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Chapter 272 | Aortic Stenosis

Disorders of the Cardiovascular System · Part 6 – Cardiovascular Disorders

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Severe aortic stenosis (AS) is defined by a valve area 40 mmHg.
  2. The three cardinal symptoms of severe AS are exertional dyspnea, angina pectoris, and syncope.
  3. Physical exam hallmark: Systolic ejection murmur at the base radiating to carotids with pulsus parvus et tardus.
  4. Bicuspid aortic valve (BAV) is the most common congenital cause, associated with aortopathy and aneurysm risk.
  5. Low-flow, low-gradient severe AS requires dobutamine stress echocardiography or CT calcium scoring for confirmation.
  6. Surgical AVR (SAVR) is indicated for symptomatic severe AS; TAVI is preferred for high-risk or elderly patients.
  7. Rheumatic heart disease is the dominant cause in low- and middle-income countries, with accelerated progression.
  8. Medications for hypertension are safe in asymptomatic AS; statins do not slow AS progression.
  9. Endocarditis prophylaxis is restricted to AS patients with prior history of endocarditis.
  10. Death after symptom onset: Angina (3 years), Syncope (3 years), Dyspnea (2 years), Heart Failure (1.5–2 years).

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Management strategy for patients with aortic stenosis
2 🖼 Figure Pathogenesis of calcific aortic stenosis
3 🖼 Figure The burden of moderate or severe mitral and aortic valve disease in...
4 🖼 Figure The global burden of rheumatic heart disease
5 🖼 Figure Four-year cumulative incidence of all-cause mortality or disabling stroke for low surgical...
6 🖼 Figure Four-year cumulative incidence of all-cause mortality or disabling stroke for low surgical...
7 🖼 Figure Figure / Illustration

1. DEFINITION & OVERVIEW

  • Aortic stenosis (AS) is the most common valve lesion among adult patients with chronic valvular heart disease.
  • AS is characterized by narrowing of the aortic valve orifice, leading to obstruction of left ventricular (LV) outflow.
  • The majority of adult patients with symptomatic, valvular AS are male.
  • AS is rarely of clinical importance until the valve orifice has narrowed to ~1 cm².
  • Severe AS is estimated to affect 3.5% of the population aged >75 years.

1.1 Classification of Severity

  • Mild AS: Valve area 1.6–2.0 cm².
  • Moderate AS: Valve area 1.0–1.5 cm².
  • Severe AS: Valve area <1.0 cm² (or <0.6 cm²/m² body surface area).
  • Aortic valve sclerosis: Focal thickening and calcification not severe enough to cause obstruction (jet velocity <2.5 m/s, peak gradient <25 mmHg).

1.2 Staging of Disease

  • Stage A: Risk factors present for development of valve dysfunction.
  • Stage B: Progressive, mild-moderate, asymptomatic valve disease.
  • Stage C: Severe in nature but clinically asymptomatic.
  • Stage C1: Asymptomatic patients with severe valve disease but compensated ventricular function.
  • Stage C2: Asymptomatic, severe disease with ventricular decompensation.
  • Stage D: Severe, symptomatic valve disease.
  • Stage D1: Symptomatic patients with severe AS and high valve gradient (>40 mmHg mean gradient).
  • Stage D2: Symptomatic, severe, low-flow, low-gradient AS with low LVEF.
  • Stage D3: Symptomatic, severe, low-flow, low-gradient AS with preserved LVEF (paradoxical).

2. EPIDEMIOLOGY

  • Valvular heart disease ranks well below ischemic heart disease, stroke, hypertension, obesity, and diabetes as a major threat to public health.
  • Prevalence of valvular heart disease increases significantly with age.
  • Community echocardiographic screening identifies previously undiagnosed, predominantly mild valvular heart disease in ~50% of the population aged >65 years.
  • In this age group, the prevalence of previously undiagnosed moderate or severe valvular heart disease is ~6%.
  • Significant left-sided valve disease may affect as many as 12–13% of adults aged >75 years.
  • Severe AS is estimated to affect 3.5% of the population aged >75 years.
  • A Swedish epidemiology study estimated the incidence of newly diagnosed valvular heart disease at 64 per 100,000 person-years, with approximately 70% of incident disease observed in individuals 65 years of age or older.
  • AS and mitral regurgitation contributed approximately one-half and one-quarter, respectively, of the valvular heart disease diagnoses in this study.

2.1 Global Burden of Rheumatic Heart Disease

  • Rheumatic fever is the dominant cause of valvular heart disease in low- and middle-income countries.
  • Prevalence has been estimated to range from as low as 1 per 100,000 school-age children in Costa Rica to as high as 150 per 100,000 in China.
  • Prevalence is higher among females than males, especially for individuals age 20–40 years.
  • Rheumatic heart disease accounts for 12–65% of hospital admissions related to cardiovascular disease and 2–10% of hospital discharges in some endemic countries.
  • Approximately 45–50 million people (575.5 per 100,000) live with rheumatic heart disease worldwide.
  • Estimated prevalence characterized by 300,000 new cases and 233,000 case fatalities (5 per 100,000) per year.
  • Highest prevalence and age-adjusted mortality rates in sub-Saharan Africa, South Asia, Central Asia, and Oceania.
  • In the United States, rheumatic heart disease accounted for 3876 deaths in 2020.
  • Although globally the age-standardized mortality rate from rheumatic heart disease declined by nearly 50% between 1990 and 2022, the prevalence of heart failure attributable to rheumatic heart disease increased by nearly 90% over the same time interval.

