Table 57.2 shows that echocardiography is more sensitive than electrocardiography in detecting LV hypertrophy in patients with AS [2]. Rounding of the LV border and apex may result from concentric LV hypertrophy. Post-stenotic dilatation of the ascending aorta is commonly seen. Calcification of the aortic valve is best seen by echocardiography or fluoroscopy.

In a study of 1,533 patients with asymptomatic AS, electrocardiographic LVH was associated at 4.3-year follow-up with a 5.8 times increase in heart failure, a 2.0 times increase in aortic valve replacement (AVR), and a 2.5 times increase in myocardial infarction, CHF, or cardiovascular death [35]. LV strain was associated with a 3.1 times increase in myocardial infarction [35].

Involvement of the conduction system by calcific deposits may occur in patients with AS. In 51 patients with AS who underwent AVR, conduction defects occurred in 58 % of 31 patients with MAC and in 25 % of 20 patients without MAC [6]. In 77 elderly patients with AS, first-degree atrioventricular block occurred in 18 %, left bundle branch block in 10 %, intraventricular conduction defect in 6 %, right bundle branch block in 4 %, and left axis deviation in 17 % of patients [36].

Complex ventricular arrhythmias may be detected by 24-h ambulatory electrocardiograms in patients with AS. Patients with complex ventricular arrhythmias associated with AS have a higher incidence of new coronary events than patients with AS and no complex ventricular arrhythmias [37].

Two-dimensional and Doppler echocardiography are very useful in diagnosing AS. Of 83 patients with CHF or angina and a systolic precordial murmur in whom severe AS was diagnosed by Doppler echocardiography, AS was not clinically diagnosed in 28 patients (34 %) [38]. Echocardiography can detect thickening, calcification, and reduced excursion of aortic valve leaflets [1]. LV hypertrophy is best diagnosed by echocardiography [2]. Chamber dimensions and measurements of LV end-systolic and end-diastolic volumes, LV ejection fraction, and assessment of global and regional LV wall motion give important information on LV systolic function.

Doppler echocardiography measures peak and mean transvalvular gradients across the aortic valve and identifies associated valve lesions. Aortic valve area (AVA) can be calculated by the continuity equation using pulsed Doppler echocardiography to measure LV outflow tract velocity, continuous-wave Doppler echocardiography to measure transvalvular flow velocity, and two-dimensional long-axis view to measure LV outflow tract area [38, 39]. The agreement in quantitation of severity of AS between Doppler echocardiography and cardiac catheterization is greater than 95 % [40]. Patients with a peak jet velocity ≥4.5 m/s had critical AS, and those with a peak jet velocity <3.0 m/s had noncritical AS. Slater et al. [41] found a concordance between Doppler echocardiography and cardiac catheterization in the decision to operate or not to operate in 61 of 73 patients (84 %) with AS. In 75 patients with AS, the Bland-Altman plot showed that 4 of 75 patients (5 %) had disagreement between cardiac catheterization and Doppler echocardiography outside the 95 % confidence limits [42].

Although most patients do not require cardiac catheterization before AVR, they require selective coronary arteriography before AVR. Patients in whom Doppler echocardiography shows a peak jet velocity between 3.6 and 4.4 m/s and an AVA >0.8 cm² should undergo cardiac catheterization if they have cardiac symptoms attributable to AS. Patients with a peak jet velocity between 3.0 and 3.5 m/s and a LV ejection fraction >50 % probably do not need AVR but should undergo cardiac catheterization if they have symptoms of severe AS [40]. Patients with a peak jet velocity between 3.0 and 3.5 m/s and a LV ejection fraction <50 % may have severe AS, requiring AVR, and should undergo cardiac catheterization [40].

In patients with severe AS, the average survival rate was 3 years after onset of angina, 3 years after onset of syncope, and 1.5–2 years after the onset of CHF [32]. At the National Institutes of Health, 52 % of patients with symptomatic severe AS not operated on were dead at 5 years [32]. At 10-year follow-up, 90 % of these patients were dead. At 4-year follow-up of patients aged 75–86 years in the Helsinki Aging Study, cardiovascular mortality was 62 % in patients with severe AS and 35 % in patients with moderate AS [53]. At 4-year follow-up, total mortality was 76 % in patients with severe AS and 50 % with moderate AS [43].

