Symptomatic Severe Aortic Stenosis

Abstract

This chapter is intended for cardiologists and all health care professionals involved in the evaluation, diagnosis, or management of patients with severe symptomatic aortic stenosis (AS). Risk factors, etiology, pathophysiological changes, symptoms due to severe AS, diagnosis, and natural history of severe symptomatic AS are discussed. The management of patients with aortic valve disease is constantly evolving by innovations in imaging and transcatheter and surgical implanted devices. Guidelines, research studies, and clinical trials are continually expanding related to severe symptomatic AS. The role of basic and advanced imaging techniques in the assessment and management of patients with severe symptomatic AS is discussed. Options to assess accurately for treating difficult scenarios associated with severe symptomatic AS disease, including medical and transcatheter, and surgical risks factors are discussed. A review of the management of potential complications along with results in clinical practice is summarized. This chapter is designed with case-based severe symptomatic AS and critical decision-making for this condition.

1. Introduction

Symptomatic severe aortic stenosis (SAS) is the most common valvular heart disease. While rheumatic heart disease (RHD) remains the most frequent etiology in developing countries worldwide, degenerative aortic stenosis (AS) and congenital bicuspid valve defect are the two usual causes in developed countries. Symptomatic SAS gradually progresses to heart failure, producing exertional dyspnea, angina, and/or syncope. A crescendo-decrescendo systolic murmur is audible in the right upper sternal border. Doppler echocardiography is the imaging of choice, showing structural and flow changes in the valvular area. At the present time, symptomatic severe AS is the most common valve lesion requiring valve replacement as the only effective treatment. Indications for the procedure depend on the Heart Valve Team with structured collaboration between cardiology and cardiac surgery, and a careful individual assessment of the suitability and risks of transcatheter aortic valve implantation (TAVI) versus aortic valve replacement (AVR), the patient’s symptoms, degree of AS severity, exercise tolerance, concurrent cardiac abnormalities, comorbidities, surgical risk, and life expectancy.

1.1 Definition of symptomatic severe aortic stenosis

Aortic stenosis (AS) is defined as severe in the presence of narrowing of the aortic valve aperture; mean pressure gradient ≥40 mmHg, peak aortic velocity ≥4 m/s, and aortic valve area (AVA) ≤1 cm² (or an indexed AVA ≤0.6 cm²/m² for the body surface). Severe AS consequently causes varying degree of blood flow of the aortic valve aperture and produces left ventricular (LV) pressure overload with symptoms (syncope, angina, and heart failure) requiring valve replacement.

1.2 Epidemiology

Severe AS is a major cause of morbidity and mortality in the elderly. The number of cases will increase because of strong association between valvular disease and age [1, 2]. Men are more affected than women. Calcified aortic valve disease (CAVD) is the most common cause of aortic stenosis in the developed world. While up to 1.5 million people in the USA suffer from AS, approximately 500,000 within this group of patients suffer from severe AS. An estimated 250,000 patients with SAS are symptomatic. Aortic stenosis is the second most common valvular lesion in the USA. It is present in about 5% of the population at age 65. For people over the age of 75 years, the prevalence of SAS is 3%. Therefore, it is relatively uncommon in the age group 65 and under in the absence of a congenital abnormality.

A meta-analysis of predominantly older studies conducted in Europe, the USA, and Taiwan found a population prevalence of AS of 12.4% and a prevalence of 3.4% of SAS in those aged 75 years and older [3]. More recent studies have shown relatively similar figures, with 4.3% in an Icelandic cohort aged ≥70 having SAS [4].

Other studies have reported that up to 33% of patients with aortic sclerosis developed AS within 4 years of follow-up [2]. In addition, aortic valve sclerosis is frequently associated with other comorbidities increasing the risk of myocardial infarction or cardiovascular death by 50%. As such, aortic valve disease has a serious impact on general health.

The burden of rheumatic heart disease (RHD) falls disproportionately on low-income countries and in low-income groups in high-income countries and is vastly different in different continents.

