Aortic stenosis (AS) is a common treatable cardiovascular problem whose prevalence is on the increase because of our aging population. From aortic sclerosis (focal areas of thickening and/or calcification) through worsening degrees of obstructive AS (characterized by more advanced valve thickening and calcification), the disease leads to ventricular dysfunction, symptoms, and death if untreated. The prevalence of aortic sclerosis is age dependent, ranging from 9% in a study in which the mean age was 54 years to 42% in a study in which the mean age was 81 years. Similarly, the prevalence of AS is age dependent, estimated at 1% of those aged over 65 years, 2.5% of those aged 75 years, and 8% of those aged 85 years.

Age-related degenerative calcific disease (>50% of cases) is the most common etiology underlying AS, followed by congenital bicuspid aortic valve disease (30%-40% of cases) and postinflammatory rheumatic disease (<10% of cases). Bicuspid aortic valve disease is the most common underlying etiology in patients needing surgery who are younger than 70 years, because of the high frequency of this congenital disease in the general population (estimated prevalence of 0.9%-2%) and the younger age of presentation of those with such anatomy (Fig. 1.1).

Tracking historical temporal changes in etiologic factors for patients with AS referred for aortic valve replacement has shown that the relative frequency of degenerative calcific aortic valve disease has increased considerably, mainly in place of postinflammatory rheumatic aortic valve disease. Multiple factors have likely driven this changing trend, including better primary and secondary prevention of rheumatic fever, improvements in life expectancy in the general population, alterations in patient referral practices, and an increased willingness of surgeons to operate on older patients with newer safer techniques for higher risk patients.

Radiation heart disease, although a rare overall cause of AS, deserves special mention because recognition of this as an underlying etiology has significant implications for prognosis and therefore management. Thickening of the aortomitral curtain should raise suspicions of radiation heart disease, which can cause pancarditis via latent changes in interstitial cells to a more profibrotic and procalcific phenotype (Fig. 1.2). Prior radiation exposure significantly increases perioperative morbidity and mortality above and beyond standard risk stratification scores (particularly with redo surgery), the implication being that surgical intervention should be delayed for as long as possible and any such intervention should aim to minimize the likelihood of reoperation.

Subvalvular AS is a congenital condition that may become manifest later in life, whereby fixed obstruction of the left ventricular outflow tract results from a discrete membrane or a tunnel-like orifice most likely as a maladaptive adaptation to abnormal localized flow dynamics. Shone syndrome refers to the association of subvalvular AS with sequential left-sided obstructive lesions. Transesophageal echocardiography is the most useful technique to distinguish this pathology from dynamic obstruction, namely hypertrophic
cardiomyopathy. Recurrence postresection has been described, whereas subvalvular AS may also result in a high-velocity, forward-flow jet lesion that may cause secondary aortic regurgitation. Even the presence of a mild leak should prompt consideration of the need for surgical intervention because it may be possible to concomitantly preserve/repair the aortic valve after resecting the membrane.

Supravalvular AS is a characteristic feature of Williams syndrome, which was first identified in 1961 by New Zealander J. C. P. Williams. It is much rarer than subvalvular AS and occurs in approximately 1 in 20,000 births. In general, supravalvular AS is caused by deletions or incompletely penetrant autosomal dominant mutations in the ELN gene that cause downregulation of the protein tropoelastin, an elastin precursor, fibers of which make up approximately 50% of the aorta. A compensatory increase in aortic smooth muscle cells ultimately leads to aortic narrowing.

Unicuspid aortic valve is a rare cause of congenital AS (estimated prevalence of 0.02% in the adult population) most commonly presenting with congestive heart failure in infancy. Most often, this is a retrospective rather than a preoperative diagnosis, more often made at pathologic examination of the surgically excised valve or at autopsy. Other associated anomalies are common and include aortic coarctation (˜37%), ventricular septal defect (˜12%), patent ductus arteriosus (˜5%), and aortic aneurysm (˜5%). It shares many of the features of bicuspid aortic valve, including valvular dysfunction, aortic dilation, aortic dissection, and dystrophic calcification, and indeed has been classified as a subset of bicuspid valve. Surgery for unicuspid aortic valve in adults is most commonly performed for mixed stenosis and regurgitation with combined aortic repair in a majority of cases. In contrast, the rarer quadricuspid valve phenotype (estimated prevalence of 0.01% in the adult population) is more commonly associated with aortic regurgitation rather than stenosis.

Aortic valve calcification is a common feature of advancing aortic valve pathology with both genetic and nongenetic causes. (The latter include standard cardiovascular risk factors, namely, age, diabetes, hypertension, obesity, dyslipidemia, smoking, and male gender.) The strongest genetic evidence predisposing to aortic valve calcification to date has come from a study that looked at more than 2.5 million gene variants, called single-nucleotide polymorphisms, in more than 6,900 people of white European background and found that a variant in the lipoprotein(a) [Lp(a)] gene locus (rs10455872) was strongly associated with having aortic valve calcification on cardiac tomography (CT) scanning. Findings were confirmed among thousands of patients from a range of ethnic backgrounds. This variant, found in 7% of the general population, also increased the risk of developing AS by more than 50%. Mediated by Lp(a) levels, this gene discovery supports a causal role for Lp(a), although it remains unanswered whether potential targeting of Lp(a) levels might reduce the incidence or progression of aortic valve disease.