Table 1 — Global Burden of Rheumatic Heart Disease (2022)

Measure Rate per 100,000 Trend (1990-2022)
YLDs (Years Lived with Disability) 400 (2022) Increasing
Prevalence 575.5 Increasing
YLLs (Years of Life Lost) 400 (2022) Decreasing
Mortality 5 Decreasing
DALYs (Disability Adjusted Life Years) 400 (2022) Increasing

2.2 Demographics in High-Income Countries

  • Prevalence estimates are derived from three population-based studies comprising a total of 11,911 individuals: The Coronary Artery Risk Development in Young Adults (CARDIA), the Atherosclerosis Risk in Communities (ARIC), and the Cardiovascular Health Study (CHS).
  • Prevalence of valvular heart disease increases significantly with age.
  • In the United States, payers used to require discrete discrimination of indication into either a bridge to transplant or destination therapy, whereas in most European countries, this artificial segregation was not used.

Table 2 — Burden of Moderate or Severe Mitral and Aortic Valve Disease in the United States

Age Group Prevalence (%)
<45 Low
45–54 Low
55–64 Moderate
65–74 High
≥75 Very High

3. ETIOLOGY & PATHOPHYSIOLOGY

  • AS in adults is due to degenerative calcification of the aortic cusps and occurs most commonly on a substrate of congenital disease (BAV), chronic (trileaflet) deterioration, or previous rheumatic inflammation.
  • A pathologic study of specimens removed at the time of aortic valve replacement (AVR) for AS in adults showed that 53% were bicuspid and 4% were unicuspid.
  • The process of aortic valve deterioration and calcification is not a passive one, but, rather, one that shares many features with vascular atherosclerosis, including endothelial dysfunction, lipid accumulation, inflammatory cell activation, cytokine release, and upregulation of several signaling pathways.
  • Eventually, a fibrocalcific response is established wherein collagen is deposited and valvular myofibroblasts differentiate phenotypically into osteoblasts and actively produce bone matrix proteins that allow for the deposition of calcium hydroxyapatite crystals.
  • Genetic polymorphisms involving the vitamin D receptor, the estrogen receptor in postmenopausal women, interleukin 10, and apolipoprotein E4 have been linked to the development of calcific AS.
  • A strong familial clustering of cases with trileaflet valves has been reported from western France.
  • Several traditional atherosclerotic risk factors have also been associated with the development and progression of calcific AS, including hypertension, low-density lipoprotein (LDL) cholesterol, lipoprotein(a) (Lp[a]), diabetes mellitus, smoking, chronic kidney disease, and the metabolic syndrome.
  • In a Canadian observational cohort study, the incidence of severe AS was 144 per 100,000 person-years. Hypertension, diabetes mellitus, and dyslipidemia accounted for approximately one-third of the population-attributable risk for severe AS.
  • Rheumatic disease of the aortic leaflets produces commissural fusion, sometimes resulting in a bicuspid-appearing valve. This condition, in turn, makes the leaflets more susceptible to trauma and ultimately leads to fibrosis, calcification, and further narrowing.
  • Mediastinal radiation can also result in late scarring, fibrosis, and calcification of the aortic leaflets. In this context, the calcification process also affects the mitral annulus.

3.1 Bicuspid Aortic Valve (BAV) Disease

  • Bicuspid aortic valve (BAV) is the most common congenital heart valve defect and occurs in 0.5–1.4% of the population with a 2–4:1 male-to-female predominance.
  • The inheritance pattern appears to be autosomal dominant with incomplete penetrance, although some have questioned an X-linked component as suggested by the prevalence of BAV disease among patients with Turner’s syndrome.
  • The prevalence of BAV disease among first-degree relatives of an affected individual is ~10%.
  • A single gene defect to explain the majority of cases has not been identified, although mutations in the NOTCH1, GATA5, and GATA4 genes have been described in some families.
  • Abnormalities in endothelial nitric oxide synthase and NKX2.5 have been implicated as well.
  • Medial degeneration with ascending aortic aneurysm formation occurs commonly among patients with BAV disease; aortic coarctation is less frequently encountered.
  • Patients with BAV disease have larger aortas than patients with comparable tricuspid aortic valve disease.
  • The aortopathy develops independently of the hemodynamic severity of the valve lesion, but directional shear forces dictated by the anatomic configuration of the valve appear to influence its expression.
  • For example, enlargement of the ascending aorta along its greater curvature is most often associated with right-left cusp fusion (Sievers classification type 1), the most common bicuspid variant.
  • Patients with BAV disease are at risk for aneurysm formation and/or dissection.
  • A BAV can be a component of more complex congenital heart disease with or without other left heart obstructing lesions, as seen in Shone’s complex (supravalvar mitral membrane, parachute mitral valve, subvalvar AS, and aortic coarctation).

Table 3 — Major Causes of Aortic Stenosis

Valve Lesion Etiologies
Aortic stenosis Congenital (bicuspid, unicuspid)
Aortic stenosis Degenerative calcific disease
Aortic stenosis Rheumatic fever
Aortic stenosis Radiation

3.2 Other Forms of Obstruction

  • In addition to valvular AS, three other lesions may be responsible for obstruction to LV outflow: hypertrophic obstructive cardiomyopathy, discrete fibromuscular/membranous subaortic stenosis, and supravalvular AS.
  • The causes of LV outflow obstruction can usually be differentiated on the basis of the cardiac examination and Doppler echocardiographic findings.