Congenital bicuspid aortic valve (BAV) is the most common form of congenial heart valve defect, being found in approximately 0.5–0.8% of the population, and is present in the third to fifth decade of life [2]. In general, women are also more likely to have smaller annular sizes and left ventricular outflow tract (LVOT) dimensions associated with concentric LV hypertrophy. In addition, women have demonstrated a higher prevalence of paradox low-flow/low-gradient AS, which has been associated with poor outcomes and worse mortality compared with high gradient AS [5].

1.3 Etiology of symptomatic SAS

Congenitally affected valve may already be stenotic at birth. The valve may be unicuspid, bicuspid, and tricuspid. BAV is most common congenial heart valve defect and may be presented with other cardiac abnormalities—coarctation of the aorta.

Acquired

1. Secondary to rheumatic inflammation of the aortic valve and often associated with mitral stenosis.

2. Degenerative calcification of the aortic cusps of unknown cause (autoimmune/degenerative) [6].

3. Other rare cases: obstructive infected vegetation, irradiation, Homozygotus type II hyperlipidemia, Paget’s disease of bone, systemic lupus erythematosus, rheumatoid involvement, and ochronosis (alkaptonuria).

Calcific degenerative AS is the common cause of left ventricular outflow tract obstruction in adult >70 years in developed countries, and risk factors for that are systemic arterial hypertension, diabetes, smoking, end-stage kidney disease, and disturbances in mineral metabolism. Natural history and prognosis of SAS is a progressive disease, and the severity increases over time. The factors that control this progression to develop severe outflow tract obstruction are unknown; it appears that in older patients, AS may progress at about twice the rate that it does in younger patients.

1.4 Pathology

The most frequent BAV phenotypes were type 1 (left–right coronary cusps fusion 64%) and type 1 (right-noncoronary cusps fusion 17%). In congenitally abnormal tricuspid aortic valve, the cusps are of unequal size and have some degree of commissural fusion; the third cusp may be unusually small. Congenital valve defect produces severe obstruction to LV outflow as well as turbulent flow, which traumatizes the leaflets and eventually leads to fibrosis, rigidity, and calcification of the valve within first few years of life. Patients with BAV have an increased incidence of aortic root dilatation (25–40% of patients) and aortic dissection.

In calcific AS (autoimmune/degenerative), early changes show chronic inflammatory cell infiltrate, lipid in lesion, and thickening of fibrosa with collagen and elastin. In severe forms of hypercholesterolemia, lipid deposits occur not only in the aortic wall but also in the aortic ring and incoherently produces AS. Subclinical calcific emboli are commonly found in calcific AS.

Rheumatic AS results from adhesions and fusion of the commissures and cusps. The leaflets and the valve ring become vascularized leading to postinflammatory fibrosis and stiffening of the cups. The valve is usually calcified, and the aortic valve orifice is reduced to a small opening, which is frequently regurgitant as well as stenotic.

The LV is concentrically hypertrophied, and muscle cells are increased in size. There is an increase of connective tissue and proliferation of fibroblasts and collagen fibers in the interstitial space.

1.5 Pathophysiology

With reduction in the aortic valve area (AVA), the primary hemodynamic abnormality is obstruction to LV outflow, which causes a systolic pressure gradient between the LV and aorta. A measurable pressure gradient between the LV and the ascending aorta can be present when the aortic valve area is reduced by 50% of normal [7, 8]. While LV pressure and wall stress increases, aortic pressure remains within the normal range until end-stage heart failure occurs. The heart normalizes wall stress by becoming hypertrophic, which develops slowly in proportion to increased LV pressure as a compensatory mechanism to the aortic valve orifice narrowing obstruction.

Diastolic properties of the LV in AS are affected [9, 10]. This diastolic abnormality results from a combination of impaired myocardial relaxation with altered chamber compliance and myocardial stiffness (structural alteration) causing increased resistance to filling.

LV systolic function measured by ejection fraction (EF) is determined by myocardium and by a combination of LV preload and afterload. As the LV afterload continues to increase, the LV uses two additional compensatory mechanisms, namely, increase of preload and increase of myocardial contractility. Both of these help maintain normal LV systolic function. Preload is not a good compensatory mechanism. Even small increases in LV volume may result increases in LV end-diastolic pressure and the corresponding increase in mean left atrial pressure, which produces pulmonary edema. When the limit of the preload reserve has been reached, and afterload mismatch or myocardial contractility is reduced, LV systolic function becomes abnormal. Clinical heart failure in those with normal LV systolic function is usually a result of LV diastolic dysfunction. The necessary LV filling to achieve an adequate stroke volume are achieved by atrial systole, which occupies only a small part of the cardiac cycle. Mean atrial pressure remains normal or is only minimally increased because of transient increase in left atrial pressure due to large a wave. Left atrial contraction has considerable benefit and loss of effective; booster atrial contraction because of any reasons results in elevations of mean atrial pressure, reduction of cardiac output, or both and may precipitate heart failure with pulmonary congestion.