In a prospective study, at 19-month follow-up (range 2–36 months), 90 % of 30 patients with CHF associated with unoperated severe AS and a normal LV ejection fraction were dead [34]. At 13-month follow-up (range 2–24 months), 100 % of 18 patients with CHF associated with unoperated severe AS and an abnormal LV ejection fraction were dead [34].

Table 57.3 shows the incidence of new coronary events in patients with no, mild, moderate, and severe AS. Independent risk factors for new coronary events in this study were prior MI, AS, male gender, and increasing age [31]. At 20-month follow-up of 40 patients with severe AS, CHF, syncope, or angina occurred in 36 of 37 patients (97 %) with new coronary events and in none of 3 patients (0 %) without new coronary events [31]. At 32-month follow-up of 96 patients with moderate AS, the symptoms of CHF, syncope, or angina occurred in 65 of 77 patients (84 %) with new coronary events and in 1 of 19 patients (5 %) without new coronary events [31]. At 52-month follow-up of 165 patients with mild AS, the symptoms of CHF, syncope, or angina occurred in 40 of 103 patients (39 %) with new coronary events and in 5 of 62 patients (8 %) without new coronary events [31].

In 981 patients with aortic sclerosis and 999 patients without aortic sclerosis, patients with aortic sclerosis had at 46-month follow-up a 1.8 times higher incidence of new coronary events than those without valvular aortic sclerosis [5]. In 5,621 men and women, AS and aortic sclerosis increased cardiovascular morbidity and mortality [44].

In 38 patients with symptomatic moderate AS and 28 patients with minimally symptomatic moderate AS, the probabilities of avoiding death from AS were 0.86 for patients and 1.0 for patients with minimally symptomatic moderate AS at 1-year follow-up, 0.77 for patients with symptomatic AS and 1.0 for patients with minimally symptomatic AS at 2 years, 0.77 for patients with symptomatic AS and 0.96 for patients with minimally symptomatic AS at 3 years, and 0.70 for patients with symptomatic AS and 0.90 for patients with minimally symptomatic AS at 4 years [45]. During 35-month follow-up, 21 patients had AVR.

At 5-year follow-up of 106 patients with unoperated AS, 60 (57 %) died [46]. Multivariate analysis showed that severity of AS, CAD, and CHF were important predictors of survival in unoperated patients. Some studies have shown that patients with asymptomatic severe AS are at low risk for death and can be followed until symptoms develop [47, 48].

Rosenheck et al. [49] followed 126 patients with asymptomatic severe AS for 22 months. Eight patients died and 59 patients developed symptoms necessitating AVR. Event-free survival was 67 % at 1 year, 56 % at 2 years, and 33 % at 4 years. Five of six deaths from cardiac disease were preceded by symptoms. Of patients with moderately or severely calcified aortic valves whose aortic jet velocity increased by 0.3 m/s or more within 1 year, 79 % underwent AVR or died within 2 years of the observed increase.

When patients with low-gradient AS due to abnormal LV ejection fraction are considered for AVR, failure to respond to dobutamine and large preoperative LV end-systolic and end-diastolic volumes are poor prognostic signs [50, 51]. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines state that dobutamine stress echocardiography is reasonable to evaluate patients with low-flow/low-gradient AS and abnormal LV ejection fraction [52], to determine the transvalvular pressure gradient, and to calculate valve area (following dobutamine infusion and during a baseline state) with the goal of assessing whether stenosis is severe or only moderate in severity.

Prophylactic antibiotics are not recommended to prevent bacterial endocarditis in patients with AS regardless of severity [53]. Patients with CHF, exertional syncope, or angina associated with moderate or severe AS should undergo AVR promptly. Medical therapy does not relieve the mechanical obstruction to LV outflow and does not relieve symptoms or progression of the disorder. Patients with asymptomatic AS should report symptoms possibly related to AS immediately to their physician. If significant AS is present in asymptomatic patients, clinical examination, an electrocardiogram, and Doppler echocardiogram should be performed at 6-month intervals. Nitrates should be used cautiously in patients with angina to prevent orthostatic hypotension and syncope. Diuretics should be used cautiously in patients with CHF to prevent decrease in cardiac output and hypotension. Vasodilators should be avoided. Digitalis should not be used in patients with CHF and normal LV ejection fraction unless needed to control a rapid ventricular rate associated with AF.