3.3 Pathophysiology of Obstruction

  • The obstruction to LV outflow produces a systolic pressure gradient between the LV and aorta.
  • When severe obstruction is suddenly produced experimentally, the LV responds by dilation and reduction of stroke volume.
  • However, in some patients, the obstruction may be present at birth and/or increase gradually over the course of many years, and LV contractile performance is maintained by the presence of concentric LV hypertrophy.
  • Initially, this serves as an adaptive mechanism because it reduces toward normal the systolic stress developed by the myocardium, as predicted by the Laplace relation (S = Pr/h, where S = systolic wall stress, P = pressure, r = radius, and h = wall thickness).
  • A large transaortic valve pressure gradient may exist for many years without a reduction in cardiac output (CO) or the development of LV dilation.
  • Ultimately, however, excessive hypertrophy becomes maladaptive, systolic function declines because of afterload mismatch, abnormalities of diastolic function progress, and irreversible myocardial fibrosis develops.
  • When AS and mitral stenosis (MS) coexist, the reduction in flow caused by MS lowers the pressure gradient across the aortic valve and, thereby, masks many of the clinical findings produced by AS.
  • The transaortic pressure gradient can be increased in patients with concomitant AR due to higher aortic valve flow rates.
  • The elevated LV end-diastolic pressure observed in many patients with severe AS and preserved ejection fraction (EF) signifies the presence of diminished compliance of the hypertrophied LV.
  • Although the CO at rest is within normal limits in most patients with severe AS, it usually fails to rise normally during exercise.
  • Loss of an appropriately timed, vigorous atrial contraction, as occurs in atrial fibrillation (AF) or atrioventricular dissociation, may cause rapid progression of symptoms.
  • Late in the course, contractile function deteriorates because of afterload excess, the CO and LV–aortic pressure gradient declines, and the mean left atrial (LA), pulmonary artery (PA), and right ventricular (RV) pressures rise.
  • LV performance can be further compromised by superimposed epicardial coronary artery disease (CAD).

4. CLINICAL FEATURES

  • AS is rarely of clinical importance until the valve orifice has narrowed to ~1 cm².
  • Even severe AS may exist for many years without producing any symptoms because of the ability of the hypertrophied LV to generate the elevated intraventricular pressures required to maintain a normal stroke volume.
  • Once symptoms occur, or the LV ejection fraction falls below normal, valve replacement is indicated.
  • Most patients with pure or predominant AS have gradually increasing obstruction over years but do not become symptomatic until the sixth to eighth decades.
  • Adult patients with BAV disease, however, develop significant valve dysfunction and symptoms one to two decades sooner.
  • Exertional dyspnea, angina pectoris, and syncope are the three cardinal symptoms.
  • Often, there is a history of insidious progression of fatigue and dyspnea associated with gradual curtailment of activities and reduced effort tolerance.
  • Dyspnea results primarily from elevation of the pulmonary capillary pressure caused by elevations of LV diastolic pressures secondary to impaired relaxation and reduced LV compliance.
  • Angina pectoris usually develops somewhat later and reflects an imbalance between the increased myocardial oxygen requirements and reduced oxygen availability.
  • CAD may or may not be present, although its coexistence is common among AS patients age >65.
  • Exertional syncope may result from a decline in arterial pressure caused by vasodilation in exercising muscles and inadequate vasoconstriction in nonexercising muscles in the face of a fixed CO, or from a sudden fall in CO produced by an arrhythmia.
  • Death in patients with severe AS occurs most commonly in the seventh and eighth decades.
  • Based on data obtained at postmortem examination in patients before surgical treatment became widely available, the average time to death after the onset of various symptoms was as follows: angina pectoris, 3 years; syncope, 3 years; dyspnea, 2 years; and heart failure, 1.5–2 years.
  • Moreover, in >80% of patients who died with AS, symptoms had existed for <4 years.
  • Among adults dying with valvular AS, sudden death, which presumably resulted from an arrhythmia, occurred in 10–20%; however, most sudden deaths occurred in patients who had previously been symptomatic.
  • Sudden death as the first manifestation of severe AS is very uncommon (~1% per year) in asymptomatic adult patients.