In most patients, severity of AS progressively increases, and the cardiac output remains within the normal range at rest, but on exercise, it no longer increases in proportion to the exercise or does not increase at all. With the development of heart failure, there is reduction in the resting cardiac output. Stroke volume may be so lowered that it results in a small gradient across the LV outflow tract in spite of SAS [11]. At equal area of AV, as the patient’s age increases, there is a progressive decrease of cardiac output with exercise and a progressive increase of LV end-diastolic pressure.

Increased myocardial oxygen needs in SAS due to hypertrophy, elevations in LV pressure, and prolongation of systolic ejection time; total coronary blood flow is increased, while coronary blood flow per 100 g of LV mass is reduced. Coronary blood flow to the subendocardium is inadequate because of reduced coronary perfusion pressure and also because hypertrophied myocardium compresses coronary arteries as they traverse the myocardium from the epicardium to the endocardium [12]. Coronary vasodilatator reserve ability is also significantly reduced. These patients may have angina pectoris even in the absence of coronary artery disease (CAD). If associated with coronary artery disease (CAD), which is not uncommon in AS, this further increases the imbalance between myocardial oxygen needs and supply.

1.6 History

Most patients with severe AS are asymptomatic. The classic triad symptoms of SAS are angina pectoris, dyspnea (on exertion, paroxysmal nocturnal dyspnea, ortopnea and pulmonary edema), and exertional presyncope or syncope. Later, the other clinical manifestations of low cardiac output symptoms of heart failure are present. Once symptoms occur in a patient with SAS without surgical treatment, the life span of the patient is very short. Typical angina pectoris occurs with or without associated CAD.

Syncope from AS is the result of reduced cerebral perfusion caused by either systemic vasodilatation under the settings of obstruction with fixed cardiac output leading to hypotension or the presence of inadequate cardiac output, an arrhythmia, or both. Nitroglycerin-induced syncope as a possible etiology of AS has to be considered.

There is an increased incidence of gastrointestinal arteriovenous malformations (Heyde syndrome) [13]. As a result, these patients are susceptible to gastrointestinal hemorrhage and anemia. Rarely, calcific systemic embolism to various organs may occur.

Patient with rheumatic AS may have a history of rheumatic fever, and those with congenital AS may give a history of a murmur since infancy.

1.7 Physical findings

Depending on the severity of AS, LV function, stroke volume, and the rigidity and calcification of the valve, there is a spectrum of physical findings in patients. The systemic arterial pressure is usually within normal limits, and the pulse pressure is narrowed. Arterial pulse is low-amplitude parvus and delayed tardus. In elderly patients with SAS, systemic arterial hypertension is common being present in about 20% of patients, half of whom have moderate or severe systolic and diastolic hypertension with the vide pulse pressure. However, a systolic blood pressure higher than 200 mmHg is rare. Hyperdynamic left ventricle—the apex beat—is usually active and displaced laterally, reflecting the presence of LV hypertrophy. A systolic thrill is generally present at the base of the heart and is palpable during expiration with the patient leaning forward. The rhythm is generally regular until very late. Atrial fibrillation suggests the possibility of associated mitral valve disease. 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 cause paradoxical splitting of the second heart sound (S2). Frequently, as a result from forceful atrial contraction, fourth heart sound (S4) is audible at the apex in many patients with SAS and reflects the presence of LV hypertrophy and an elevated LV end-diastolic pressure. A third heart sound (S3) generally occurs when the LV dilates and fails. The systolic ejection murmur, which begins shortly after first heart sound (S1), increases in intensity to reach the peak toward the middle of ejection and ends just before aortic valve closure (crescendo-decrescendo murmur between S1 and S2), loudest at the base of the heart in the second right intercostat space, transmitted upward along carotid arteries. In elderly, occasional downward radiation of AS murmur to the cardiac apex (Gallavardin phenomenon) may be confused with mitral regurgitation murmur. In almost all the patients with severe AS, the murmur is at least grade III/VI. In patients with severe AS and heart failure with decreased stroke volume, murmur may be relatively soft and brief. Ejection clicks, which are rare in elderly patients with acquired AS, may be confused with split S1. The murmur intensity is reduced during the provocative maneuvers (Valsava strain and squatting) or following premature beat can increase murmur.

