Aortic valvular disease is a major cause of morbidity and mortality worldwide. Although the incidence of aortic regurgitation has decreased over the past half century owing to a dramatic decline in the incidence of syphilis and rheumatic fever, the prevalence of aortic stenosis is increasing because of the aging population. Close monitoring of symptoms and/or the development of left ventricular (LV) remodeling and dysfunction is required to provide timely interventional therapy in patients with aortic stenosis or regurgitation.

The etiology of valvular heart disease (VHD) has changed over the past several decades. Several of the factors contributing to these changes include the advancements of technology, life expectancy of patients, novel prosthetic devices, and underlying cardiomyopathies.¹ Currently, aortic stenosis is the most common valvular disorder that requires interventional therapy in industrialized countries. In the United States, moderate to severe aortic stenosis is present in approximately 2.8% to 3.4% of the population older than age 75 years, and has a prevalence upward of 10% in the eighth decade of life.²,³ On the contrary, rheumatic fever and syphilis, common causes of aortic regurgitation in the first half of the past century, have almost disappeared in industrialized countries,¹ aortic regurgitation is less prevalent than is aortic stenosis, with moderate and severe aortic regurgitation occurring in 0.5% of the population in the Framingham study; any degree of aortic regurgitation was seen in 5% of the population.⁴ This chapter discusses pathophysiology, diagnosis, and management of aortic stenosis and aortic regurgitation.

The aortic valve is composed of three leaflets that have three cusps (right, left, and noncoronary cusps) that are attached to the annulus. The normal aortic valve area (AVA) is 3 cm² to 5 cm² with complete leaflet separation. The most common causes of aortic stenosis are calcification of an anatomically “normal” (tricuspid) aortic valve that occurs with aging, whereas calcification of a congenital bicuspid aortic valve occurs at a younger age. Bicuspid aortic valve, with a prevalence of approximately 2%, is the most common cause of aortic stenosis in those younger than age 70 years.³ An overlap in age exists in patients with severe tricuspid and bicuspid aortic stenosis undergoing aortic valve replacement (AVR) ( e-Figure 11.1).⁵ The valvular appearance of the common causes of aortic stenosis is shown in Figure 11.1.

Adjusted mortality rates for coronary artery disease have declined in the United States since the 1960s. Approximately 45% of this decline is attributed to a reduction in risk factors.⁶ Trends in the prevalence of aortic stenosis, however, are much less clear and not well defined. Several factors determine the prevalence of calcific aortic stenosis. As the population ages, the prevalence is expected to increase because aortic stenosis increases with advancing age. Improvements in surgical techniques and transcatheter valve replacement are also expected to increase the prevalence of the disease because these patients live longer after these procedures. In contrast, controlling risk factors is expected to decrease the prevalence of aortic stenosis.⁷ In a nationwide Swedish study, the mortality rate and age-adjusted mortality in aortic stenosis declined substantially from 1989 to 2009.⁸ This decrease in mortality was similar to that observed with heart failure and acute myocardial infarction. Controlling risk factors in a large proportion of the population may have contributed to a decrease in the overall prevalence of aortic stenosis, as was the case with coronary atherosclerosis. This decrease due to risk factor control could offset the increase in the prevalence of aortic stenosis expected from the aging population and better management of the disease. Thus, the age of the population, better risk factor control, and effective management of the disease are the major determinants of the prevalence of calcific aortic stenosis at any particular time and in any specific population.

Traditionally, calcification of the tricuspid aortic valve resulting in aortic stenosis was thought to be secondary to a wear and tear effect on the valve due to the aging process. Newer developments, however, suggested that calcific aortic stenosis is the result of an active inflammatory process in which genetic, anatomic, and environmental risk factors contribute to the development of the disease. Several of these risk factors involved in the development of coronary atherosclerosis, such as arterial hypertension, high cholesterol, and smoking
actively contribute to the development and progression of calcific aortic stenosis. Severe hypercholesterolemia in children or adults may be associated with aortic stenosis. Radiation therapy to the chest also increases the risk of aortic stenosis and coronary artery disease. It is speculated that the initial event of calcific aortic stenosis is damage to the endothelium, caused by stress allowing the entry of lipids. This, in turn, initiates an inflammatory process where T cells, myocytes, mast cells, and CD3-positive leucocytes accumulate. Inflammation results in the stimulation of neoangiogenesis with new vessel formation; rupture of the fragile new vessels may occur, which also contribute to the acceleration and progression of the disease. The atherosclerotic process over time may differentiate into various pathways including calcification. Despite the close association, however, between atherosclerosis and calcific aortic stenosis, many patients with risk factors and coronary atherosclerosis do not have aortic stenosis, and conversely many patients with aortic stenosis do not have coronary atherosclerosis.⁵,⁷,⁹

A 2015 study of patients undergoing AVR found that 62% of patients with a tricuspid aortic valve and calcific aortic stenosis and 26% of patients with a bicuspid aortic valve and calcific aortic stenosis required concomitant coronary artery bypass surgery (Figure 11.2).⁵ It seems, therefore, that other parameters in addition to coronary atherosclerosis risk factors contribute to the development of calcific aortic stenosis. Anatomic abnormalities in the aortic valve, more prominent in the bicuspid and less prominent in the tricuspid aortic valve, certainly play an important role. The increased mechanical stress of a bicuspid aortic valve results in increased structural degeneration and calcification at an earlier age. A stiff aorta (related to aging, risk factors, atherosclerosis, etc) may also contribute to the development of calcific aortic stenosis. Studies using magnetic resonance techniques have shown different patterns of blood flow in the root of the aorta in various disorders and diseases and in the elderly. In support of this observation, other studies have shown that the first abnormalities in patients who develop calcific aortic stenosis occur at the site of the aortic valve leaflets where turbulent blood flow is present. It is also known that valvular and vascular calcifications are inversely related to mineral density of the bones. Several disorders and diseases that affect mineral metabolism in the bones, such as osteoporosis, chronic kidney disease, Paget disease, and others, are associated with valvular calcification.⁵,⁷,⁹ Recent studies have shown that plasma-converting enzyme—angiotensin-converting enzyme 2 (ACE2)—activity is directly related to the severity of calcification in aortic stenosis. Thus, the renin-angiotensin-aldosterone system, and especially tissue ACE2 activity, facilitates the development of calcific aortic stenosis.⁹,¹⁰ In addition to traditional risk factors, several genetic variants have been associated with the development of aortic stenosis, and one such variant has been described in the lipoprotein(a) locus (rs10455872).¹¹

