Aortic Valvular Stenosis: Causes, Risk Factors, Diagnosis, Treatment by NJE

• <30 years: congenital.
• 30 to 65 years: congenital or rheumatic fever.
• >65 years: degenerative calcification of aortic.

Prevalence

• Affects 1.3% of the population 65 to 74 years old, 2.4% 75 to 84 years old, 4% >84 years old.
• Bicuspid aortic valve: 1-2% of the population. Bicuspid aortic valve predisposes to the development of AS at an earlier age.

ETIOLOGY AND PATHOPHYSIOLOGY OF AORTIC VALVULAR STENOSIS

• Progressive aortic leaflet thickening and calcification result in LV outflow obstruction. Obstruction causes increased afterload and over time, decreased cardiac output.
• Increase in LV systolic pressure is required to preserve cardiac output; this leads to development of concentric left ventricular hypertrophy (LVH). The compensatory LVH preserves ejection fraction but adversely affects heart functioning.
  • LVH impairs coronary blood flow during diastole by compression of coronary arteries and reduced capillary ingrowth into hypertrophied muscle.
  •  LVH results in diastolic dysfunction by reducing ventricular compliance.

• Diastolic dysfunction necessitates stronger left atrial (LA) contraction to augment preload and maintain stroke volume. Loss of LA contraction by atrial fibrillation can induce acute deterioration.
• Diastolic dysfunction may persist after relief of aortic stenosis due to the presence of interstitial fibrosis.
• Angina: increased myocardial demand due to higher LV pressure. Myocardial supply is compromised due to LVH.
• Syncope (exertional): can be multifactorial from inability to augment cardiac output due to the fixed obstruction to LV outflow; arrhythmias; or most commonly, abnormal baroreceptor response resulting in failure to appropriately augment blood pressure.
• Heart failure: Eventually, LVH cannot compensate for increasing afterload resulting in high LV pressure and volume, which are accompanied by an increase in LA and pulmonary pressures.
• Degenerative calcific changes to aortic valve.
  •  Mechanism involves mechanical stress to valve leaflets as well as atherosclerotic changes to the valve tissue. Bicuspid valves are at higher risk for mechanical stress.
  •  Early lesions: subendothelial accumulation of oxidized LDL and macrophages and T lymphocytes(inflammatory response).
  •  Disease progression: fibroblasts undergo transformation into osteoblasts. Protein production of osteopontin, osteocalcin, and bone morphogenic protein-2 (BMP-2), which modulates the calcification of leaflets.

• Congenital: unicuspid valve, bicuspid valve, tricuspid valve with fusion of commissures, hypoplastic annulus.

• Rheumatic fever: chronic scarring with fusion of commissures.

RISK FACTORS OF AORTIC VALVULAR STENOSIS

• Congenital unicommissural valve or bicuspid valve.
  • Unicommissural valve: Most cases were detected during childhood.
  • Bicuspid valve: predisposes to the development of AS earlier in adulthood (4th to 5thdecade) compared to tricuspid valve (6th to 8th decade).

• Rheumatic fever 
  • The prevalence of chronic rheumatic valvular disease has declined significantly in the UnitedStates.
  • Most cases are associated with mitral valve disease.

• Degenerative calcific changes
  • Most common cause of acquired AS in the United States.
  • Risk factors are similar to that of coronary artery disease (CAD) and include the following:hypercholesterolemia, hypertension, smoking, male gender, age, and diabetes mellitus.

COMMONLY ASSOCIATED CONDITIONS OF AORTIC VALVULAR STENOSIS

• CAD (50% of patients)
• Hypertension (40% of patients): results in Òdouble-loadedÓ left ventricle (dual source ofincreased afterload as a result of obstruction from AS, and hypertension)
• Aortic insufficiency (common in calcified bicuspid valves and rheumatic disease)
• Mitral valve disease: 95% of patients with AS from rheumatic fever (RF) also have mitral valvedisease
• LV dysfunction and CHF
• Acquired von Willebrand disease: Impaired platelet function and decreased vWF results inbleeding (ecchymosis and epistaxis) in 20% of AS patients. Severity of coagulopathy is directlyrelated to severity of AS.
• Gastrointestinal arteriovenous malformations (AVMs)
• Cerebral or systemic embolic events due to calcium emboli.

DIAGNOSIS OF AORTIC VALVULAR STENOSIS

HISTORY

• Primary symptoms: angina, syncope, and heart failure (3). Angina is the most frequent symptom. Syncope is often exertional. Heart failure symptoms include fatigue, exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and shortness of breath.
• Palpitations
• Neurologic events (transient ischemic attack or cerebrovascular accident) secondary to embolization
• Geriatric patients may have subtle symptoms such as fatigue and exertional dyspnea.
• Note: Symptoms do not always correlate with valve area (severity of AS) but most commonly occur when aortic valve area is <1 cm2, jet velocity is > 4.0 m/s, or the mean transvalvular gradient is ≥ 40 mm Hg.