1.8 Electrocardiogram

An electrocardiogram (ECG) reveals LV hypertrophy in the majority of patients (85%) with severe AS. There is no close correlation between electrocardiographic signs of LV hypertrophy, and the absence of these signs does not exclude severe obstruction. In fact, the ECG may be entirely normal in some of these patients. In advanced cases, P wave abnormality—left atrial enlargement, ST segment depression, and T wave inversion in standard leads I and aVL and in the left precordial leads are evident. ST depression exceeding 0.3 mV in patients with AS indicates LV strain and suggests severe LV hypertrophy, and septal pseudoinfarct pattern can be seen. Atrial fibrillation can be seen at late stages or as a consequence of coexistent mitral valve disease or hyperthyreosis.

The ECG may show different bundle branch block and axis deviation (in 10% of all cases). In some patients, the conduction abnormality results from aortic valve calcification extending into the specialized conducting tissue, which may even produce heart block (in 5% of cases). Serial ECGs performed over time (months to years) can be valuable in demonstrating the progression of the disease.

Ambulantory ECG recording frequently shows complex ventricular arrhythmias, particularly in cases with myocardial dysfunction, and may be needed in patient suspected or having an arrhythmia or painless ischemia.

2. Investigational imaging modalities

It is clinically validated that the volume quantification of aortic valve calcification using multislice computed tomography (CT) scanning demonstrates a close, nonlinear relationship to echocardiographic parameters for the severity of AS [14].

Cardiac magnetic resonance imaging (MRI) is not yet validated clinically but has been used for the assessment of AS. AVA measurements made with cardiac MRI have shown excellent correlation with those made by Doppler echocardiography.

2.1 B-type natriuretic peptide

B-type natriuretic peptide (BNP) may provide incremental prognostic information in predicting symptom onset in patients with AS [15]. A high or steadily rising BNP may predict the short-term need for valve replacement in SAS. Preoperative BNP provides prognostic information on postoperative outcome [14]. In evaluating data from a Japanese multicenter registry comprising 3815 patients with severe AS, it was found that increased BNP levels were associated with a greater risk for AS-related adverse event (aortic valve-related death or heart failure hospitalization) in these patients [15, 16, 17].

2.2 Chest X-ray

Even in the presence of significant AS, the cardiac size often is normal. Severe valvular AS in later, more severe stages of the disease, as the LV dilates, there is increasing evidence of left ventricular enlargement. The radiographic sings of pulmonary congestion and redistribution of blood flow with left atrial enlargement may be evident. Aortic calcification is often associated with the poststenotic dilatation of the ascending aorta.

2.3 Transthoracic echocardiography

Transthoracic echocardiography (TTE) using two-dimensional (2D) imaging, color flow mapping, and spectral Doppler are important and well-established methods for the primary assessment of aortic valve disease. It relies on three parameters, namely, the peak velocity (PVeI), the mean pressure gradient (MPG), and the aortic valve area (AVA). Error measurement may occur in all three. These parameters should be concordant with SAS being defined by a PVel >4 m/s, an MPG >40 mmHg, and an AVA <1 cm² (Figure 1). Discordant grading is defined based upon the observation that one parameter suggests a moderate AS, while the other suggests an SAS. The measurement of LV outflow tract (LVOT) diameter is the main source of error for the calculation of the AVA and, if below 1 cm², should be adjusted for body surface area (BSA). Discordant grading is still between 20% and 30%, thus representing a common clinical problem. The most appropriate way of classifying patients is first to consider whether AVA and MPG are concordant and second to consider the flow (stroke volume index—SVI). Thus, among patients with an AVA below 1 cm² (and preserved ejection fraction), four groups can be identified according to MPG and stroke volume index (SVI) proposed threshold of 35 ml/m², which is now widely accepted (see Table 1) [18].

