ETIOLOGY AND PATHOGENESIS Common causes of acute aortic regurgitation include ascending aortic dissection with distor- tion of the normal valve architecture, infective endocarditis with destruction of a valve leaflet, traumatic disruption, and spontaneous rupture or prolapse of a valve cusp secondary to degen- erative diseases of the valve. Acute aortic regur- gitation also may occur with sudden dehiscence of the sewing ring of a prosthetic valve and after operative or balloon valvuloplasty. The many causes of chronic aortic regurgitation are fundamentally related to two structural defects: those involving the valve leaflets and cusp or those involving the aortic root. Causes of valve leaflet disease include rheumatic heart disease, congenital abnormalities of the aortic valve (espe- cially bicuspid valves), calcific degenerative valve disease, myxomatous degeneration, or infective endocarditis. Rheumatic disease is characterized by shortening and scarring of the cusps and is fre- quently accompanied by mitral valve involvement (Fig. 28-1). Congenitally bicuspid valves occur in up to 2% of the population, with a marked male predominance. This abnormality often presents as aortic stenosis or a mixed stenosis–regurgitation lesion, but 10% have pure regurgitation. Infective endocarditis may cause aortic regurgitation by several mechanisms, including perforation of a sin- gle leaflet or a flail leaflet or by weakening of the cusp and valve annulus as a result of an expanding aortic root abscess. Aortic root disease is responsible for approxi- mately half of all clinically significant regurgita- tion cases. Common aortic root problems caus- ing aortic regurgitation include Marfan’s syndrome with annuloaortic ectasia and ascend- ing aortic dissection that may distort valve struc- ture and undermine support of the leaflets. In V ALVULAR HEART DISEASE systemic hypertension, aortic regurgitation may occur because the presence of long-standing hypertension can result in dilation of the ascend- ing aorta with distortion of the valve and chron- ic damage to the valve leaflets. Less common causes of aortic regurgitation include syphilitic aortitis, ankylosing spondylitis, osteogenesis imperfecta, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Behçet’s syndrome, ulcerative colitis, discrete subaortic stenosis, and ventricular septal defect with pro- lapse of an aortic cusp (Fig. 28-2). Natural History The natural history of chronic aortic regurgita- tion is incompletely known. Data from the presurgical era indicate that patients with chron- ic, severe aortic insufficiency who have angina or heart failure have a prognosis similar to those with severe aortic stenosis, with mortality rates of at least 10 to 20% per year. Asymptomatic patients with normal left ventricular (LV) func- tion develop symptoms or LV dysfunction at a rate of about 4% annually, but the occurence of sudden death is rare (<0.2% per year). It is important to note, however, that 25% of patients die or progress to LV dysfunction before manifesting symptoms, emphasizing the importance of serial quantitative assessments of LV function. The subset of asymptomatic patients who have LV dysfunction predictably has higher event rates, with more than 25% developing symptoms annually. CLINICAL PRESENTATION The presentation of aortic insufficiency varies with the onset (acute or chronic) and the degree of compensatory changes to volume overload (Table 28-1). In acute aortic regurgitation, the 265 Incompetence of the aortic valve results in volume overload of the left ventricle. The distinction between acute and chronic forms of aortic regurgitation is important in terms of etiologies, associat- ed diseases, prognosis, and treatment. Timothy A. Mixon and Gregory J. Dehmer Chapter 28 Aortic Insufficiency
Transcript
ETIOLOGY AND PATHOGENESISCommon causes of acute aortic regurgitation
include ascending aortic dissection with distor-tion of the normal valve architecture, infectiveendocarditis with destruction of a valve leaflet,traumatic disruption, and spontaneous ruptureor prolapse of a valve cusp secondary to degen-erative diseases of the valve. Acute aortic regur-gitation also may occur with sudden dehiscenceof the sewing ring of a prosthetic valve and afteroperative or balloon valvuloplasty.
