WORKUP

Lab Studies:

• No specific laboratory blood tests are required in the workup of AR. However, serologic testing may be required when attempting to distinguish the various etiologies of AR.

Imaging Studies:

• Two-dimensional echocardiography and Doppler

• M-mode features of AR include the following:
  • Diastolic flutter of the mitral valve (can be both anterior and posterior mitral valve leaflet)

  • Diastolic flutter of the aortic valve

  • Premature closure of the mitral valve (severe AR)

  • Premature opening of the aortic valve (severe elevated LV end-diastolic pressure)

  • Diastolic LV septal fluttering

  • LV volume overload (hyperkinesis of the LV walls with LV dilatation)

  • LVESD (>55 mm indicates poorer surgical outcome)

• On 2-dimensional echocardiography, look for the following features:
  • Flail aortic valve

  • Dilatation of the sinuses of Valsalva (particularly in patients with Marfan syndrome or bicuspid aortic valve problems)

  • Ascending aortic aneurysm

  • Incomplete closure of the aortic valve cusps on the parasternal short-axis view of the aortic valve

  • High-frequency diastolic fluttering of the anterior leaflet of the mitral valve during diastole

  • Reverse doming of the anterior mitral valve leaflet

  • LV volume overload pattern

  • Measurements of LV end-diastolic and end-systolic dimensions and volumes, shortening fractions, and EFs - Critical in determining the optimal time for valve replacement

  • Measurement of aortic regurgitant fraction, regurgitant orifice size, and regurgitant volumes - Now available with Doppler echocardiography

• Color-flow Doppler should be used as follows:
  • Determine the regurgitant jet height and/or LV outflow tract (LVOT) height in the parasternal long-axis view (mild [1+] <25%, moderate [2+] 25-46%, moderately severe [3+] 47-64%, severe [4+] >65%).

  • Determine the regurgitant jet area and/or LVOT area in the parasternal short-axis view of the aortic valve (mild [1+] <20%, moderate [2+] 20-40%, moderately severe [3+] 40-60%, severe [4+] >60%).

  • Proximal acceleration (flow convergence) indicates aortic insufficiency is grade 3+ or 4+.

• Continuous-wave Doppler should be used as follows:
  • Determine the spectral strength of the regurgitant jet. Grade 1+ produces spectral tracing stain sufficient for detection but is not enough for clear delineation. In grade 2+, complete spectral tracing can barely be seen. In grade 3+, distinct darkening of spectral tracing is visible, but density is less than antegrade flow. Grade 4+ produces dark-stained spectral tracing.

  • Determine the slope of the aortic insufficiency spectral display. In general, steeper slopes indicate more severe aortic insufficiency.

  • Determine the pressure half-time of the aortic insufficiency spectral display. In general, a pressure half-time less than or equal to 300 m/s indicates significant aortic insufficiency.

• Pulsed-wave Doppler should be used as follows:
  • The pulse-wave mapping technique is used mostly prior to color Doppler.

  • Velocity of more than 1.5 m/s is consistent with marked AR.

  • Mitral inflow has a restrictive filling pattern.

  • Reversal of flow in the descending thoracic aorta and/or abdominal aorta indicates that aortic insufficiency is moderately severe (3+ or 4+). This phenomenon requires careful placement of the sample volume in the descending aorta, distal to the takeoff of the left subclavian artery. The flow in the descending aorta may also be seen with color-flow Doppler, although this method is more prone to error.

• Radionuclide imaging should be used as follows:

• Radionuclide angiography findings can help determine the AR regurgitant fraction and the left-to-right ventricular stroke volume ratio. An accurate noninvasive assessment of the severity of AR can be determined if concomitant mitral regurgitation, tricuspid regurgitation, or pulmonary regurgitation is not present.

• Left-to-right ventricular stroke volume ratio of 2 or more denotes severe AR.

• MRI or ultrafast CT scanning are as follows:

• These techniques can provide accurate measurements of regurgitant volumes, ventricular end-systolic and diastolic volumes, and the regurgitant orifice.

• These techniques are expensive and not yet widely available.

• Chest radiograph findings are as follows:

• In acute AR, little cardiac enlargement may be present, but, in chronic AR, enlargement is marked.

• Dilatation of the ascending aorta may suggest that aortic root disease is responsible for AR.

• Pulmonary congestion can be observed in patients who have developed LV dysfunction or in those with acute AR.