Figure 1.

Severe calcific AS (TTE).

High flow/high gradient; MPG > 40 mmHg; SIV ≥ 35 ml/m^2	Low flow/high gradient; MPG > 40 mmHg; SVI < 35 ml/m^2
High flow/low gradient; MPG ≥ 40 mmHg; SVI ≥ 35 ml/m^2	Low flow/low gradient; MPG < 40 mmHg; SVI < 35 ml/m^2

Table 1.

Four groups according to MPG and stroke volume index (SVI) for AVA below 1 cm² with preserved EF.

Among 1704 patients with a valve area below 1 cm², 24% presented with discordant grading (AVA < 1 cm² and MPG < 40 mmHg). In the vast majority, the flow was normal, while low flow was observed in only 3%. Patients with discordant grading and a low flow had the worst prognosis. The flow is a prognostic factor, whatever the reason or the cause of the depressed flow. One main debate of recent years in the domain of valvular heart disease has indeed been whether the patients with discordant grading should be managed according to the valve area (thus as SAS) or according to MPG (usually moderate AS). Flow consideration has added a supplementary level of confusion. As resting echocardiography is inconclusive, it requires the use of additional methods. With the use of computed tomography in the workup evaluation before TAVI, the anatomy of the aortic annulus has been well described. The measurement of LVOT diameter is a main source of error for the calculation of the AVA; some have suggested combining CT and echocardiography. Calcium scoring is a reliable flow-independent method for the assessment of AS severity. Aortic valve calcification is the leading process of AS [19]. The degree of aortic valve calcification can be quantitatively and accurately assessed in vivo using computed tomography [20]. Agaston calcium scoring is highly correlated with echocardiographic hemodynamic severity and has validated its diagnostic value for the diagnosis of SAS. For the same degree of aortic valve calcification, females experienced a higher hemodynamic obstruction. Thresholds are different in males and females (approximately 2000 and 1250 AU, respectively), because pathophysiology is different in males and females; female leaflets are more fibrotic than those of males [21]. Calcium scoring measurements and the thresholds have recently been implemented in the latest version of the ESC/EACTS guidelines on valvular disease [22]. In the case of discordant grading, calcium scoring should be performed as the first-line test. If the diagnosis of SAS is established (and if the patient is symptomatic), intervention should be promptly considered. Threshold numbers provide a probability of having or not having SAS. Thus, a woman with a score of 3000 is very likely to present with SAS, whereas a man with a score of 700 is very unlikely to present with SAS. Discordant grading is common in clinical practice, and the first step is to look for error measurements and adjusted for BSA. Among patients with discordant grading (AVA < 1 cm² and MPG < 40 mmHg), those with low flow are much less frequent than those with normal flow. Flow does not provide any diagnostic information regarding AS severity, but provides prognostic information. In most cases of discordant grading, echocardiography alone cannot differentiate a true SAS that generally benefits from AVR versus a pseudosevere AS that should be managed conservatively. This is why some have suggested combining aortic valve calcium scoring as a quantitative and flow-independent method of assessing AS severity. In many patients, the severity of AS is incorrectly estimated by M-mode or 2D echocardiography. Echo/Doppler, when properly applied, is extremely useful for estimating the valve gradient and AVA noninvasively; compared with results obtained at cardiac catheterization, the standard error of the estimate of mean gradient in the best laboratories is 10 mmHg [23, 24]. Guidelines for assessing the severity of AS based on Doppler-obtained gradient are with normal cardiac output and normal heart rate.

Transesophageal echocardiography (TOE) is performed in moderate or severe aortic valve disease when adequate examination cannot be obtained with TTE technique and has suboptimal image quality to estimate valve disease severity. LVOT diameter can be measured from multiple mid-esophageal views with greater precision. TOE also plays important roles in the intraoperative evaluation and guidance of aortic valve procedures. Immediately before and after cardiac surgery, the velocities and gradients across native or prosthetic aortic valve can be interrogated. According to a prospective study, 51 patients in detecting BAV had a sensitivity of 95.5% and a specificity of 96.5%. TOE remains an alternative strategy, especially when CT is contraindicated (Figures 2 and 3).

