nishimura, RA, Otto, CM, Sorajja, P.

Enriquez-Sarano, M, Tajik, AJ. “Clinical practice. Aortic regurgitation”. N Engl J Med. vol. 351. 2004. pp. 1539-46.

Bekeredjian, R, Grayburg, PA. “Valvular heart disease: aortic regurgitation”. Circulation. vol. 112. 2005. pp. 125-134.

Babu, AN, Kymes, SM, Carpenter Fryer, SM. “Eponyms and the diagnosis of aortic regurgitation: what says the evidence”. Ann Intern Med. vol. 138. 2003. pp. 736-742.

Evangelista, A, Tornos, P, Sambola, A. “Long-term vasodilator therapy in patients with severe aortic regurgitation”. NEJM. vol. 353. 2005. pp. 1342(Small RCT of 95 patients with severe AR treated with open-label enalapril, nifedipine, or no vasodilator therapy that showed no difference of vasodilator therapy with 7 years of follow-up.)

Elder, DH, Wei, L, Szwejkowski, BR. “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. vol. 58. 2011. pp. 2084(Retrospective cohort study using database in Tayside, Scotland including over 2,000 patients with AR showing that patients treated with ACE inhibitors or ARBs had significantly lower all-cause mortality and fewer CV and AR related events.)

Scognamiglio, R, Fasoli, G, Ponchia, A. “Long-term nifedipine unloading therapy in asymptomatic patients with chronic severe aortic regurgitation”. J Am Coll Cardiol. vol. 16. 1990. pp. 424(Early Italian RCT of enalapril versus placebo in 72 patients with asymptomatic severe chronic AR that showed improved LV end-diastolic volume, LV mass, and LVEF on echo.)

Scognamiglio, R, Rhimtoola, SH, Fasoli, G. “Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function”. N Engl J Med. vol. 331. 1994. pp. 689(Early Italian RCT of nifedipine versus digoxin in 143 patients with asymptomatic severe chronic AR and preserved LV systolic function showed that fewer patients in the nifedipine group progressed to LV dysfunction and surgical AVR than in the digoxin group after 6 years of follow-up.)

Kaneko, T, Eljiofor, JI, Neely, RC. “Aortic regurgitation with markedly reduced left ventricular function is not a contraindication for aortic valve replacement”. Ann Thorac Surge. vol. pii. pp. S0003-4975. (Study of 485 patients undergoing surgical AVR for severe AR showing that patients with LVEF <35% had similar survival and surgical outcomes as those with better LV function. Independent predictors of survival were age, preoperative creatinine, history of atrial fibrillation, and New York Heart Association class III or IV.)

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