Aortic Stenosis - Comprehensive Review

1. Definition and Epidemiology

• Present in ~15% of adults ≥65 years old
• Severe AS (valve area <1 cm²) affects ~2% of those ≥65 years
• Prevalence is 3% in patients ≥75 years old
• Calcific AS rarely becomes clinically severe before age 70 in those with a tricuspid valve

2. Etiology

FIGURE 72.2 from Braunwald's: Comparison of tricuspid and bicuspid aortic valve structures showing different fusion patterns - Braunwald's Heart Disease, p. 697

3. Pathophysiology

3a. Molecular Mechanisms of Calcification

1. Lipid infiltration and oxidative stress initiate the cascade - analogous to atherosclerosis
2. Inflammatory cells are recruited; cytokines are elaborated
3. Valve interstitial cells (VICs) undergo osteogenic reprogramming
4. Mineralization of the extracellular matrix progresses (fibrocalcific remodeling)
5. Genetic factors contribute: Lipoprotein(a) [Lp(a)] is the strongest genetic association (SNP in Lp(a) associated with AS, HR 1.68). Other polymorphisms: vitamin D receptor, IL-10, TGF-β receptor, ApoE4

3b. Hemodynamic Consequences

1. LV pressure overload → concentric LV hypertrophy (LVH) as the compensatory response
2. LVH maintains wall stress (by Laplace's law: stress = P × r / 2h) and preserves ejection fraction for years-decades
3. However, LVH causes:
   • Increased LV stiffness → diastolic dysfunction (impaired early filling, LA dependence)
   • Increased myocardial oxygen demand with reduced coronary flow reserve → angina even without obstructive CAD
4. As stenosis worsens, LV cannot sustain adequate output → symptoms emerge
5. Eventually, LV decompensates → systolic dysfunction, pulmonary hypertension, right heart failure

4. Classification of Severity (ACC/AHA Stages)

Important: Over one-third of patients with AVA ≤1.0 cm² have a peak velocity <4 m/s or mean gradient <40 mmHg - the "low-flow, low-gradient" problem. These patients need careful distinction from truly moderate AS.

• Hemodynamic progression occurs in nearly all patients once even mild obstruction is present
• Interval from mild to severe: 5-10+ years (highly variable)
• Faster progression with: older age, heavier calcification, renal insufficiency, hypertension, obesity, metabolic syndrome, smoking, hyperlipidemia, elevated Lp(a)

5. Clinical Features

5a. The Classic Triad (Cardinal Symptoms)

5b. Other Manifestations

• Atrial fibrillation - poorly tolerated because the non-compliant LV is dependent on atrial kick for filling
• Acquired von Willebrand syndrome - mechanical disruption of large vWF multimers by turbulent flow; occurs in 67-92% of severe AS; causes a bleeding tendency (Heyde syndrome when associated with GI angiodysplasia)
• Systemic embolization (calcific emboli, rarely)

6. Physical Examination

7. Investigations

7a. Echocardiography (First-line, Gold Standard)

• Valve morphology: leaflet number, thickening, calcification, mobility
• Quantification:
  • Peak jet velocity (Vmax)
  • Mean pressure gradient - by modified Bernoulli equation: ΔP = 4v²
  • Aortic valve area (AVA) by continuity equation: AVA = SV / VTI_AV, where SV = CSA_LVOT × VTI_LVOT
    • This is based on conservation of flow: flow in LVOT = flow through AV (in absence of shunts)
• LV size and EF - mandatory; reduced EF alters interpretation
• LV wall thickness - degree of hypertrophy
• Doppler velocity ratio (VTI_LVOT/VTI_AV): <0.25 suggests severe AS

7b. Chest X-Ray

• Rounded cardiac apex - LVH (concentric pattern)
• Post-stenotic dilatation of ascending aorta (prominent first right cardiac arch)
• Aortic valve calcification - better seen on lateral view
• In late disease: pulmonary venous congestion

Fig. 14.42 from Grainger & Allison: CXR of AS showing rounded left ventricular profile and ascending aortic dilatation - Grainger & Allison's Diagnostic Radiology

7c. ECG

• LVH (increased voltage + repolarization changes/strain pattern)
• Left axis deviation
• Left bundle branch block
• ST depression / T-wave inversion in lateral leads (strain pattern)

7d. Cardiac CT

• Aortic valve calcium score (AVC): Useful adjunct when echo findings are discordant; high calcium burden confirms true severe AS
• CT angiography: Aortic annulus sizing before TAVR; assessment of coronary anatomy; vascular access planning

7e. Cardiac Catheterization

• Now reserved for cases where non-invasive assessment is inconclusive
• Direct measurement of transvalvular gradient (Gorlin formula for AVA)
• Coronary angiography when PCI or CABG may be planned alongside valve surgery

7f. BNP / NT-proBNP

• Elevated levels reflect LV pressure overload and wall stress
• Useful for detecting subclinical LV decompensation in asymptomatic patients
• Elevated BNP predicts faster progression and adverse outcomes

8. Low-Flow, Low-Gradient AS (Special Situations)

• AVA ≤1.0 cm², mean gradient <40 mmHg, LVEF <50%, LV stroke volume index <35 mL/m²
• Distinguish true severe AS from "pseudo-severe" using dobutamine stress echo
• More common in men with dilated cardiomyopathy

• AVA ≤1.0 cm², mean gradient <40 mmHg, LVEF ≥50%, LV stroke volume index <35 mL/m²
• More common in women with small, hypertrophied LV cavities and AF
• High aortic valve calcium score on CT helps confirm true severity