Figure 2.

Bicuspid aortic valve (TOE).

Figure 3.

Bicuspid aortic valve area.

3D TTE allows the confirmation of AS etiology, such as calcific/degenerative or rheumatic, and clarifies both the location and the extent of these pathologies. 3D TTE has high reproducibility and agreement with TOE, although this correlation is in part dependent upon the quality of 2D TOE views. In addition, 3D is especially helpful in measuring the dimensions of the LVOT, which is the major potential source of error.

Cardiac CT assessment is particularly useful when echocardiographic findings are conflicting and is part of the AS diagnosis algorithm in guidelines. Furthermore, CT is now considered mandatory in the preprocedural evaluation of TAVR, the preferred modality for the evaluation of aortic annulus size and shape, number of cusps, degree of calcification, coronary ostia height from annulus, atherosclerotic burden, and aortic dimensions (for prosthesis sizing).

2.4 Cardiac catheterization—angiography

In general, cardiac catheterization is not necessary to determine the severity of AS. Catheterization of the left-side heart and coronarography for further hemodynamic assessment should generally be carried out when clinical findings are not consistent with echocardiography results. Cardiac catheterization remains the gold standard technique to assess accurately the severity of AS by measuring simultaneous LV and ascending aortic pressures and measuring cardiac output by either technique.

Selective angiography, coronarography, is gold standard for the presence of CAD, and its site and severity can be estimated. This should be performed in all patients older than 35 years who are being considered for valve surgery. Coronary angiography should also be performed in patients younger than 35 years if they have symptoms or signs suggesting CAD or having two or more risk factors for premature CAD, excluding gender. Generally, in patients with AS who are older than 50 years, CAD was reported to be 50%. In young patient coronary, arteriography need not to be performed with no atherosclerotic risk factors and in circumstances where the risk involved outweighs the benefits.

Radionuclide studies to evaluate myocardial perfusion at rest and exercise may be considered as a part of the complete workup of aortic stenosis. Radionuclide ventriculography may provide information on LV function, including left ventricular ejection fraction (LVEF), end-systolic valium (ESV), and end-diastolic valium (EDV).

Exercise stress testing in symptomatic SAS patients may precipitate ventricular tachyarrhythmias and ventricular fibrillation. It is contraindicated, but, occasionally, closely monitored exercise test may be needed to assess exercise capacity in a patient with severe AS who denies all symptoms.

Calculated AVA on echo/Doppler ultrasound may be very small because of severe stenosis or because the small stroke volume only opens the valve to a limited extent. The infusion of an inotropic agent, such as dobutamine, which results in an increase of stroke volume and heart rate, is usually helpful to make a correct diagnosis. When dobutamine infusion gradient increases in SAS, the AVA does not increase or increases minimally, few percent. Cardiac output and LV and aortic pressures are measured simultaneously, and AVA is calculated before and during dobutamin infusion.

2.5 Management

A number of steps are involved in clinical decision-making for patients with symptomatic severe AS. The first is a complete clinical evaluation. Next is the disease of all cardiac vales, ventricular function, and hemodynamic effects, as well as CAD. Other organs disease should be diagnosed and the severity assessed. The following criteria should be kept in mind: accuracy, reliability, lowest risk to patient, and reasonable cost. The duration of the asymptomatic period after the development SAS is unknown.

In severe AS patients with the symptoms, the average life expectancy is 2–3 years with heart failure and almost all patients are dead in 1–2 years, and the combination of symptoms is much more a sign of greatly reduced survival. The exact incidence of sudden death is difficult to determine but may be nearly 5%.