Other Tests:

• Electrocardiography findings can reveal the following, although they are not an accurate predictor of the severity of AR:

• LV hypertrophy

• Left axis deviation

• Left atrial enlargement

• LV volume overload pattern (prominent Q waves in leads I, aVL, and V₃ to V₆ and relatively small r waves in V₁)

• LV conduction defect (late in disease process)

• Exercise treadmill testing

• Assessment of functional capacity and symptomatic responses in patients with a history of equivocal symptoms

• Evaluation of symptoms and functional capacity before participation in athletic activities

Procedures:

• Cardiac catheterization

• Indications
  • This should be performed for coronary angiography studies before AVR in patients at risk for CAD, including men older than 35 years, premenopausal women older than 35 years with coronary risk factors, and postmenopausal women.

  • It can be used to assess the severity of regurgitation when noninvasive test results are inconclusive or discordant with clinical findings regarding the severity of regurgitation or the need for surgery.

  • Use cardiac catheterization to assess LV function when noninvasive test results are inconclusive or discordant with clinical findings regarding LV dysfunction and the need for surgery in patients with severe AR.

• Qualitative assessment (aortic angiogram)
  • In mild AR (1+), a small amount of contrast enters the left ventricle during diastole and clears with each systole.

  • In moderate AR (2+), more contrast enters with each diastole, and faint opacification of the entire LV chamber occurs.

  • In moderately severe AR (3+), the LV chamber is well opacified and equal in density when compared with the ascending aorta.

  • In severe AR (4+), complete dense opacification of the LV chamber occurs on the first beat and the left ventricle is more densely opacified than the ascending aorta.

• Simultaneous aortic and LV pressure tracing (signs of severe AR)
  • Wide pulse pressure may be present.

  • Brisk aortic pressure upstroke can be observed.

  • LV diastolic pressure increases rapidly.

  • Near equilibration of aortic and LV pressure occurs at diastole.

Recent data suggest that patients with a wide variety of congenital heart lesions (including bicuspid aortic valves) have underlying distortion of the aortic root. These patients were found to have abnormalities of smooth muscle, elastin, collagen, and ground substance in the ascending aorta over a wide variety of ages. Programmed cell death (apoptosis) of neural crest derivative cells within the proximal aorta has also been demonstrated in patients with bicuspid aortic valve problems.

These aortic abnormalities predispose to progressive proximal aortic dilatation, aneurysm formation, or aortic rupture. These proximal aortic changes occur regardless of the underlying severity of aortic valvular disease and can be observed in patients with nonregurgitant bicuspid valves.

TREATMENT

Medical Care: Vasodilator therapy is designed to optimize LV loading conditions and achieve a favorable remodeling process through systolic unloading and reduction in regurgitant volume. Treat asymptomatic patients with chronic severe AR and dilated but normal LV systolic function medically, and monitor their cases for development of indications for AVR. Patients with mild AR and normal LV size require no therapy other than endocarditis prophylaxis.

• Long-term vasodilator therapy with nifedipine reduces or delays the need for AVR in asymptomatic patients with severe AR and normal LV function. Nifedipine has also been shown to reduce LV size and mass significantly; however, do not use nifedipine in patients with LV dysfunction because calcium channel blockers generally are contraindicated in patients with CHF.

• Enalapril therapy achieves significant LV mass regression, LV end-diastolic and end-systolic volume index reduction, and renin-angiotensin system suppression. Enalapril may have favorable influence on the natural history of chronic AR by delaying the need for AVR.

• Digoxin and diuretics can be used to relieve symptoms of congestion.

• Antibiotic prophylaxis for endocarditis is discussed as follows:

• AR leads to damaged endothelial lining of the valve and predisposes the valve to platelet and fibrin deposition.

• In the presence of bacteremia, colonization of platelets and/or fibrin deposition can lead to bacterial endocarditis; thus, antibiotic prophylaxis is important for preventing this serious complication.

• Acute AR usually is severe and rapidly leads to LV decompensation, failure, and cardiogenic shock. The treatment of choice for acute AR is AVR. Medical therapy can be used as a bridge to surgery but should not replace it.

• Dobutamine reduces afterload and assists with forward outflow. It also has a positive inotropic effect.

• Vasodilators achieve significant LV mass regression, LV end-diastolic and end-systolic volume index reduction, and renin-angiotensin system suppression.

• Intra-aortic balloon pump is contraindicated in AR.