4.1 Physical Examination Findings

  • The heart rhythm is generally regular until late in the course; at other times, AF should suggest the possibility of associated mitral valve disease.
  • Hypertension occurs commonly among older adults with AS.
  • In the late stages, however, when stroke volume declines, the systolic pressure may fall and the pulse pressure narrow.
  • The carotid arterial pulse rises slowly to a delayed peak (pulsus parvus et tardus).
  • A thrill or anacrotic “shudder” may be palpable over the carotid arteries, more commonly the left.
  • In the elderly, the stiffening of the arterial wall may mask this important physical sign.
  • In many patients, the a wave in the jugular venous pulse is accentuated. This results from the diminished distensibility of the RV cavity caused by the bulging, hypertrophied interventricular septum.
  • The LV impulse is sometimes displaced laterally in the later stages of the disease.
  • A double apical impulse (with a palpable S) may be appreciated, particularly with the patient in the left lateral recumbent position.
  • A systolic thrill may be present at the base of the heart to the right of the sternum when leaning forward or in the suprasternal notch.
  • Auscultation: An early systolic ejection sound is frequently audible in children, adolescents, and young adults with congenital BAV disease. This sound usually disappears when the valve becomes calcified and rigid.
  • As AS increases in severity, LV systole may become prolonged so that the aortic valve closure sound no longer precedes the pulmonic valve closure sound, and the two components may become synchronous, or aortic valve closure may even follow pulmonic valve closure, causing paradoxical splitting of S.
  • The sound of aortic valve closure can be heard most frequently in patients with AS who have pliable valves; calcification diminishes the intensity of this sound.
  • Frequently, an S4 is audible at the apex and reflects the presence of LV hypertrophy and an elevated LV end-diastolic pressure; an S3 generally occurs late in the course when the LV dilates and its systolic function becomes severely compromised.
  • The murmur of AS is described as an ejection (mid) systolic murmur that commences shortly after S1, increases in intensity to reach a peak toward the middle of ejection, and ends just before aortic valve closure.
  • It is characteristically low-pitched, rough, and rasping in character, and loudest at the base of the heart, most commonly in the second right intercostal space.
  • It is transmitted upward along the carotid arteries.
  • Occasionally, it is transmitted downward and to the apex, where it may be confused with the systolic murmur of mitral regurgitation (MR) (Gallavardin effect).
  • In almost all patients with severe obstruction and preserved CO, the murmur is at least grade III/VI.
  • In patients with mild degrees of obstruction or in those with severe stenosis with heart failure and low CO in whom the stroke volume and, therefore, the transvalvular flow rate are reduced, the murmur may be relatively soft and brief.

4.2 Laboratory Examination

  • ECG: In most patients with severe AS, there is LV hypertrophy. In advanced cases, ST-segment depression and T-wave inversion (LV “strain”) in standard leads I and aVL and in the left precordial leads are evident.
  • However, there is no close correlation between the ECG and the hemodynamic severity of obstruction, and the absence of ECG signs of LV hypertrophy does not exclude severe obstruction.
  • Systemic hypertension can coexist and also contribute to the development of hypertrophy.
  • Echocardiogram: The key findings on transthoracic echocardiogram are thickening, calcification, and reduced systolic opening of the aortic valve leaflets and LV hypertrophy.
  • Eccentric closure of the aortic valve cusps is characteristic of congenitally bicuspid valves.
  • Transesophageal echocardiography imaging can display the obstructed orifice extremely well, but it is not routinely required for accurate characterization of AS.
  • The valve gradient and aortic valve area can be estimated by Doppler measurement of the transaortic velocity.
  • Severe AS is defined by a valve area <1 cm², whereas moderate AS is defined by a valve area of 1–1.5 cm² and mild AS by a valve area of 1.6–2 cm².
  • Aortic valve sclerosis, conversely, is accompanied by a jet velocity of <2.5 m/s (peak gradient <25 mmHg).
  • LV dilation and reduced systolic shortening reflect impairment of LV function.
  • There is a robust experience with the use of longitudinal strain to characterize earlier changes in LV systolic function before a decline in EF can be appreciated.
  • Doppler indices of impaired diastolic function are frequently seen.
  • The frequency with which echocardiography should be repeated during follow-up is dictated by the severity of stenosis (Table 272-2).
  • Echocardiography is useful for identifying coexisting valvular abnormalities, differentiating valvular AS from other forms of LV outflow obstruction, and measuring the aortic root and proximal ascending aortic dimensions.
  • These aortic measurements are particularly important for patients with BAV disease.
  • Dobutamine stress echocardiography can be useful for the evaluation of patients with AS and severe LV systolic dysfunction (low-flow, low-gradient, severe AS with reduced EF), in whom the severity of the AS can often be difficult to judge.
  • Patients with severe AS (i.e., valve area <1 cm²) with a relatively low mean gradient (<40 mmHg) despite a normal EF (low-flow, low-gradient, severe AS with normal EF) are often hypertensive, and efforts to control their systemic blood pressure should be optimized before Doppler echocardiography is repeated.
  • The use of dobutamine stress echocardiography in this setting is not advised.
  • When there is continued uncertainty regarding the severity of AS in patients with reduced CO and reduced or normal LVEF, quantitative analysis of the amount of aortic valve calcium with chest computed tomography (CT) can be helpful.
  • Aortic valve calcium scores that define severe AS differ for men and women, as men tend to have relatively more calcification and women more fibrosis of the valve leaflets.
  • There is increasing use of chest CT angiography to assess aortic valve morphology and function.
  • It has become the imaging method of choice to plan for transcatheter aortic valve implantation (TAVI).
  • Finally, the use of cardiac magnetic resonance (CMR) imaging to screen for the presence of increased extracellular volume (interstitial fibrosis) and late gadolinium enhancement (replacement fibrosis) in patients with severe AS is an area of active investigation.
  • Chest X-Ray: The chest x-ray may show no or little overall cardiac enlargement for many years.
  • Hypertrophy without dilation may produce some rounding of the cardiac apex in the frontal projection and slight backward displacement in the lateral view.
  • A dilated the ascending aorta along its greater curvature is most often associated with right-left cusp fusion (Sievers classification type 1), the most common bicuspid variant.
  • Aortic valve calcification may be discernible in the lateral view, but it is usually readily apparent on fluoroscopic examination or by echocardiography; the absence of valvular calcification on fluoroscopy in an adult suggests that severe valvular AS is not present.
  • In later stages of the disease, as the LV dilates, there is increasing roentgenographic evidence of LV enlargement, pulmonary congestion, and enlargement of the LA, PA, and right-sided heart chambers.