The many causes of chronic aortic regurgitationare fundamentally related to two structuraldefects: those involving the valve leaflets and cuspor those involving the aortic root. Causes of valveleaflet disease include rheumatic heart disease,congenital abnormalities of the aortic valve (espe-cially bicuspid valves), calcific degenerative valvedisease, myxomatous degeneration, or infectiveendocarditis. Rheumatic disease is characterizedby shortening and scarring of the cusps and is fre-quently accompanied by mitral valve involvement(Fig. 28-1). Congenitally bicuspid valves occur inup to 2% of the population, with a marked malepredominance. This abnormality often presents asaortic stenosis or a mixed stenosis–regurgitationlesion, but 10% have pure regurgitation. Infectiveendocarditis may cause aortic regurgitation byseveral mechanisms, including perforation of a sin-gle leaflet or a flail leaflet or by weakening of thecusp and valve annulus as a result of an expandingaortic root abscess.
Aortic root disease is responsible for approxi-mately half of all clinically significant regurgita-tion cases. Common aortic root problems caus-ing aortic regurgitation include Marfan’ssyndrome with annuloaortic ectasia and ascend-ing aortic dissection that may distort valve struc-ture and undermine support of the leaflets. In
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systemic hypertension, aortic regurgitation mayoccur because the presence of long-standinghypertension can result in dilation of the ascend-ing aorta with distortion of the valve and chron-ic damage to the valve leaflets. Less commoncauses of aortic regurgitation include syphiliticaortitis, ankylosing spondylitis, osteogenesisimperfecta, systemic lupus erythematosus,rheumatoid arthritis, psoriatic arthritis, Behçet’ssyndrome, ulcerative colitis, discrete subaorticstenosis, and ventricular septal defect with pro-lapse of an aortic cusp (Fig. 28-2).
Natural History The natural history of chronic aortic regurgita-
tion is incompletely known. Data from thepresurgical era indicate that patients with chron-ic, severe aortic insufficiency who have anginaor heart failure have a prognosis similar to thosewith severe aortic stenosis, with mortality ratesof at least 10 to 20% per year. Asymptomaticpatients with normal left ventricular (LV) func-tion develop symptoms or LV dysfunction at arate of about 4% annually, but the occurence ofsudden death is rare (<0.2% per year). It isimportant to note, however, that 25% ofpatients die or progress to LV dysfunctionbefore manifesting symptoms, emphasizing theimportance of serial quantitative assessments ofLV function. The subset of asymptomaticpatients who have LV dysfunction predictablyhas higher event rates, with more than 25%developing symptoms annually.
CLINICAL PRESENTATION The presentation of aortic insufficiency varies
with the onset (acute or chronic) and the degreeof compensatory changes to volume overload(Table 28-1). In acute aortic regurgitation, the
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Incompetence of the aortic valve results in volume overload of the left ventricle. The distinctionbetween acute and chronic forms of aortic regurgitation is important in terms of etiologies, associat-ed diseases, prognosis, and treatment.
Timothy A. Mixon and Gregory J. Dehmer
Chapter 28
Aortic Insufficiency
Rheumatic Heart DiseaseAortic Insufficiency
Aortic insufficiency: Valve viewed from above; thickened, short cusps with triangular deficiency
Shortened cusps of aortic valve with exposure of sinuses and dilatation of aorta: “Jet lesion” on septal wall of L. ventricle
Concentric hypertrophy with some dilatation of L. ventricle resulting from aortic insufficiency, causing chordae tendineae to elongate and run in a relatively horizontal direction, thus impeding closure of mitral valve and leading to secondary mitral insufficiency
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Figure 28-1
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Syphilitic Heart Disease
Incompetent aortic valve with taut, separated cusps viewed from above
Dilated and markedly sclerotic thoracic aorta with widened aortic ring and narrowing of coronary ostia; hypertrophy of L. ventricle with regurgitant lesion on ventricular septum
Calcification of ascending aorta and dilatation of thoracic aorta
Stellate scar in media of aorta
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Figure 28-2
presentation is often dramatic. LV hypertrophyhas not developed, so ventricular compliance isnormal and remains so despite the suddenregurgitation. The acute volume overload ispoorly tolerated because the left ventricle isabruptly and dramatically distended, resulting inimpaired systolic function (based on the dias-tolic pressure–volume curve). The left ventricleis unable to acutely compensate for the largeregurgitant volume. Forward cardiac output isreduced and LV end-diastolic pressure is greatlyincreased. Tachycardia occurs in a futile attemptto increase cardiac output. The regurgitationresults in premature mitral valve closure withoccasional diastolic mitral regurgitation. As aresult, the patient with acute regurgitation usu-ally appears severely ill, manifesting tachycardia,hypotension, peripheral vasoconstriction, andpulmonary congestion and edema, but lacksmany physical signs of chronic regurgitation.Fatigue, apathy, agitation, or a decline in mentalfunction may develop as a manifestation of theabrupt decrease in forward cardiac output.