Potential genetic markers of accelerated valvular calcification have also been investigated in family members with calcific bicuspid aortic valve disease. Here, linkage studies identified a nonsense mutation in NOTCH1 on chromosome 9q34-35 as a susceptibility locus. This finding was supported by the discovery of a NOTCH1 frameshift mutation in an unrelated family with similar aortic valve disease, suggesting that haploinsufficiency of NOTCH1 is a genetic cause of aortic valve malformations and calcification. Decreased NOTCH signaling has been linked to a molecular pathway for aortic valve calcification, via increased expression of bone morphogenic protein 2 as well as RUNX2 (a central transcriptional regulator of osteoblast-specific genes), with the net result of increased aortic valve calcification.

Supravalvular AS, as discussed earlier, is a characteristic feature of Williams syndrome and is caused by a hemizygous deletion of about 26 genes (including the elastin gene) from the long arm of chromosome 7, resulting in a distinctive “elfin” phenotype, an unusually cheerful demeanor and ease with strangers, developmental delay coupled with strong language skills, and transient hypercalcemia.

Pathologic mechanisms underlying degenerative aortic valve disease are complex and likely involve multiple genetic and environmental factors. Nonetheless, most current theories addressing degenerative aortic valve disease pathology invoke abnormal pathologic responses to increased mechanical stresses including activation of transforming growth factor beta, cytokine elaboration, mononuclear cell infiltration, and myofibroblast-induced matrix remodeling. These pathologic processes have many similarities with the inflammatory intimal remodeling seen in atherosclerotic vascular disease such as deposition of low-density lipoprotein cholesterol, Lp(a), and ultimately calcium. Distinguishing inciting factors from contributors to progression has not yet been fully elucidated. Ultimately, valve thickening and calcification lead to increased aortic valve leaflet compliance and loss of elasticity as a result of ongoing chronic inflammation.

It seems likely but is not definitively proven that patients who develop AS progress through aortic sclerosis initially. According to the 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines, the transition from sclerotic to stenotic change is defined by the presence of mild obstruction to blood flow, characterized by increased transaortic valve velocities with a cutoff point defined as a peak aortic jet velocity of 2 m/s or greater (Fig. 1.3). It is estimated that aortic sclerosis progresses to clinical AS at a rate of <2% per year. Despite this low rate of progression to stenosis, aortic sclerosis is associated with a significantly increased risk of cardiovascular morbidity and mortality: 68% increased risk of coronary events (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.31-2.15); a 27% increased risk of stroke (HR: 1.27; 95% CI: 1.01-1.60), a 69%
increased risk of cardiovascular mortality (HR: 1.69; 95% CI: 1.32-2.15), and a 36% increased risk of all-cause mortality (HR: 1.36; 95% CI: 1.17-1.59).

Once AS is present, it appears to progress inexorably over time. With moderate AS, the average annual rate of progression is estimated as a decrease in valve area of 0.1 cm², which roughly corresponds to an increase in velocity of 0.3 m/s, and an increase in mean pressure gradient of 7 mm Hg. However, while progression may be more rapid in older patients and in those with more severe leaflet calcification, there can be marked individual variability in progression rates, mandating regular clinical and echocardiographic follow-up in all patients with asymptomatic mild-to-moderate AS. When severe AS is detected in patients without symptoms, the likelihood of overt symptom development is high, with 50% to 70% of patients experiencing an adverse cardiovascular event within the next 2 years. Therefore, patients with asymptomatic severe AS require particularly frequent monitoring for progressive disease not least because symptom onset may be insidious and may indeed go unrecognized by the patient. With bicuspid aortic valve disease, severe AS remains the most common reason for intervention.

Recent ACC/AHA valve guidelines have, for the first time, applied a more detailed staging system for disease progression, similar to that used in heart failure. Stage A refers to “at risk” asymptomatic patients with risk factors for development of AS (aortic sclerosis or bicuspid aortic valve). Stage B covers “progressive” asymptomatic AS (namely, mild-to-moderate severity AS with peak aortic jet velocity of 2 to 2.9 m/s and 3 to 3.9 m/s, respectively)
(Fig. 1.3). Stage C covers asymptomatic severe AS (C1 if left ventricular ejection fraction is ≥50%; C2 if left ventricular ejection fraction is <50%). Severe AS is defined at or beyond thresholds in four different hemodynamic parameters: peak aortic jet velocity of ≥4 m/s, mean transaortic valve gradient of ≥40 mm Hg, estimated aortic valve area of ≤1 cm², or an indexed aortic valve area ≤0.6 cm²/m² (Fig. 1.3). These thresholds do not completely overlap; in fact, at normal flow rates, an aortic valve area of 0.8 cm² correlates with a mean aortic valve gradient of 40 mm Hg, but the rationale for using this higher threshold is that the prognosis of patients with AS is poorer when the aortic valve area is <1.0 cm² (hence, some people use the term “moderately severe” for aortic valve area between 0.8 and 1.0 cm² because some patients in this category may benefit from valve intervention). A further subclassification using the term “very severe” AS has been advocated when peak aortic jet velocity is ≥5 m/s or when the mean transaortic valve gradient is ≥60 mm Hg, reflecting an increased recognition that prognosis is worse with more advanced disease. Stage D refers to symptomatic patients with severe AS, three subcategories of which have been defined: D1—high-gradient symptomatic severe AS (with normal transvalvular flow rates); D2—low-flow, low-gradient symptomatic severe AS (with low transvalvular aortic volume flow rates caused by reduced left ventricular ejection fraction); and D3—low-flow, low-gradient symptomatic severe AS and left ventricular ejection fraction ≥50% (with low transvalvular aortic volume flow rates caused by a small hypertrophied left ventricle with a low stroke volume).