Table 57.4 lists four Class I indications and one Class II_a indication for performing AVR in patients with AS [52]. Although the ACC/AHA guidelines do not recommend AVR in patients with asymptomatic severe AS and normal LV ejection fraction, there are data suggesting otherwise [54–58]. Ninety-nine of 338 patients (29 %) with asymptomatic severe AS had AVR during 3.5-year follow-up. Survival at 1, 2, and 5 years was 67, 56, and 38 %, respectively, for unoperated patients and 94, 93, and 90 %, respectively, for those with AVR [54]. In unoperated patients, beta-blocker use reduced mortality by 48 %, and statins use reduced mortality by 48 % [54] (Chap.​ 54).

Of 622 patients with asymptomatic severe AS, 166 (27 %) developed symptoms and had AVR [55]. Another 97 patients (16 %) had AVR in absence of symptoms. At 3-year follow-up, 52 % of 622 patients had developed symptoms, underwent AVR, or died. The most important risk factor for 10-year mortality was absence of AVR (hazard ratio = 3.53, p < 0.001) [55].

Of 197 patients with asymptomatic severe AS, early AVR was performed in 102 patients (52 %) [56]. The estimated actuarial 6-year all-cause mortality rates were 2 % for AVR and 32 % for the conventional treatment group [56]. Despite being asymptomatic, patients with very severe AS have a poor prognosis [57]. Early elective AVR should be considered in these patients [57]. Of 73 patients with severe AS who did not undergo AVR, 15 (14 %) died at 15-month follow-up [58]. Of these 73 patients, symptoms were thought to be unrelated to the AS in 31 patients. Exercise stress tests for symptoms were performed in only 4 % of 42 asymptomatic patients [58].

Asymptomatic patients with low-gradient severe AS and normal LV ejection fraction with reduced stroke volume index had at 46-month follow-up aortic valve events similar to those with normal stroke volume index [59]. Of 248 patients with severe AS and a normal LV ejection fraction, 94 had a low gradient (<30 mmHg mean gradient) (group 1), 87 had a moderate gradient (30–40 mmHg mean gradient) (group 2), and 67 had a severe gradient (>40 mmHg mean gradient) (group 3) [60]. Symptoms were present in 49 % of group 1 patients, in 55 % of group 2 patients, and in 60 % of group 3 patients. At 45–60-month follow-up, the incidence of AVR or death was 71 % for group 1, 77 % for group 2, and 76 % for group 3. Kaplan-Meier survival curves for time to death in all three groups were significantly better for patients with AVR versus no AVR [60]. E/E¹ _lateral was an independent predictor of time to death in patients who did not receive AVR [61].

Echocardiography is recommended in asymptomatic patients with AS every 1 year for severe AS, every 1–2 years for moderate AS, and every 3–5 years for mild AS [52]. Echocardiography should be repeated more frequently if there are changes in symptoms or LV function.

The bioprosthesis has less structural failure in elderly patients than in younger patients and may be preferable to the mechanical prosthetic valve for AS replacement in the elderly due to the anticoagulation issue [62, 63]. Patients with mechanical prostheses need anticoagulant therapy indefinitely. Patients with porcine bioprostheses may be treated with aspirin in a dose of 75–100 mg daily unless the patient has AF, abnormal LV ejection fraction, previous thromboembolism, or a hypercoagulable condition [52, 63]. Table 57.5 lists four Class I indications and two Class II_a indications for antithrombotic therapy in patients with AVR [52]. Follow-up was performed at 12.6 years in patients aged 65–80 years undergoing AVR with a biological (24,410 patients) or mechanical (14,789 patients) prosthesis [64]. Long-term mortality was similar for both prostheses (hazard ratio (HR) = 1.06). Bioprostheses had a higher risk of reoperation (HR = 2.55) and endocarditis (HR = 1.6) but lower risk of stroke (HR = 0.87) and hemorrhage (HR = 0.66) [64].