Chronic aortic regurgitation may be asympto-matic for years. When symptoms develop, they
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are usually indolent, reflecting the slow, progres-sive nature of the disease. Frequent complaintsinclude exertional dyspnea, orthopnea, andparoxysmal nocturnal dyspnea, all reflectingcongestive heart failure (CHF), and palpitations.Angina pectoris may be produced by concur-rent coronary artery disease or low diastolic per-fusion pressure and a reduction in coronaryblood flow during diastole because of the aorticregurgitation–induced LV hypertrophy. As aorticregurgitation develops, the left ventricle slowlyenlarges primarily with eccentric hypertrophy,although concentric hypertrophy also occursfrom increased afterload (Fig. 28-3). LV end-dias-tolic volume increases in response to the regur-gitation with an increase in chamber compli-ance; accordingly the increased end-diastolicvolume is not associated with major increases inend-diastolic pressure. Increased stroke volumemaintains normal forward cardiac output, usual-ly without significant increases in heart rate.Greatly augmented stroke volume leads tomany of the classic findings of chronic aorticregurgitation (Table 28-2 and Fig. 28-3); thepatient sometimes experiences an unpleasant
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Table 28-1Hemodynamic Features of the Stages of Severe Aortic Regurgitation
Chronic, Severe Chronic, SevereAcute Severe Regurgitation Regurgitation Regurgitation (Compensated) (Late Decompensation)
LV compliance Not increased Increased No longer increased
LVEDP ↑↑↑ Normal ↑↑↑LV dimensions Normal ↑↑ ↑↑Aortic SBP Normal or low ↑ Normal or low
Aortic DBP Normal ↓↓ Normal
Pulse pressure Normal / ↑ ↑↑↑ Normal
LVEF Normal Normal / ↑ ↓Total stroke volume ↑ ↑↑↑ ↑Heart rate ↑↑↑ Normal ↑↑Regurgitant volume Large Very large Large
Effective cardiac output ↓↓ Normal ↓Arterial pulse volume Normal / ↑ ↑↑↑ Normal
↑ indicates slight increase; ↑↑ , moderate increase; ↑↑↑ , severe increase; ↓ , slight decrease; ↓↓ , moderate decrease; ↓↓↓ , severe decrease; LV,left ventricular; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction. Arrows are not used in the first row because the changes in LV compliance are complex. In acute severe regurgitation, compliance is not really nor-mal, but not increased. In last column, compliance is not really normal, but is reduced compared with the state described in the middle column.
L. ventricular hypertrophy and dilatation: Increased voltageof QRS in all leads; inverted T in severalL. ventricular enlargement
Aortic pressure
L. ventricular pressure
I Sounds II I
I
II
III
aVR
aVL
aVF
V1 V2 V3
V4 V5 V6
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Figure 28-3
awareness of each contraction, especially ifirregular beats lead to a pause with a furtherincrease in preload. Low aortic diastolic pres-sure from the regurgitation of the incompetentvalve into the left ventricle usually results in awide pulse pressure. During exercise, systemicvascular resistance and diastolic filling perioddecrease, resulting in less regurgitation per car-diac cycle. This increases forward cardiac out-put without substantial increases in LV end-dias-tolic pressure. In some patients, the ability of theleft ventricle to compensate for the chronic vol-ume overload eventually is exceeded and LVfailure develops. As the LV ejection fraction (EF)decreases, the ventricle dilates further, initiatinga vicious cycle. Throughout this process, fibrosisof the myocardium slowly contributes to thedevelopment of irreversible LV dysfunction. Typ-ical symptoms of CHF may become evident atthis stage.