Surgical Care: Surgical treatment of AR almost always requires replacement of the diseased valve with a prosthetic valve. The surgical mortality rate for AVR probably is 3%, although the mortality rate may be higher if patients also need coronary artery bypass grafts. In addition, the long-term complications of prosthetic valves need to be considered.

• AVR is indicated in patients with normal systolic function (defined as EF >0.50 at rest) who have New York Heart Association (NYHA) functional class III or IV symptoms. Also consider patients with Canadian Heart Association functional class II-IV angina pectoris for surgery. In many patients with NYHA functional class II dyspnea, the etiology of symptoms often is unclear and clinical judgment is required.

• Patients with NYHA functional class II, III, or IV symptoms and with mild-to-moderate LV systolic dysfunction (EF 0.25-0.49) should undergo AVR. Patients with functional class IV symptoms have worse postoperative survival rates and a lower likelihood of recovery of systolic function when compared to patients with less severe symptoms, but AVR improves ventricular loading conditions and expedites subsequent management of LV dysfunction.

• Symptomatic patients with severe LV dysfunction (EF <0.25) pose difficult management issues. Most patients develop irreversible myocardial damage and may not show improved LV function or NYHA functional class after AVR; however, some patients may gain meaningful recovery of LV function. Surgery carries an operative mortality rate of approximately 10%, but medical therapy alone carries a mortality rate of higher than 20% per year; thus, high-risk AVR may be a viable option when compared to the even worse prognosis associated with medical therapy alone.

• Asymptomatic patients with evidence of LV systolic dysfunction (EF <0.50) should undergo AVR. The postoperative recovery of LV function and survival is strongly associated with preoperative LV function; thus, do not delay AVR for patients with evidence of LV dysfunction.

• Asymptomatic patients with severe AR and normal LV function but with severe LV dilatation (end-diastolic dimension >75 mm or end-systolic dimension >55 mm) should undergo AVR. These patients tend to progress to symptomatic or LV dysfunction rapidly. Postoperative survival and reduction of LV dimension in this subgroup of patients are excellent.

• Preoperative predictors of poor postoperative survival and LV function include the following:

• LVESD greater than 55 mm

• LVEF less than 0.50

• NYHA CHF class III, IV

• Duration of CHF symptoms longer than 12 months

Consultations:

• Cardiologist

• Cardiothoracic surgeon

Diet: Place patients on a low-sodium diet with fluid restriction when CHF symptoms appear.

Activity: Asymptomatic patients with normal LV systolic function may participate in all forms of normal daily physical activity, including mild forms of exercise and, in some cases, competitive athletics; however, isometric exercise (eg, weight lifting) should be avoided. Patients with evidence of LV dysfunction or low cardiac reserve should not engage in vigorous sports or heavy exertion.

MEDICATION

Vasodilator therapy has reduced severity of AR and LV volume and mass successfully, postponing the need for surgical intervention.

Drug Category: Angiotensin-converting enzyme inhibitors -- Competitive inhibitors of angiotensin-converting enzyme (ACE). Reduce angiotensin II levels, decreasing aldosterone secretion.

Drug Name	Enalapril (Vasotec) -- ACE-I produces a small increase in EF and significant decrease in LV volume and mass. Effective vasodilator therapy requires adjustment of dosage to achieve a decrease in arterial pressure.
Adult Dose	5 mg PO bid for 2 wk initially; if hemodynamically stable, increase to 10 mg PO bid for 2 wk, then to 20 mg PO bid maintenance
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; second or third trimester pregnancy, breastfeeding, history of angioneurotic edema, significant renal artery stenosis
Interactions	NSAIDs may reduce hypotensive effects; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in second and third trimester of pregnancy; caution in renal impairment, valvular stenosis, severe CHF, or angioedema; oliguria, seizures, and unpredictable effects on BP may occur in children

Drug Category: Calcium channel blockers -- Inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and conduction velocity.

Drug Name	Nifedipine (Procardia) -- Produces significant fall in arterial pressure, reduces LV volume and mass, increases EF, and delays need for AVR in asymptomatic patients with severe AR and normal LV systolic function. Effective vasodilator therapy requires adjustment of dosage to decrease arterial pressure.
Adult Dose	10 mg PO bid initially, then titrate to 20 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; CHF, cardiogenic shock, acute MI
Interactions	Alcohol, cimetidine, and ranitidine increase bioavailability and effect; antihypertensive medications produce an additive effect; may decrease quinidine levels; may increase digoxin levels; rifampin, phenobarbital, and phenytoin decrease effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Renal or hepatic dysfunction; breastfeeding; may cause lower extremity edema; allergic hepatitis is rare

Drug Category: Cardiac glycosides -- Inhibit sodium-potassium ATPase. Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and calcium. Vagomimetic action leads to reduced activity of sympathetic nervous system.