Table 4 — Frequency of Follow-Up Echocardiography in Aortic Stenosis

Stage of Disease Frequency of Echocardiography
Progressive (stage B) Every 3–5 years (mild severity, Vmax 2.0–2.9 m/s)
Every 1–2 years (moderate severity, Vmax 3.0–3.9 m/s)
Severe asymptomatic (stage C1) Every 6–12 months (Vmax >4 m/s)

5. DIFFERENTIAL DIAGNOSIS

  • In addition to valvular AS, three other lesions may be responsible for obstruction to LV outflow: hypertrophic obstructive cardiomyopathy, discrete fibromuscular/membranous subaortic stenosis, and supravalvular AS.
  • The causes of LV outflow obstruction can usually be differentiated on the basis of the cardiac examination and Doppler echocardiographic findings.
  • Rheumatic AS is almost always associated with involvement of the mitral valve and with aortic regurgitation (AR).

5.1 Other Forms of LV Outflow Obstruction

  • Hypertrophic obstructive cardiomyopathy (HOCM).
  • Discrete fibromuscular/membranous subaortic stenosis.
  • Supravalvular AS.

6. INVESTIGATIONS & DIAGNOSIS

  • Right- and left-sided heart catheterization for invasive assessment of AS is performed infrequently but can be useful when there is a discrepancy between the clinical and noninvasive findings.
  • Concern has been raised that attempts to cross the aortic valve for measurement of LV pressures are associated with a risk of cerebral embolization.
  • Catheterization can also be useful in three distinct categories of patients: (1) patients with multivalvular disease, in whom the role played by each valvular deformity should be defined to aid in the planning of operative treatment; (2) young, asymptomatic patients with noncalcific congenital AS, to define the severity of obstruction to LV outflow, because operation or percutaneous aortic balloon valvuloplasty (PABV) may be indicated in these patients if severe AS is present, even in the absence of symptoms; and (3) patients in whom it is suspected that the obstruction to LV outflow may not be at the level of the aortic valve but rather at the sub- or supravalvular level.
  • Coronary angiography is indicated to screen for CAD in appropriate patients with severe AS who are being considered for surgical or transcatheter valve intervention.
  • Angiography can be performed invasively at the time of catheterization for hemodynamic assessment or with noninvasive CT techniques.
  • Decision-making regarding the need for coronary artery revascularization at the time of aortic valve intervention is individualized.
  • The incidence of infective endocarditis (Chap. 133) has increased with the aging of the population, the more widespread prevalence of vascular grafts and intracardiac devices, the emergence of more virulent multidrug-resistant microorganisms, and the growing epidemic of injection drug use.
  • North American age-standardized incidence rates for endocarditis increased from 10.1 per 100,000 population in 1990 to 12.54 per 100,000 population in 2019.
  • The more restricted use of antibiotic prophylaxis since 2007 has not been convincingly associated with an increase in incidence rates for infective endocarditis cases attributable to oropharyngeal pathogens.
  • Infective endocarditis has become a relatively more frequent cause of acute valvular regurgitation.
  • Valve surgery during the acute phase of infective endocarditis is performed in ~50–60% of hospitalized patients.
  • Duration of intravenous antibiotic use may be shortened in selected cases.

6.1 Diagnostic Criteria for Severe AS

  • Severe AS is defined by a valve area 40 mmHg with a normal CO or an effective aortic orifice area of ~<1 cm² (or ~<0.6 cm²/m² body surface area in a normal-sized adult).

6.2 Imaging Modalities

  • Transthoracic echocardiogram: Key findings are thickening, calcification, and reduced systolic opening of the aortic valve leaflets and LV hypertrophy.
  • Transesophageal echocardiography: Can display the obstructed orifice extremely well, but not routinely required.
  • Chest CT angiography: Imaging method of choice to plan for TAVI. Assesses aortic valve morphology and function.
  • Cardiac magnetic resonance (CMR): Screening for increased extracellular volume (interstitial fibrosis) and late gadolinium enhancement (replacement fibrosis).

7. MANAGEMENT & TREATMENT

  • In patients with severe AS (valve area 5.5 cm).
  • Operation for aneurysm disease is recommended at smaller aortic diameters (4.5–5.0 cm) for patients with a family history of an aortic catastrophe and for patients who exhibit rapid aneurysm growth (>0.5 cm/year).
  • Patients with asymptomatic moderate or severe AS who are referred for coronary artery bypass grafting surgery should also have AVR.
  • The majority (~80%) of patients with symptomatic severe AS referred for surgery are considered low risk for perioperative death or major complication.
  • Operative risk increases as a function of age, comorbidities, and the need for concomitant aortic or other heart valve surgery or coronary artery bypass grafting.
  • A 2023 analysis from the STS Adult Cardiac Surgery Database reported a generally 5-year survival rate of 95% following isolated surgical AVR (SAVR) in low-risk AS patients of mean age 74 years.
  • The indications for SAVR in the asymptomatic patient have been the subject of intense debate, as surgical outcomes in selected patients have continued to improve.
  • Relative indications for which surgery is reasonable include an abnormal response to treadmill exercise; rapid progression of AS, especially when urgent access is needed.
  • Shared decision-making with younger patients must be individualized, although increasing numbers of patients age <65 now opt for a biological valve replacement.
  • Approximately 10–20% of bioprosthetic valves evidence primary valve failure by 15 years, requiring re-replacement (or valve-in-valve TAVI, see below), and an approximately equal percentage of patients with mechanical prostheses develop thromboembolic complications.