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Physical Examination In acute severe aortic regurgitation, systolic BP
is normal or decreased and diastolic BP is slightlyelevated, resulting in a pulse pressure that is usu-ally normal. Although tachycardia is usually pres-ent, the precordium is relatively quiet. The firstheart sound is soft because of premature closureof the mitral valve and may be absent in severeacute regurgitation. The second heart sound isalso soft, and a third heart sound is frequently pres-ent due to the rapid early diastolic filling of theventricle. A fourth heart sound is uncommon. Incontrast to chronic aortic regurgitation, the dias-tolic murmur of acute regurgitation is often short,ending well before the end of diastole, and soft inintensity. A systolic murmur is also present, but notparticularly loud due to the reduced forward out-put. A second diastolic murmur, the Austin Flintmurmur, is a mid diastolic rumble similar to mitralstenosis best heard at the apex. Possible mecha-nisms of this murmur include relative mitral steno-sis from the regurgitant jet displacing the anteriormitral leaflet, impedance of left atrial outflow, orvibrations induced by the regurgitant jet. AnAustin Flint murmur indicates that aortic regurgita-tion is severe.
In chronic, compensated aortic regurgitation,increased carotid pulse volumes may be accom-panied by a bruit or transmitted systolic murmur.Peripheral pulses are bounding due to the widepulse pressure, with systolic hypertension and alow diastolic BP. The LV apical impulse isenlarged and displaced inferiorly and laterally.The first heart sound is normal or soft and thesecond heart sound may be normal, single, orparadoxically split. Ejection clicks may be heard,especially in patients with a dilated aortic root. Afourth heart sound can be detected as LV hyper-trophy develops and a third heart sound occurswhen the left ventricle decompensates. The dias-tolic murmur of chronic aortic regurgitation isbest heard at the base of the heart along the leftsternal edge or in the second right intercostalspace. It is best detected with the diaphragm ofthe stethoscope while the patient is leaning for-ward during held expiration. The etiology of theregurgitation is more likely to be valvular if themurmur is louder to the left of the sternum,whereas aortic root disease is often the cause ifthe murmur is louder to the right of the sternum.
Quincke’s sign Capillary pulsations noted inthe nail beds or fingertipswith each cardiac cycle
Hill’s sign Popliteal systolic pressureexceeding brachial pressureby 30–60 mm Hg
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The diastolic murmur begins at the second heartsound and continues for a variable portion ofdiastole. Severity of the regurgitation is bettercorrelated with the length rather than the intensi-ty of the murmur. However, when the left ventri-cle begins to fail and end-diastolic pressureincreases, the murmur shortens again. A systolicmurmur may be present from increased forwardflow across the aortic valve or concomitant aor-tic stenosis. An Austin Flint murmur, if present,indicates severe aortic regurgitation.
DIFFERENTIAL DIAGNOSIS The hallmarks of chronic aortic regurgitation
are an increased pulse pressure and diastolicdecrescendo murmur heard at the upper sternalborder. Several other conditions can mimic aorticregurgitation and should be considered in the dif-ferential diagnosis. First, patients with pulmonicregurgitation have a blowing diastolic decrescen-do murmur, but would not usually have a widepulse pressure or bounding carotid pulse. Themurmur of pulmonic regurgitation shouldincrease with inspiration; the pulmonic valve clo-sure sound is often increased in intensity and aright ventricular (RV) heave may be present. ECGwould show signs of RV strain or hypertrophyrather than left-sided abnormalities and chest radi-ography would show signs of RV enlargement. Inadults, there is usually a comorbid condition caus-ing pulmonary hypertension and therefore thepulmonary regurgitation. Second, in those pre-senting at a younger age the diagnosis of a patentductus arteriosus should be considered. It causesa wide pulse pressure, as seen in aortic regurgita-tion, but the murmur is continuous with a low-pitched diastolic component. ECG in this condi-tion would be normal or show signs of LVhypertrophy and chest radiography would showincreased flow in the pulmonary vasculature.Third, if symptoms of dyspnea and chest painbegin suddenly, a ruptured sinus of Valsalvaaneurysm should be considered. The pulse pres-sure is usually increased, but the murmur wouldbe continuous rather than diastolic only. Chestradiography would show signs of increased flowin the pulmonary vasculature. Finally, a coronaryarteriovenous fistula may present with a murmurthat can be confused with aortic regurgitation.The murmur should be continuous, but occasion-
ally the diastolic component can dominate, mim-icking aortic regurgitation. Echocardiographyand, if necessary, cardiac catheterization can beperformed to distinguish all of these conditionsfrom aortic regurgitation.