Drug Name	Digoxin (Lanoxin) -- Pharmacologic consequences include an increase in the force and velocity of myocardial systolic contraction (positive inotropic action) and slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect). Use in patients with heart failure is associated with 25% reduction in the frequency of hospitalization for heart failure. Use is not associated with mortality benefit.
Adult Dose	<70 years and good renal function: 0.25 mg PO qd general initial dose >70 years or impaired renal function: 0.125 mg PO qd general initial dose Marked renal impairment: 0.0625 mg general initial dose 0.4-0.6 mg if rapid digitalization with IV loading is needed; produces detectable effect in 5-30 min; 0.1- to 0.3-mg additional doses may be administered cautiously at 6- to 8-h intervals until clinical evidence of an adequate effect
Pediatric Dose	Adjust loading and daily maintenance dose by body weight Digitalization in infants and children not generally recommended; suggested doses are as follows: TDD Premature infants: 0.02-0.03 mg/kg if tab; 0.015-0.025 mg/kg if cap, IV, or IM in divided doses Full-term infants: 0.025-0.035 mg/kg if tab; 0.02-0.03 if cap, IV, or IM in divided doses 1-24 months: 0.035-0.06 mg/kg if tab; 0.03-0.05 mg/kg if cap, IV, or IM in divided doses 2-5 years: 0.03-0.04 mg/kg if tab; 0.025-0.035 mg/kg if cap, IV, or IM in divided doses 5-10 years: 0.02-0.035 mg/kg if tab; 0.015-0.030 mg/kg if cap, IV, or IM in divided doses >10 years: 0.01-0.015 mg/kg if tab; 0.008-0.012 if cap, IV, or IM in divided doses May accomplish digitalization by giving half TDD in first dose followed by 2 doses that are one fourth TDD given at 8- to 12-h intervals Maintenance dose Premature infants: 0.005-0.0075 mg/kg if tab; 0.004-0.006 mg/kg if cap, IV, or IM divided q12h Full-term infants: 0.006-0.01 mg/kg if tab; 0.005-0.008 if cap, IV, or IM divided q12h 1-24 months: 0.010-0.015 mg/kg if tab; 0.0075-0.012 mg/kg if cap, IV, or IM divided q12h 2-5 years: 0.0075-0.01 mg/kg if tab; 0.006-0.009 mg/kg if cap, IV, or IM divided q12h 5-10 years: 0.005-0.01 mg/kg if tab; 0.004-0.008 mg/kg if cap, IV, or IM divided q12h >10 years: 0.0025-0.005 mg/kg if tab; 0.002-0.003 if cap, IV, or IM qd or divided q12h See prescribing information in PDR for more detailed information
Contraindications	Documented hypersensitivity (hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin), ventricular fibrillation
Interactions	Potassium-depleting diuretics are a major contributing factor to digitalis toxicity; quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise serum digoxin concentrations because of a reduction in clearance and/or in volume of distribution of drug, digitalis intoxication may result
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Because digoxin slows sinoatrial and AV conduction, drug commonly prolongs PR interval; may cause severe sinus bradycardia or sinoatrial block in preexisting sinus node disease, and may cause advanced or complete heart block in preexisting incomplete AV block; patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation after use; unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), do not prescribe digoxin to such patients

Drug Category: Diuretics -- Increase urine flow. These agents are ion transport inhibitors that decrease the reabsorption of sodium at different sites in the nephron. Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) or in treating hypertension, in which their diuretic action causes decreased blood volume.