The progression of VHD, and especially the progression of aortic stenosis, can be categorized into stages. Stage A are
patients at risk for development of valvular disease. Stage B are patients with mild to moderate disease that are asymptomatic. Stage C are patients that have severe disease, but remain asymptomatic: Stage C1 patients have preserved LV function, and stage C2 patients have decompensated LV function. Stage D are patients who are symptomatic because of severe valvular disease.

The classic triad of symptoms associated with aortic stenosis includes lightheadedness and/or syncope, heart failure, and chest pain. The onset of these symptoms is known to reflect advanced disease and correlates with increased mortality. This was elegantly described in 1968 by Ross and Braunwald, who published the well-known “aortic stenosis mortality curve” that displays the rapid decline of survival associated with the onset of symptoms (Figure 11.2).¹²

As aortic stenosis progresses, it results in increased afterload, which if left untreated can cause LV hypertrophy, myocardial fibrosis, and, ultimately, manifest as heart failure. This causes classic symptoms of heart failure; shortness of breath and orthopnea are common and a decrease in exercise tolerance and increased fatigue can also occur. Severe symptoms with end-stage disease include severe dyspnea, orthopnea, pulmonary edema, and paroxysmal nocturnal dyspnea. Angina also presents as a late symptom and reflects, among others, an increase in oxygen consumption due to hypertrophied myocardium.

A thorough history and physical examination are often sufficient to obtain a level of suspicion regarding aortic valve disease.

The most common imaging modality for the diagnosis of aortic stenosis is transthoracic echocardiography (TTE) and Doppler echocardiography. TTE and Doppler echocardiography can be used to diagnose aortic stenosis in a noninvasive, radiation-free, and inexpensive manner. It is also the modality of choice for monitoring the progression of disease.
Transesophageal echocardiogram (TEE) can also provide additive information when needing to better visualize valve morphology, vegetations associated with infective endocarditis, leaflet perforation, or flail leaflets.

Using TTE and Doppler echocardiography, current guidelines define severe aortic stenosis as AVA less than or equal to 1.0 cm², peak aortic jet velocity greater than or equal to 4 m/sec, and a mean aortic transvalvular gradient greater than or equal to 40 mm Hg (Table 11.2).¹³ Figure 11.3 shows the continuous-wave Doppler pattern and peak velocity of severe aortic stenosis.

Discrepant values that confound the diagnosis of severe aortic stenosis may be present and need special consideration. Low-flow, low-gradient severe aortic stenosis (AVA ≤1 cm²) presents with a nonsevere transvalvular gradient (ie, ≤40 mm Hg). This is often seen in patients with poor LV systolic function (ie, LV ejection fraction <50%), resulting in a reduced forward stroke volume (stroke volume index <35 mL/m²) and, thus, a low gradient.¹⁴ Dobutamine stress echocardiography (DSE) can be used in this clinical scenario to differentiate patients with true severe aortic stenosis from those with “pseudoaortic stenosis” resulting from a decrease in aortic leaflet excursion due to severe LV systolic dysfunction. In true severe aortic stenosis, as dobutamine is administered stroke volume is augmented, the aortic valve gradient increases, and the AVA remains in the severe range. Conversely, in pseudoaortic stenosis, dobutamine infusion augments stroke volume and the transvalvular gradient, and the AVA increases as aortic valve leaflet excursion improves.

Low-flow, low-gradient severe aortic stenosis can also be seen in patients with preserved LV systolic function (ie, LV ejection fraction >50%). Often referred to as paradoxical low-flow, low-gradient aortic stenosis, patients with this condition are challenging to diagnose because they often have small LV cavities, normal LV ejection fraction, and infusion of dobutamine does little to augment their stroke volume or gradient. These patients are important to identify because intervention has been shown to improve outcomes.¹⁵

In assessment of aortic stenosis, the most common technical error leading to the misdiagnosis of severe aortic stenosis by echocardiogram is the underestimation of the left ventricular outflow tract (LVOT) diameter. The LVOT diameter is used in the continuity equation to calculate AVA and, when measured incorrectly, can lead to inaccurate assessment of the severity of aortic stenosis. Multidetector computed tomography (MDCT) and cardiac magnetic resonance imaging (MRI) can more accurately measure the LVOT and provide additive information when needed. For example, MDCT can be used to determine aortic valve calcium scoring¹⁶; an aortic valve calcium score greater than 2000 AU in men and greater than 1200 AU in women can help differentiate severe aortic stenosis from nonsevere aortic stenosis.¹⁷ Cardiac MRI is also used to evaluate the degree of myocardial fibrosis, an important factor that provides prognostic information beyond that provided by LV ejection fraction and LV volumes.

Cardiac catheterization is recommended and relied on only when noninvasive imaging is inconclusive or there are discrepancies between echocardiographic findings and clinical symptoms or findings. In the patient with severe aortic stenosis, coronary angiogram is often performed before aortic valve intervention to evaluate the need for coronary artery revascularization.