7.1 Medical Treatment

  • Activity restriction: Strenuous physical activity and competitive sports should be avoided in patients with severe AS.
  • Medications: Beta blockers and ACE inhibitors are generally safe for asymptomatic patients with preserved LV systolic function.
  • Nitroglycerin: Helpful in relieving angina pectoris in patients with CAD.
  • Statins: Do not slow the rate of progression of AS; use driven by ASCVD prevention.
  • RAAS inhibitors: Do not slow the rate of progression of AS.

7.2 Surgical Treatment

  • Surgical Aortic Valve Replacement (SAVR): Indicated for symptomatic severe AS, LV systolic dysfunction, or BAV disease with aneurysmal root.
  • Transcatheter Aortic Valve Implantation (TAVI): Preferred for high-risk or elderly patients.
  • Endocarditis Prophylaxis: Restricted to AS patients with a prior history of endocarditis.

7.3 Management Algorithm

  • Stage A: Risk factors present for development of valve dysfunction.
  • Stage B: Progressive, mild-moderate, asymptomatic valve disease.
  • Stage C: Severe in nature but clinically asymptomatic.
  • Stage C1: Asymptomatic patients with severe valve disease but compensated ventricular function.
  • Stage C2: Asymptomatic, severe disease with ventricular decompensation.
  • Stage D: Severe, symptomatic valve disease.
  • Stage D1: Symptomatic patients with severe AS and high valve gradient (>40 mmHg mean gradient).
  • Stage D2: Symptomatic, severe, low-flow, low-gradient AS with low LVEF.
  • Stage D3: Symptomatic, severe, low-flow, low-gradient AS with preserved LVEF (paradoxical).
  • Patients with symptomatic severe AS (left side of the diagram, jet velocity ≥4m/s) should be referred for AVR (SAVR or TAVI).
  • Asymptomatic patients with severe AS (jet velocity ≥4m/s) should be referred for AVR (SAVR or TAVI) for LVEF 5 m/s, or elevated B-type natriuretic peptide (BNP), provided the patient is considered low risk for complications related to AVR.

Table 5 — Management Strategy for Patients with Aortic Stenosis

Stage Criteria Recommendation
Stage B Vmax 2.0–2.9 m/s Monitor every 3–5 years
Stage B Vmax 3.0–3.9 m/s Monitor every 1–2 years
Stage C1 Vmax >4 m/s Monitor every 6–12 months
Stage D1 Vmax ≥4 m/s, Mean Gradient ≥40 mmHg AVR (SAVR or TAVI)
Stage D2 Vmax ≥4 m/s, EF <50% AVR (SAVR or TAVI)
Stage D3 Vmax ≥4 m/s, SVI <35 mL/m² AVR (SAVR or TAVI)
Stage D3 Vmax ≥5 m/s AVR (SAVR or TAVI)
Stage D3 BNP >3x normal AVR (SAVR or TAVI)
Stage D3 Rapid disease progression AVR (SAVR or TAVI)

8. PROGNOSIS & COMPLICATIONS

  • Death in patients with severe AS occurs most commonly in the seventh and eighth decades.
  • Based on data obtained at postmortem examination in patients before surgical treatment became widely available, the average time to death after the onset of various symptoms was as follows: angina pectoris, 3 years; syncope, 3 years; dyspnea, 2 years; and heart failure, 1.5–2 years.
  • Moreover, in >80% of patients who died with AS, symptoms had existed for <4 years.
  • Among adults dying with valvular AS, sudden death, which presumably resulted from an arrhythmia, occurred in 10–20%; however, most sudden deaths occurred in patients who had previously been symptomatic.
  • Sudden death as the first manifestation of severe AS is very uncommon (~1% per year) in asymptomatic adult patients.
  • Calcific AS is a progressive disease, with an annual reduction in valve area averaging 0.1 cm² and annual increases in peak jet velocity and mean valve gradient averaging 0.3 m/s and 7 mmHg, respectively.
  • A 2023 analysis from the STS Adult Cardiac Surgery Database reported a generally 5-year survival rate of 95% following isolated surgical AVR (SAVR) in low-risk AS patients of mean age 74 years.

8.1 Complications

  • Heart failure: Orthopnea, paroxysmal nocturnal dyspnea, and pulmonary edema occur only in the advanced stages of the disease.
  • Severe pulmonary hypertension leading to RV failure and systemic venous hypertension, hepatomegaly, AF, and tricuspid regurgitation (TR) are usually late findings in patients with isolated severe AS.
  • Sudden death: Occurs in 10–20% of adults dying with valvular AS, usually in previously symptomatic patients.
  • Infective endocarditis: Incidence has increased with aging population, vascular grafts, and injection drug use.