Drug Name	Furosemide (Lasix) -- Like torsemide and bumetanide, is a potent loop diuretic. Compared to all other classes of diuretics, these drugs have the highest efficacy in mobilizing sodium and chloride from the body. Loop diuretics inhibit the Na+, K+, and Cl- cotransport in the ascending limb of the loop of Henle. Furosemide and other loop diuretics are indicated in treatment of edema associated with CHF, cirrhosis of the liver, and renal disease, including nephrotic syndrome. May be used to treat hypertension alone or in combination with other antihypertensive agents.
Adult Dose	Individualize according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response 20-80 mg PO administered as a single dose is usual initial dose; repeat or increase 6-8 h later if needed; dose may be titrated carefully up to 600 mg/d in patients with clinically severe edematous states; at higher doses, careful clinical observation and close laboratory monitoring are particularly important
Pediatric Dose	2 mg/kg PO administered as a single dose is usual dose in infants and children; dosage may be increased by 1-2 mg/kg no sooner than 6-8 h after previous dose if needed; not to exceed 6 mg/kg
Contraindications	Documented hypersensitivity; anuria
Interactions	May increase ototoxic potential of aminoglycoside antibiotics, especially in impaired renal function
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse; observe all patients receiving furosemide therapy for signs or symptoms of fluid or electrolyte imbalance; asymptomatic hyperuricemia can occur, and gout may be precipitated

Drug Category: Direct-acting adrenergic agonists -- Act directly on alpha- and beta-receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla.

Drug Name	Dobutamine (Dobutrex) -- Synthetic direct-acting catecholamine and beta-receptor agonist. Increases cardiac contractility and output in CHF. At therapeutic dose, mainly an inotropic agent, while producing comparatively mild chronotropic and vasodilative effects. As compared to other sympathomimetic drugs, does not significantly increase myocardial oxygen demands, which is its major advantage compared to other direct-acting catecholamines.
Adult Dose	Start at low rate (1 mcg/kg/min IV infusion) titrated at intervals of few minutes guided by the patient's response, including systemic blood pressure, urine flow, frequency of ectopic activity, heart rate, and, if possible, measurement of cardiac output, central venous pressure, and/or pulmonary capillary wedge pressure 2-20 mcg/kg/min IV usual range, but clinical response dictates optimal infusion rate
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, idiopathic hypertrophic subaortic stenosis
Interactions	Animal studies indicate that may be ineffective if patient recently received a beta-blocking drug; in this case, peripheral vascular resistance may increase
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	During administration, monitor ECG and blood pressure continuously; monitor pulmonary wedge pressure and cardiac output whenever possible to aid in safety and efficacy of infusion

FOLLOW-UP

Further Inpatient Care:

• Admit for testing and surgical intervention.

Further Outpatient Care:

• Close monitoring for symptom development is warranted.

• Serial echocardiograms should be performed to evaluate LV function, LV dimensions (end-systolic and end-diastolic), and the severity of AR.

• Serial multigated angiogram scans should be performed to monitor the LVEF and the volume of the left ventricle.

• Exercise stress testing should be performed to determine functional capacity and symptomatic response in patients with a history of equivocal symptoms.

• Carefully monitor medication doses and adverse effects.

In/Out Patient Meds:

• Medications include calcium channel blockers and ACE inhibitors.

• Avoid calcium channel blockers in patients with CHF.

• Use digoxin and diuretics for patients with CHF.

Transfer:

• Transfer may be required for further diagnostic evaluation and surgical intervention.

Deterrence/Prevention:

• Endocarditis prophylaxis is discussed as follows:

• AR leads to damaged endothelial lining of the valve and predisposes the valve to platelet and fibrin deposition.

• In the presence of bacteremia, colonization of platelets and/or fibrin deposition can lead to bacterial endocarditis; thus, antibiotic prophylaxis is important for preventing this serious complication.

• Patients with LV dysfunction or CHF symptoms should not engage in vigorous sports or heavy exertion.

Complications:

• Congestive heart failure

• Infective endocarditis

• Arrhythmia

• Sudden death

Prognosis:

• Asymptomatic patients with normal LV function have a mortality rate of less than 0.2% per year. The rate of progression to symptoms and/or LV dysfunction is less than 5% per year.

• Patients with angina have a mortality rate of higher than 10% per year.

• Patients with CHF have a mortality rate of higher than 20% per year.

Patient Education:

• Educate patients about symptoms associated with severe AR.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Antibiotic prophylaxis for prevention of aortic valve endocarditis is an important part of continuing medical care of patients with significant AR.

• Intra-aortic balloon pump use for hemodynamic support is contraindicated in patients with hemodynamically significant (ie, moderate or severe) AR.

• Symptomatic patients (NYHA class III, IV) with severe AR should undergo valve replacement, regardless of LV systolic function.

PICTURES

Caption: Picture 1. Aortic regurgitation. The light blue jet represents the aortic regurgitant flow on this 2-dimensional color Doppler echocardiogram showing severe aortic regurgitation.
Picture Type: Image