A United Kingdom heart valve registry of 1,100 patients aged ≥80 years (56 % women) who underwent AVR showed that the 30-day mortality was 6.6 % [65]. The actuarial survival was 89 % at 1 year, 79 % at 3 years, 69 % at 5 years, and 46 % at 8 years. Survival of patients with severe AS, a LV ejection fraction <35 %, and a low transvalvular gradient at 1 year and 4 years was 82 and 78 %, respectively, in 39 patients who underwent AVR versus 41 and 15 %, respectively, in 56 patients in a control group [66]. In 242 patients, mean age 83 years, with AS who had AVR, actuarial survival was 92 % at 1 year and 66 % at 5 years [67]. Concomitant CABGS did not affect late survival [67].

Paroxysmal or chronic AF is a risk factor for mortality in patients with severe AS and a LV ejection fraction ≤35 % undergoing AVR [68]. AVR is associated with a reduction in LV mass and in improvement of LV diastolic filling [69]. At 41-month follow-up of 100 patients with AVR, the yearly cardiac mortality rate was 8 % in patients with electrocardiographic LV hypertrophy and repetitive ventricular premature complexes ≥2 couplets per 24 h during 24-h ambulatory monitoring compared to 0.6 % in patients without either of these findings [70].

If LV systolic dysfunction in patients with severe AS is associated with critical narrowing of the aortic valve rather than myocardial fibrosis, it often improves after successful aortic valve replacement [71]. In 154 patients with AS and a LV ejection fraction ≤35 % who underwent AVR, the 30-day mortality was 9 %. The 5-year survival was 69 % in patients without significant CAD and 39 % in patients with significant CAD. NYHA functional class III or IV was present in 58 % of patients before surgery versus 7 % of patients after surgery. Postoperative LV ejection fraction was measured in 76 % of survivors at a mean of 14 months after surgery. Improvement in LV ejection fraction was found in 76 % of patients [71].

AVR is the procedure of choice for symptomatic elderly patients with severe AS. The actuarial survival of 50 elderly patients with symptomatic severe AS in whom AVR was refused (45 patients) or deferred (5 patients) was 57 % at 1 year, 37 % at 2 years, and 25 % at 3 years [72]. On the basis of the available data, balloon aortic valvuloplasty should be considered for elderly patients with symptomatic severe AS who are not candidates for AVR or transcatheter aortic valve implantation (TAVI) and possibly for patients with severe LV dysfunction as a bridge to subsequent valve surgery [73, 74].

The United Kingdom Transcatheter Aortic Valve Implantation (TAVI) Registry followed prospectively 870 high-risk patients, mean age 82 years, with severe AS undergoing 877 TAVI procedures [75]. Survival was 92.9 % at 30 days, 78.6 % at 1 year, and 73.7 % at 2 years [75].

Of 442 patients with severe AS at increased surgical risk, mean age 82 years, 78 were treated with medical management, 107 with AVR, and 257 with TAVI [76]. At 30-month follow-up, mortality was 49 % lower for AVR compared with medical treatment and 62 % lower for TAVI compared with medical treatment. At 1 year, 92.3 % of AVR patients, 93.2 % of TAVI patients, and 70.8 % of medically treated patients were NYHA functional class I or II [76].

In the Placement of Aortic Transcatheter Valve (PARTNER) trial, 699 high-risk patients with severe AS, mean age 84 years, were randomized to AVR or TAVI [77]. All-cause mortality was 3.4 % for the TAVI group versus 6.5 % for the AVR group at 30 days and 24.2 % for the TAVI group versus 26.8 % for the AVR group at 1 year. Major stroke was 3.8 % for the TAVI group versus 2.1 % for the AVR group at 30 days and 5.1 % for the TAVI group versus 2.4 % for the AVR group at 1 year. Major vascular complications at 30 days were 11.0 % for the TAVI group versus 3.2 % for the AVR group. At 1 year, there were similar improvements in cardiac symptoms for both groups [77]. In the PARTNER trial, among inoperable patients with severe AS, compared with standard care, TAVI caused improvements in health-related quality of life maintained for at least 1 year [78]. At 2-year follow-up of 699 patients in the PARTNER trial, all-cause mortality was 33.9 % for TAVI and 35.0 % for AVR [79]. Stroke was 7.7 % for TAVI and 4.9 % for AVR. Moderate or severe paravalvular aortic regurgitation (AR) was 6.9 % for TAVI and 0.9 % for AVR and was associated with increased late mortality [79].