DIAGNOSTIC APPROACHWith chronic aortic regurgitation, the ECG fre-
quently shows left-axis deviation and LV hyper-trophy. The findings are nonspecific and mayinclude interventricular conduction defects, non-specific ST-segment and T-wave changes, and PR-interval prolongation, especially if the etiology isinflammatory. These findings are not accuratepredictors of the severity of regurgitation.
Chest radiography in chronic aortic insufficiencyshows LV dilatation that may be massive (so called“cor bovinum”). Enlarged aortic root size suggeststhe etiology of the regurgitation. The pulmonaryvasculature may be engorged with fluid during adecompensated state. With acute aortic insuffi-ciency, there is minimal cardiac enlargement, withflorid pulmonary edema the only finding.
Echocardiography is valuable for the initialassessment of acute and chronic aortic regurgi-tation and for serial follow-up examinations(Fig. 28-4). Complete echocardiography pro-vides information about the etiology and severi-ty of aortic regurgitation, the presence of con-comitant valve disorders, and the state of LVcompensation assessed by chamber size, func-tion, and wall thickness. The severity of regurgi-tation can be estimated semiquantitatively bymeasuring the width or cross-sectional area ofthe regurgitant jet in relation to the LV outflowtract cross-sectional area by the finding of holo-diastolic flow reversal in the descending aorta orby measuring the pressure half-time of the regur-gitant jet. Severity can be determined quantita-tively by the pressure half-time method or by thecontinuity equation that yields the regurgitantvolume and fraction. Additionally, informationfrom echocardiography, notably LVEF andchamber dimensions, can be followed serially todetermine the timing of surgical intervention.
Aortic regurgitation can also be evaluated bycardiac catheterization. Hemodynamic tracingsin severe aortic regurgitation show a wide pulsepressure and an elevated LV end-diastolic pres-sure (Fig. 28-3). Aortic root angiography provides
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100
ECG
ECG
Echo
PCG SM
S1 S2
S1 S2 S1 S2S1 S2
DM
AML
PML
PML
AML E f A
C
50
0
EfC
LA
LVEDP
Ao 150
100
50
0
Ao
LV
ECG, pressure tracings, M-mode echocardiogram (Echo), and phonocardiograms (PCG) from a patient with acute severe (left) and chronic severe (right) aortic regurgitation.
A indicates A point corresponding to the peak upward motion of the mitral valve leaflet after atrial systole; AML, anterior mitral valve leaflet; Ao, aorta; C, C point where the two mitral leaflets come together; DM, diastolic murmur; E, E point corresponding to the maximal excursion of the anterior mitral valve leaflet after early diastolic opening; EDP, end-diastolic pressure; f, flutter of anterior mitral valve leaflet; LA, left atrium; LV, left ventricle; PML, posterior mitral valve leaflet; S1, first heart sound; S2, second heart sound; SM, systolic murmur.
With permission from Morganroth J, Perloff JK, Zeldis SM, Dunkman WB. Acute severe regurgitation: Pathophysiology, clinical recognition, and management. Ann Intern Med 1977;87:223–232.
Hemodynamics and Heart Sounds in Patients With Acute and Chronic Severe Aortic Regurgitation
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272
Figure 28-4
a semiquantitative assessment of severity, basedon the speed and completeness of LV opacifica-tion. Quantitatively, regurgitant volume andregurgitant fraction are calculated using thestroke volume from LV angiography and for-ward cardiac output obtained by the thermodi-lution or Fick methods.
MANAGEMENT AND THERAPYAcute Aortic Regurgitation
Whatever the etiology, acute aortic insufficien-cy necessitates rapid diagnosis, with aggressivemedical and surgical therapy, if feasible. Medicalstabilization includes afterload-reducing agentsto augment forward cardiac output, but worsen-ing hypotension may preclude implementationof afterload-reducing therapy. Intraaortic ballooncounterpulsation is contraindicated because itincreases regurgitation. Slowing the heart rate is
not recommended because it prolongs the dias-tolic filling period and thus lengthens the timeduring which regurgitation can occur. However,if acute aortic dissection is the etiology of theregurgitation, β-blockers may reduce the force ofLV ejection. Long-term administration of β-block-ers is important in patients with Marfan’s syn-drome because it slows the rate of aortic dilata-tion and progression to aortic complications, afavorable effect while awaiting definitive surgicalintervention.