PHYSICAL EXAM

• Auscultation 
  •  Harsh, systolic crescendo-decrescendo murmur is best heard at 2nd right sternal border andradiates into the carotid arteries. Peak of murmur correlates with severity of stenosis; later peaking murmur suggests greater severity.
  • High-pitched blowing diastolic murmur suggests associated aortic insufficiency.
  • Paradoxically split S2 or absent A2. Note: Normally split S2 reliably excludes severe AS.
  • S4 due to stiffening of the left ventricle.

• Other associated signs include Pulsus parvus et tardus: decreased and delayed carotid upstroke. LV heave. Findings of CHF: pulmonary and/or lower extremity edema.

DIFFERENTIAL DIAGNOSIS

• Mitral regurgitation: high-frequency, pansystolic murmur, best heard at the apex, often radiates to the axilla.
• Hypertrophic obstructive cardiomyopathy: also systolic crescendo-decrescendo murmur butbest heard at left sternal border and may radiate into axilla. Murmur intensity increases bychanging from squatting to standing and/or by Valsalva maneuver.
• Discrete fixed subaortic stenosis: 50-65% has associated cardiac deformity (patent ductusarteriosus [PDA], ventricular septal defect [VSD], aortic coarctation).
• Aortic supravalvular stenosis: Williams syndrome, homozygous familial hypercholesterolemia.

DIAGNOSTIC TESTS & INTERPRETATION OF AORTIC VALVULAR STENOSIS

Initial Tests (lab, imaging)

• Chest x-ray (CXR) 
  • May be normal in compensated, isolated valvular AS. 
  • Boot-shaped heart reflective of concentric hypertrophy.     
  • Post stenotic dilatation of ascending aorta and calcification of aortic valve (seen on lateral PA CXR).

• ECG: often normal ECG (ECG is nondiagnostic), or may show LVH, LA enlargement, andnonspecific ST-and T-wave abnormalities.
• Echo indications.
  • Initial workup.

• Doppler echocardiogram: primary test in the diagnosis and evaluation of AS.
• Assesses valve anatomy and severity of disease.
• Assesses LV wall thickness, size, and function,and pulmonary artery pressure.
  • In known AS and changing signs/symptoms. 
  • In known AS and pregnancy due to hemodynamic changes of pregnancy.

• Echo findings
  • Aortic valve thickening, calcification.
  • Decreased aortic valve excursion.
  • Reduced aortic valve area.
  • Transvalvular gradient across aortic valve.
  • LVH and diastolic dysfunction.
  • LV ejection fraction.
  • Wall-motion abnormalities suggesting CAD.
  • Evaluate for concomitant aortic insufficiency or mitral valve disease.

• AS severity based on echo values
  • Stage A (at risk): bicuspid aortic valve, sclerosis, or other congenital abnormality; mean pressure gradient: 0 mm Hg; jet vel. <2 m/s.
  • Stage B (progressive): bicuspid or trileaflet valve.
    • Mild: mean pressure gradient: <20 mmHg; jet vel. 2.0 to 2.9 m/s.
    •  Moderate: mean pressure gradient: 20 to 40 mm Hg; jet vel. 3.0 to 3.9 m/s.
  • Stage C (asymptomatic severe AS):
    • C1 (without LV dysfunction): AVA ≤1.0 or AVAi ≤0.6 cm2/m2; mean pressure gradient: 40 to 60 mm Hg; jet vel. ≥4 to 5 m/s.
    • C2 (with LV dysfunction): AVA ≤1.0 or AVAi ≤0.6 cm2/m2; mean pressure gradient: ≥40mm Hg; jet vel. ≥4 m/s.
  • Stage D (symptomatic severe AS):
    • D1 (high-gradient): AVA ≤1.0 cm2; mean pressure gradient: >40 mm Hg; jet vel. >4 m/s.
    • D2 (low-flow/low-gradient with reduced EF <50%): AVA ≤1.0 cm2; mean pressuregradient: <40 mm Hg; jet vel. <4 m/s.
    • D3 (low-gradient, normal EF ≥50% or paradoxical low-flow severe AS): AVA ≤1.0 cm2; AVAi ≤0.6 cm2/m2 and stroke volume index <35 mL/m2; mean pressure gradient: <40 mm Hg; jet vel. <4 m/s.