9. Management

9a. Medical Management

• Treat comorbidities: Hypertension, diabetes, dyslipidemia
• Statins: Despite initial observational promise, randomized trials (SALTIRE, SEAS) showed no benefit in slowing AS progression. Still indicated for concurrent atherosclerotic disease
• Avoid: Vasodilators (nitrates, ACE inhibitors, ARBs) in severe AS - can precipitate hypotension by reducing preload in a preload-dependent, fixed-output state
• Diuretics: Used cautiously for pulmonary congestion - avoid excessive preload reduction
• Beta-blockers: Used carefully; the hypertrophied LV needs adequate heart rate for filling
• AF management: Rapid AF extremely poorly tolerated; rate/rhythm control is important
• Endocarditis prophylaxis: No longer routinely recommended per current guidelines
• Lp(a)-lowering (e.g., RNA-targeted therapies): Under active investigation as disease-modifying treatment

9b. Valve Intervention - Indications

• Symptomatic severe AS (Stage D) - AVR (surgical or TAVR) without delay
• Asymptomatic severe AS (Stage C2) with LVEF <50%
• Asymptomatic severe AS (Stage C1) undergoing other cardiac surgery

• Asymptomatic very severe AS (Vmax ≥5 m/s) with low surgical risk
• Asymptomatic severe AS with rapid progression (Vmax increase ≥0.3 m/s/year) and low surgical risk

9c. Surgical Aortic Valve Replacement (SAVR)

• Gold standard for younger, lower-risk patients
• Tissue (bioprosthetic) valve preferred in older adults (avoids anticoagulation; durability adequate for remaining lifespan); degenerates more slowly in older patients
• Mechanical valve considered in younger patients (<65 years) willing to accept lifelong anticoagulation
• Operative mortality: <2% at experienced centers for low-risk patients; higher with LV dysfunction

9d. Transcatheter Aortic Valve Replacement (TAVR)

• PARTNER trial (inoperable patients): 1-year mortality TAVR 30% vs. medical therapy 50%
• High/intermediate surgical risk: TAVR showed similar 30-day and 1-year survival vs. SAVR
• Low-risk patients (PARTNER 3, Evolut Low Risk) (mean age 73): Composite risk of death/stroke/hospitalization at 1 year was significantly lower with TAVR (8.5% vs. 15.1%), shorter hospital stay, less new-onset AF

• Symptomatic severe AS of any age with high or prohibitive surgical risk, if predicted survival >12 months with acceptable quality of life
• Patients >80 years or those with life expectancy <10 years
• Ages 65-80: Either SAVR or TAVR after shared decision-making

• Higher: stroke, vascular complications, permanent pacemaker implantation, paravalvular leak
• Lower: new-onset AF, shorter hospital stay

9e. Balloon Aortic Valvuloplasty (BAV)

• Percutaneous balloon dilation of the aortic valve
• Very high restenosis rate; not a definitive treatment
• Used as a bridge to TAVR/SAVR in hemodynamically unstable patients or as palliation in those ineligible for any definitive intervention

10. Asymptomatic Severe AS - Surveillance

• Serial Doppler echocardiography: every 6-12 months for severe AS
• Exercise stress testing: Recommended in apparently asymptomatic patients to unmask true symptoms; ~50% develop symptoms or abnormal findings on exercise testing
• BNP/NT-proBNP: Monitoring for subclinical LV stress
• The strongest predictor of symptom development is the severity of aortic valve calcification and the initial hemodynamic gradient

11. Special Situations

Perioperative/Anesthesia Considerations

• Moderate-to-severe AS is associated with increased risk of perioperative cardiovascular complications
• Asymptomatic severe AS can proceed to major elective noncardiac surgery with appropriate hemodynamic monitoring and preserved ventricular function
• Symptomatic severe AS: Valve replacement should be considered before elective noncardiac surgery
• Hemodynamic goals during anesthesia: Maintain adequate preload, avoid tachycardia (reduces diastolic filling time in stiff LV), avoid hypotension, maintain sinus rhythm

Pregnancy (Maternal-Fetal Medicine)

• Severe AS poorly tolerated in pregnancy (fixed obstruction cannot accommodate the normal 50% increase in cardiac output)
• Management requires multidisciplinary team; balloon valvuloplasty or even SAVR may be needed

Aortic Stenosis with Concomitant Amyloidosis

• Increasingly recognized: transthyretin amyloidosis (ATTR) co-exists with AS in ~15% of TAVR patients
• Apical sparing pattern on LV strain imaging, bone scintigraphy (Perugini grade 2+), and CMR (transmural late gadolinium enhancement) are diagnostic
• Carries worse prognosis and requires specific ATTR treatment (tafamidis)

12. Prognosis Summary

• Asymptomatic severe AS: Annual mortality ~1-2%; event rate ~10% per year for developing symptoms
• Symptomatic severe AS without intervention:
  • Angina: ~50% 5-year mortality
  • Syncope: ~50% 3-year mortality
  • Heart failure/dyspnea: ~50% 2-year mortality
• After successful AVR or TAVR: Survival approximates age-matched controls; dramatic symptom improvement and quality of life benefit

• Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 12th ed. - Chapters 72-73 (Calcific AS, TAVR)
• Guyton and Hall Textbook of Medical Physiology, 14th ed. - p. 291
• Symptom to Diagnosis: An Evidence-Based Guide, 4th ed. - p. 9318-9350
• Grainger & Allison's Diagnostic Radiology, 6th ed. - p. 1700-1768
• Miller's Anesthesia, 10th ed. - p. 3908-3909
• Textbook of Clinical Echocardiography - Chapters on Valvular Stenosis Assessment