At 2-year follow-up of 180 patients, mean age 84 years, with low-flow inoperable severe AS in the PARTNER trial, mortality was 76 % in the standard therapy group versus 46 % for TAVI [80]. At 2-year follow-up of 350 patients, mean age 84 years, with low-flow inoperable severe AS in the PARTNER trial, mortality was 40 % for AVR versus 38 % for TAVI [80]. At 2-year follow-up of the inoperable group in the PARTNER trial, mortality in patients with a normal stroke volume index was 38 % for TAVI versus 53 % for medical management [80].

One-third of 270 patients undergoing a CoreValve TAVI needed a permanent pacemaker implanted within 30 days [81]. In 138 patients undergoing TAVI, mean age 79 years, with no prior history of AF, new-onset AF developed in 44 patients (32 %) at a median time of 48 h after TAVI [82]. A modified procedure of transapical TAVI with a balloon-expandable prosthesis was associated with a low incidence of relevant prosthetic regurgitation [83].

At 42-month follow-up of 339 patients, mean age 81 years, who had TAVI because they were considered to be inoperable or at very high surgical risk, 188 (56 %) had died [84]. The causes of late death in 152 patients were noncardiac comorbidities in 59 %, cardiac death in 23 %, and unknown in 18 % [84]. TAVI results in similar hemodynamic and long-term clinical outcomes for high-risk surgical patients with low-gradient severe AS and for those with typical severe AS [85].

In the United States, the Society of Thoracic Surgeons (STS)/ACC Transcatheter Valve Therapy Registry showed that 7,710 patients underwent TAVR (20 % who were inoperable and 80 % who were high-risk but operable) [86]. The median age was 84 years, 49 % were women, and the median STS predicted risk of mortality was 7 %. A transfemoral approach was performed in 64 % of patients, a transapical approach in 29 % of patients, and other alternative approaches in 7 % of patients. Inhospital mortality was 5.5 % and major vascular injury was 6.4 %. At 30-days follow-up, the incidence of mortality was 7.6 % (52 % due to a noncardiovascular cause), stroke was 2.8 %, dialysis-dependent renal failure was 2.8 %, and re-intervention was 0.5 % [86].

The 2012 ACCF/American Association for Thoracic Surgery/Society for Cardiovascular Angiography and Interventions/STS expert consensus document on transcatheter aortic valve replacement recommended TAVI in patients with severe, symptomatic, calcific stenosis of a trileaflet aortic valve who have aortic and vascular anatomy suitable for TAVR and a predicted survival greater than 1 year and who have a prohibitive surgical risk as defined by an estimated 50 % or greater risk of mortality or irreversible morbidity at 30 days or other factors such as frailty, prior radiation therapy, porcelain aorta, and severe hepatic or pulmonary disease [87]. These guidelines also state that TAVR is a reasonable alternative to AVR in patients at high surgical risk (PARTNER Trial Criteria: STS ≥8 %), with the major complications from TAVR being mortality (3–5 %), stroke (6–7 %), access complications (17 %), pacemaker insertion (2–9 % for Sapien and 19–43 % for CoreValve), bleeding, prosthetic dysfunction, paravalvular aortic regurgitation, acute kidney injury, coronary occlusion, valve embolization, and aortic rupture [87].

On the basis of the available data, AVR should be performed in operable patients with severe AS. TAVI should be performed in nonoperable patients with symptomatic severe AS to improve survival and quality of life compared with medical management.

After TAVI, treatment with clopidogrel for 3 months in addition to aspirin is widely practiced. However, a study of 161 patients randomized to clopidogrel for 3 months (a loading dose of 300 mg on the day before TAVI followed by 75 mg daily) plus aspirin 100 mg daily or aspirin 100 mg daily alone showed no difference in major adverse cardiac and cerebrovascular events at 30 days and at 6 months [88]. These data need confirmation by a larger study.