Diagnostic Procedures

• Exercise stress testing
  • Asymptomatic patients with severe AS (5)[B]: helpful to uncover subtle symptoms orchanges, abnormal BP (increase <20 mm Hg), and ECG changes (ST depressions). 1/3 ofpatients develop symptoms with exercise testing; STOP testing at this point.
  • Symptomatic patients (5)[B]: DO NOT perform exercise stress testing, as it may inducehypotension or ventricular tachycardia.
  • CHF patients (5)[B]: Dobutamine stress echocardiography is reasonable to evaluate patients with low-flow/low-gradient AS and LV dysfunction.

• Cardiac catheterization
  • Perform prior to aortic valve replacement in patients with suspected CAD (5)[B]. Determines need for coronary artery bypass graft (CABG). If an unambiguous diagnosis of AS, perform only coronary angiography.
  • Can also use if noninvasive testing is inconclusive or if there is discrepancy between severity of symptoms and findings on echo.
  • Measures transvalvular flow and transvalvular pressure gradient, which facilitates calculation of effective valve area.
  • Hemodynamic measurements with an infusion of dobutamine can be useful for evaluation of patients with low-flow/low-gradient AS and LV dysfunction.

TEST INTERPRETATION 

• Aortic valve: nodular calcification on valve cusps (initially at bases), cusp rigidity, cusp thickening, and fibrosis.
• LVH, myocardial interstitial fibrosis.
• 50% incidence of concomitant CAD.

TREATMENT OF AORTIC VALVULAR STENOSIS

MEDICATION 

• No effective medical therapy for severe or symptomatic AS.
• Prevention: currently no recommended medical therapy. Statins have been thought to slowprogression if initiated during mild disease.However, this has not been supported by large,randomized controlled trials.
• Antibiotic prophylaxis against recurrent RF is indicated for patients with rheumatic AS (penicillin G 1,200,000 U IM q4wk; duration varies with age and history of carditis).
• Antibiotic prophylaxis is no longer indicated for prevention of infective endocarditis.
• Comorbidities: hypertension: angiotensin-converting enzyme (ACE) inhibitors, start with low dose and increase cautiously. Be cautious of vasodilators, which may cause hypotension.

SURGERY/OTHER PROCEDURES 

• The only proven treatment for AS is valve replacement.
• Indications for aortic valve replacement (AVR) surgery:
  • Symptomatic and severe high-gradient AS by history or exercise testing.
  • Asymptomatic, severe AS and LVEF < 50%.
  • Severe AS (stage C or D) when undergoing other cardiac surgery.
• AVR surgery is reasonable in patients who are:
  • Asymptomatic with severe AS with jet vel. ≥5 m/s and low surgical risk, decreased exercise tolerance, or have an exercise fall in blood pressure.
  • Symptomatic stage D2, with a low-dose dobutamine stress with jet vel. ≥4.0 m/s or meanpressure gradient ≥40 mm Hg with ≤1.0 cm2 at any dobutamine dose.
  • Symptomatic stage D3 with LVEF >50% if clinical and hemodynamic data support valveobstruction as likely cause of symptoms. 
  • Stage B who are undergoing other cardiac surgery, or asymptomatic stage C1 with rapiddisease progression and low surgical risk.
• Transcatheter aortic valve replacement (TAVR) offers a less invasive option for some patients.
  • For those who are high at surgical risk and considered inoperable, TAVR has demonstratedsuperiority to medical therapy.
  • For those who are high at surgical risk, TAVR has demonstrated noninferiority to surgicalAVR.
  • For those who are intermediate at surgical risk, TAVR may emerge as a reasonablealternative to surgical risk, though this indication has not yet been approved in the UnitedStates.
  • Valve-in-valve TAVR can be considered in high-risk patients with failed surgically implantedbioprosthetic valves.

• Percutaneous balloon valvuloplasty may have role in palliation or as a bridge to valvereplacement in hemodynamically unstable or high-risk patients but is not recommendedas an alternative to valve replacement.

FOLLOW-UP RECOMMENDATIONS

• Advise patients to immediately report symptoms referable to AS.
• Asymptomatic patients: yearly history and physical.
• Serial ECHO: yearly for severe AS, every 1 to 2 years for moderate AS, every 3 to 5 years for mild AS.

PATIENT EDUCATION

Physical activity limitations

• Asymptomatic mild AS: no restrictions.
• Asymptomatic moderate to severe AS: Avoid strenuous exercise. Consider exercise stress test.

PROGNOSIS

• 25% mortality/year in symptomatic patients who do not undergo valve replacement; averagesurvival is 2 to 3 years without AVR surgery.
• Median survival in symptomatic AS (3): heart failure: 2 years; syncope: 3 years; angina: 5years
• Perisurgical mortality: AVR surgery has 4% mortality rate; AVR + CABG has 6.8% mortalityrate
• Adverse postoperative prognostic factors: age, heart failure (HF) New York Heart Association(NYHA) class III/IV, cerebrovascular disease, renal dysfunction, CAD