All the patients with symptomatic SAS need careful periodic follow-up. In patients with SAS, heavy physical activity should be avoided even in the asymptomatic stage. In the treatment of congestive heart failure in SAS, sodium restriction, digitalis glycoside, and cautious administration of diuretics are indicated, but care must be taken to avoid volume depletion. Surgical aortic valve replacement (SAVR) should be advised for the patient with symptomatic SAS. Older patients and even young patients with calcified rigid valves need valve replacement. There is good outcome after surgery, particularly in patients without any comorbid conditions. Clearly, aortic valve replacement (AVR) is indicated for all the symptomatic patients will normal LV function as soon as possible, with LV dysfunction urgent and with heart failure emergent. The operative mortality of AVR in patients without associated CAD, heart failure, and other comorbid cases may be 1–2% in centers with experienced and skilled staff. There are no many prospective randomized trials of AVR in SAS. Two studies have compared the results of AVR with medical treatment during the same time period in a symptomatic patient with normal LV systolic pump function. Patients who had valve replacement had much better survival than those treated medically [25]. These differences in survival between those treated medically and surgically are so large that AVR significantly improves the survival of those with SAS [26, 27]. Patients with associated CAD should have coronary bypass surgery at the same time as valve surgery because it results in a lower operative and late mortality risk. Postoperatively, LV hypertrophy regresses toward normal after 2 years; the regression continues at a slower rate for up to 10 years after AVR.

Percutaneous balloon aortic valvuloplasty may be performed as a palliative, emergency measure in critically ill adult patients who are not surgical candidates or as a bridge to AVR in critically ill patients. Best results from valvuloplasty are obtained in the patients with a commissural BAV in whom 60–70% reduction in gradient and 60% increase in the AVA can be expected. Calcific AS has leaflet fusion, but the problem in acquired calcific AS is due more to the rigidity of the valve leaflets. In this latter group of patients, balloon valvuloplasty fractures leaflet calcium and temporarily expands the aortic annulus. This procedure in acquired calcific AS increases the effective systolic valve area for 0.3 cm², which is small, but it does relieve symptoms at rest or during mild-to-moderate exertion in most patients with severe AS. Unfortunately, high incidences of valvular restenosis, up to 50%, within 1 year after balloon dilatation make this procedure temporary palliation. Mortality rate associated with the procedure is 3–7%. Another 6% develop serious complications, including perforation, myocardial infarction, and severe aortic regurgitation. Nevertheless, this procedure may be useful in patients who refuse surgery, in patients with heart failure who need an urgent, major noncardiac surgical procedure, in patients with life-threatening AS and advanced extracardiac disease, and as a bridge to surgery in patients at risk for AVR with severe LV dysfunction.

In symptomatic SAS patient, the outlook, despite medical treatment, is very poor and can be improved significantly by AVR. If concomitant coronary disease is present, AVR and coronary artery bypass graft (CABG) should be performed simultaneously. The choice of prosthesis is determined by the expected longevity and by his/her ability to tolerate anticoagulation. In a prospective, randomized study of 310 patients aged 55–70 years, follow-up at 13 years showed that valve failures and reoperations were more frequent in the bioprosthetic group than in the mechanical prosthesis group. Bioprosthetic aortic valves were significantly less durable than mechanical valves. However, there were no differences between the two types of valves regarding the rate of survival and major adverse prosthesis-related events. The operative risk in this group of patients is relatively high 10%, which is considerably lower than the risk involved by nonoperative treatment. Operation should, if possible, be carried out before frank LV failure develops; at this late stage, the operative risk is high about 15–20%. Long-term postoperative survival correlates inversely with LV dysfunction and comorbiditis. Since many patients with symptomatic SAS are elderly, particular attention must be directed to the renal, hepatic, and pulmonary function before procedure is recommended.

2.6 Intervention for symptomatic severe aortic stenosis

Symptomatic SAS has a poor prognosis, and early intervention is recommended for severe high-gradient AS (mean transaortic gradient ≥40 mmHg or peak velocity ≥ 4 m/s, Class I recommendation) and severe low-flow, low-gradient AS (<40 mmHg) with reduced ejection fraction (EF) and either evidence of contractile reserve (Class I) or with SAS confirmed on CT calcium scoring (Class IIa).

Alain Criblier performed the first percutaneous transcatheter aortic valve implantation (TAVI) in 2004 as a great progress in the management of SAS. Many studies have demonstrated that this technique is noninferior to SAVR and superior to medical therapy in inoperable patients with symptomatic SAS. It is safer than SAVR in the elderly with symptomatic SAS, who are not suitable for SAVR as assessed by the Heart Team. According to the current guidelines, this is a class I recommendation of treatment.