9. SPECIAL CONSIDERATIONS

  • Age: Shared decision-making with younger patients must be individualized, although increasing numbers of patients age 0.5 cm/year).
  • Global Considerations: While LVAS are available worldwide, their use and indications vary from country to country. In the United States, payers used to require discrete discrimination of indication into either a bridge to transplant or destination therapy, whereas in most European countries, this artificial segregation was not used.
  • Xenotransplantation: On January 7, 2022, the first genetically edited pig-to-human heart xenotransplantation was performed. The porcine xenograft was derived from a 10-gene edited animal with four genes that were knocked out (targeting three carbohydrate antigens associated with hyperacute rejection and one anticardiac growth gene) and six genes that were knocked in (targeting human complement regulation, coagulation, and anti-inflammatory pathways). Two transplants have been performed in living human recipients with limited survival of 2 months or less, with death occurring due to delayed graft dysfunction and subsequent loss.
  • Total Artificial Heart: The SynCardia total artificial heart is a pulsatile, implantable pump that consists of two polyurethane ventricles with pneumatically driven diaphragms and four tilting disc valves. This requires excision of the native ventricles and thus cannot be employed as a myocardial recovery strategy.
  • Newer devices: Newer pumps are in development that are designed to overcome challenges inherent in current-generation LVAS. Engineering continues to advance in this field, and we await devices that provide physiologic and synchronized pulsatile flow (rather than the unnatural transapical to aortic flow with current LVADs). The next paradigm shift will likely require a return to natural and pulsatile flow LVAS that are more biocompatible (as opposed to hemocompatible), responsive to physiologic requirements (smart pumps), and forgettable (without an external device to power its components).

9.1 Novel Devices

  • Total Artificial Heart: The SynCardia total artificial heart is a pulsatile, implantable pump that consists of two polyurethane ventricles with pneumatically driven diaphragms and four tilting disc valves. This requires excision of the native ventricles and thus cannot be employed as a myocardial recovery strategy.
  • Specific clinical issues: This device operates on a steep physiologic curve and has little adaptability to tolerate either systemic blood pressure changes or large shifts in blood volume. As the ventricles are excised, most patients exhibit a sharp decline in renal function due to the loss of natriuretic peptide expression by the myocardium. Severe hemolysis is common due to the presence of four mechanical valves, and aberrant erythropoiesis is noted, leading to a severe anemia.
  • Newer artificial hearts: Using biocompatible surfaces are under study (CARMAT), as well as those that use continuous flow technology (BIVACOR).

9.2 Xenotransplantation

  • On January 7, 2022, the first genetically edited pig-to-human heart xenotransplantation was performed.
  • The porcine xenograft was derived from a 10-gene edited animal with four genes that were knocked out (targeting three carbohydrate antigens associated with hyperacute rejection and one anticardiac growth gene) and six genes that were knocked in (targeting human complement regulation, coagulation, and anti-inflammatory pathways).
  • Two transplants have been performed in living human recipients with limited survival of 2 months or less, with death occurring due to delayed graft dysfunction and subsequent loss.
  • There are substantial ongoing concerns with continued immunologic barriers (despite gene modification), costs of donor organ development and recovery, ethical considerations, and considerations of transmission of zoonoses.

10. KEY PEARLS & CLINICAL TRAPS

  • Low-flow, low-gradient severe AS: Patients with severe AS (i.e., valve area <1 cm²) with a relatively low mean gradient (<40 mmHg) despite a normal EF (low-flow, low-gradient, severe AS with normal EF) are often hypertensive, and efforts to control their systemic blood pressure should be optimized before Doppler echocardiography is repeated.
  • Masking by AR: When AS and mitral stenosis (MS) coexist, the reduction in flow caused by MS lowers the pressure gradient across the aortic valve and, thereby, masks many of the clinical findings produced by AS.
  • Bicuspid Aortic Valve: Adult patients with BAV disease develop significant valve dysfunction and symptoms one to two decades sooner than trileaflet valves. Patients with BAV disease are at risk for aneurysm formation and/or dissection.
  • Physical Exam Clues: The carotid arterial pulse rises slowly to a delayed peak (pulsus parvus et tardus). A thrill or anacrotic “shudder” may be palpable over the carotid arteries, more commonly the left. In the elderly, the stiffening of the arterial wall may mask this important physical sign.
  • Murmur Characteristics: The murmur of AS is described as an ejection (mid) systolic murmur that commences shortly after S1, increases in intensity to reach a peak toward the middle of ejection, and ends just before aortic valve closure. It is characteristically low-pitched, rough, and rasping in character, and loudest at the base of the heart, most commonly in the second right intercostal space.
  • Endocarditis Prophylaxis: The need for endocarditis prophylaxis is restricted to AS patients with a prior history of endocarditis.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Management strategy for patients with aortic stenosis

Caption: FIGURE 272-4 Management strategy for patients with aortic stenosis. Preoperative and coronary risk factors. Cardiac catheterization and angiography may also be helpful do not meet criteria for intervention should be monitored with clinical and American College of Cardiology methodology for treatment recommendations. Class I are considered reasonable to perform; Class IIb recommendations may be considered. risk factors are present for the development of valve dysfunction; stage B refers to in nature but clinically asymptomatic; stage C1 characterizes asymptomatic patients asymptomatic, severe disease with ventricular decompensation; stage D refers to severe, patients with severe aortic stenosis and a high valve gradient (>40 mmHg mean aortic stenosis and low left ventricular ejection fraction (LVEF); and stage D3 preserved LVEF (paradoxical, low-flow, low-gradient severe aortic stenosis). Patients — Figure 272-1: Global burden of rheumatic heart disease. (A) Global map of age-standardized rheumatic heart disease mortality rate per 100,000 in 2022. Mortality rates are highest in South Asia and Oceania. (B) Global rheumatic heart disease estimates per 100,000 by measure with shaded 95% uncertainty interval, 1990–2022.