With acute aortic dissection, the clinical pic-ture may be dominated by other sequelae,including myocardial infarction (MI) from com-promise of a coronary artery (most commonlythe right coronary artery), hemopericardiumwith tamponade, hemorrhagic shock, or strokedue to involvement of a great vessel. When aor-tic regurgitation occurs as a result of infective
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endocarditis, surgery occasionally can be delayeda few days, allowing further antibiotic therapy, butshould not be postponed if there is significanthemodynamic instability or CHF. Despite concernsabout placing a prosthetic valve during an infec-tion, the risk of recurrence of infection is fairly low.
Chronic Aortic RegurgitationValve replacement should be considered for
most patients with symptomatic severe aorticregurgitation, unless comorbid conditions pre-clude surgery. Preoperative LV systolic perform-ance is the major determinant of postoperativeprognosis in terms of LV function, symptoms ofheart failure, and survival rate. In general, symp-tomatic patients with reduced LV function whoundergo valve replacement have reduced post-operative survival rates, whereas those with pre-served LV function have an excellent prognosis.However, there is a subgroup of patients withreduced LV function who show substantialimprovement in LV function after valve replace-ment. In this subgroup, improvement in LV func-tion resulted from the elimination of valve regur-gitation and left ventricle volume overload andreversal of the imbalance between excessiveafterload and the combination of preloadreserve and compensatory hypertrophy (socalled “afterload mismatch”). Key factors forimprovement in LV function and prognosis aftersurgery are early identification of patients withminimal or no symptoms yet early signs of LVdysfunction and potential valve replacement,before severe symptoms develop.
There is controversy, however, regarding thetiming of surgery in asymptomatic patients withsevere regurgitation. Vasodilator therapy canreduce the degree of regurgitation, increase for-ward cardiac output, and delay the necessity ofvalve replacement. Accordingly, vasodilator ther-apy is recommended for asymptomatic patientswith severe aortic regurgitation who have hyper-tension or a normal EF with enlarged LV volumes.Vasodilators are not recommended in patientswith lesser degrees of regurgitation or if the EFand cardiac volumes are normal. Surgery is rec-ommended in asymptomatic patients with severeaortic regurgitation who have a depressed LVEF(<0.50), severe ventricular dilatation (LV end-sys-tolic dimension >55 mm or end-diastolic dimen-
sion >75 mm) or are undergoing surgery on a dif-ferent valve, the aorta, or coronary arteries. Datathat suggest that an exercised-induced decreasein LVEF has independent prognostic value inpatients undergoing surgery are inconsistent. Themost common surgical procedure is valvereplacement, but alternative approaches includeuse of the patient’s pulmonary valve (Ross proce-dure) or valve repair (see chapter 34). Valverepair is most feasible in patients with perforationof a leaflet due to endocarditis or when redun-dancy of the free edge of one of the leafletsresults in leaflet prolapse. Concomitant aorticroot reconstruction is often necessary in aorticdissection and Marfan’s syndrome.
surgery is becoming more common as surgicaltechniques are perfected. The entire surgical pro-cedure is performed through a small incision tothe right of the sternum rather than the tradition-al median sternotomy. This approach appears toshorten length of stay and recovery periodsbefore returning to work, but it is unclearwhether there are any long-term advantages orhazards. Percutaneous alternatives to surgicalvalve replacement are also being developed.
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Bonow RO, Carabello B, deLeon AC Jr, et al. ACC/AHA guide-lines for the management of patients with valvular heart dis-ease: a report of the American College of Cardiology/Amer-ican Heart Association Task Force on Practice Guidelines(Committee on Management of Patients with ValvularHeart Disease). J Am Coll Cardiol 1998;32:1504–1514.
Cosgrove DM, Rosenkranz ER, Hendren WG, et al. Valvulo-plasty for aortic insufficiency. J Thorac Cardiovasc Surg1991;102:571–576.
Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, DallaVolta S. Nifedipine in asymptomatic patients with severeaortic regurgitation and normal left ventricular function. NEngl J Med 1994;331:689–694.
Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression ofaortic dilatation and the benefit of long term beta-adren-ergic blockade in Marfan’s syndrome. N Engl J Med1994;330:1335–1341.
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