Figure 2

Pathogenesis of calcific aortic stenosis

Caption: FIGURE 272-3 Pathogenesis of calcific aortic stenosis. Lipid and inflammatory cell eventually to formation of disorganized collagen (fibrosis) and calcium hydroxyapatite process. AA, arachidonic acid; ACE, angiotensin-converting enzyme; ALP, alkaline triphosphate; ATX, autotaxin; A2AR, adenosine A2A receptor; BMP, bone phosphodiesterase; IL, interleukin; 5-LO, 5-lipoxygenase; LDL, low-density lipoprotein; associated phospholipase A2; lysoPA, lysophosphatidic acid; lysoPC, phospholipid; Ox-LDL, oxidized LDL; RANKL, receptor activator of nuclear factor-κB secreted PLA2; TGFβ, transforming growth factor β; TNF, tumor necrosis factor; VEGF, permission from B Lindman et al: Calcific aortic stenosis. Nat Rev Dis Primers 2:16006, — Figure 272-2: The burden of moderate or severe mitral and aortic valve disease in the United States. Prevalence estimates are derived from three population-based studies comprising a total of 11,911 individuals: The Coronary Artery Risk Development in Young Adults (CARDIA), the Atherosclerosis Risk in Communities (ARIC), and the Cardiovascular Health Study (CHS).

Figure 3

The burden of moderate or severe mitral and aortic valve...

Caption: FIGURE 272-2 The burden of moderate or severe mitral and aortic valve disease in the States. Prevalence estimates are derived from three population-based studies total of 11,911 individuals: The Coronary Artery Risk Development in Young Adults the Atherosclerosis Risk in Communities (ARIC), and the Cardiovascular Health Study (Reproduced with permission from VT Nkomo, JM Gardin, TN Skelton, et al: Burden valvular heart diseases: a population-based study, Lancet 368(9540):1005-1011, 2006.) — Figure 272-3: Pathogenesis of calcific aortic stenosis. Lipid and inflammatory cell infiltration occurs across damaged endothelium. A cascade of events follows that leads eventually to formation of disorganized collagen (fibrosis) and calcium hydroxyapatite (bone) deposition. Valvular interstitial cells (VIC) are critical participants in this active process.

Figure 4

The global burden of rheumatic heart disease

Caption: FIGURE 272-1 The global burden of rheumatic heart disease. (A) Global map of are highest in South Asia and Oceania. (B) Global rheumatic heart disease estimates disability-adjusted life-years; YLDs, years lived with disability; YLLs, years of life lost. diseases and risks, 1990-2022. J Am Coll Cardiol 82:2350, 2023.) — Figure 272-4: Management strategy for patients with aortic stenosis. Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is a discrepancy between clinical and noninvasive findings. Patients who do not meet criteria for intervention should be monitored with clinical and echocardiographic follow-up.

Figure 5

Four-year cumulative incidence of all-cause mortality or disabling stroke for...

Caption: FIGURE 272-6 Four-year cumulative incidence of all-cause mortality or disabling stroke for low surgical risk aortic stenosis patients assigned to self-expanding transcatheter aortic valve implantation (SE-TAVR; n = 730) or surgical aortic valve replacement (SAVR; n = 684). In this study, TAVR was noninferior to SAVR and marginally superior to SAVR for the combined endpoint. (Reproduced with permission from JK Forrest et al: 4-year outcomes of patients with aortic stenosis in the EVOLUT low risk trial. J Am Coll Cardiol 82:2163, 2023.) — Figure 272-5: Total artificial heart (SynCardia) device. A pulsatile, implantable pump that consists of two polyurethane ventricles with pneumatically driven diaphragms and four tilting disc valves. Requires excision of the native ventricles.

Figure 6

Four-year cumulative incidence of all-cause mortality or disabling stroke for...

Caption: FIGURE 272-6 Four-year cumulative incidence of all-cause mortality or disabling stroke for low surgical risk aortic stenosis patients assigned to self-expanding transcatheter aortic valve implantation (SE-TAVR; n = 730) or surgical aortic valve replacement (SAVR; n = 684). In this study, TAVR was noninferior to SAVR and marginally superior to SAVR for the combined endpoint. (Reproduced with permission from JK Forrest et al: 4-year outcomes of patients with aortic stenosis in the EVOLUT low risk trial. J Am Coll Cardiol 82:2163, 2023.) — Figure 272-6: Genetically edited pig-to-human heart xenotransplantation. The porcine xenograft was derived from a 10-gene edited animal with four genes knocked out and six genes knocked in to target rejection and inflammatory pathways.

Figure 7

: Comparison of surgical aortic valve replacement (SAVR) and transcatheter...

Caption: Figure 272-7: Comparison of surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI). Illustrates procedural approaches and valve types (mechanical vs. bioprosthetic).

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.