In real life, there is a high rate of delayed TAVI intervention, as shown in Improve Outcomes in Aortic Stenosis (IMPULE) enhanced registry, which included 2171 participants with an established TAVI indication in symptomatic SAS from nine European countries of mean age 77.9 years, with 48% females. According to the recent guidelines, 24.8% of these patients did not receive TAVI or SAVR intervention within 3 months after the indication was made.

The best choice for intervention for SAS in an individual patient has become increasingly complex because of minimal access surgery, rapid-deployment valves, resilient valves, and later-generation TAVI devices.

The options for aortic valve intervention have become broader and need to be discussed by the multidisciplinary Aortic Heart Valve Team based within a heart valve center for the best approach according to the best available clinical evidence and the patient’s preference. The decision regarding the indication, timing, and modality of the surgical approach and prosthesis merits careful consideration.

Selected patients for aortic valve surgery, because of significant comorbidities, such as chronic obstructive airways disease, cerebrovascular disease, and renal disease, become more common in an aging population. In some patients, their symptoms and long-term prognosis are affected more by their comorbidities than by valvular diseases and make intervention unlikely (Class III recommendation). Coexisting cardiac or aortic pathology may require concomitant procedures [28].

The assessment of operative risk has been facilitated by scoring systems to estimate the risks of cardiac surgery, e.g., the Society for Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) and EuroSCORE II risk scoring systems [28, 29].

2.7 Choice of intervention modality in symptomatic severe AS

The evidence supporting the current recommendations is limited for TAVI in patients aged <75 years, and for low-risk patients, and there remain concerns about the durability of TAVI valves.

Several studies have been published on intermediate-risk patients (STS-PROM 4–8%) since the 2012 ESC/EACTS Valvular Heart Disease guidelines [30, 31, 32]. These have shown that TAVI is noninferior to AVR in intermediate-risk patients with respect to death and disabling stroke and even superior when transfemoral access is possible [30].

Patients treated with TAVI had higher rates of pacemaker implantation and moderate-to-severe paravalvular leak and lower rates of major bleeding, acute kidney injury, and new-onset atrial fibrillation compared with AVR. The 5-year outcomes of the PARTNER 2 study also show higher rates of complications in the TAVI group compared with surgery for at least mild paravalvular leak (33.3% versus 6.3%), rehospitalization (33.3% versus 25.2%), and aortic valve reintervention (3.2% versus 0.8%) [33].

The authors, similar to the results of earlier studies, patients treated with TAVI compared with AVR, conclude that TAVI may be the preferred option over AVR in low-risk patients with severe aortic stenosis who are candidates for bioprosthetic AVR.

Regarding the choice of intervention in symptomatic SAS, the current guidelines emphasize the role of the Heart Valve Team with structured collaboration between cardiology and cardiac surgery and a careful individual assessment of the suitability and risks of TAVI versus AVR (Class I). In general, AVR should be favored for patients with an STS-PROM score or EuroSCORE II <4% (logistic EuroSCORE I <10%) Class I).

Surgical AVR should also be favored in patients with associated cardiac conditions requiring concomitant surgery, e.g., complex severe coronary artery disease, severe primary mitral valve or tricuspid valve disease, ascending aortic aneurysm, and septal hypertrophy requiring myectomy.

Anatomical and technical considerations favoring surgery are unsuitable aortic root anatomy (low coronary height above the annulus and extreme annular diameter), valve morphology (bicuspid aortic valve and degree and pattern of calcification), and the presence of aortic or left ventricular thrombus.

TAVI is recommended for patients judged unsuitable for AVR by the Heart Valve Team (Class I), in particular, patients at higher surgical risk (STS-PROM score or EuroSCORE II ≥4% [logistic EuroSCORE I ≥10%]) or especially elderly patients with suitable access for transfemoral TAVI. Finally, balloon valvuloplasty may be considered as a bridge to surgery or TAVI in unstable patients (or in patients with symptomatic SAS needing urgent major noncardiac surgery) or diagnostically in patients with comorbidities to help to define the contribution of AS to symptoms or organ dysfunction (Class IIb) [34, 35, 36].

In a study including 3687 patients with SAS, Hermiller [29] showed that the 30-day and 1-year mortality after TAVI increases in the following conditions: Charlson comorbidity index score >5, STS-PROM score >7%, home oxygen use, serum albumin level less than 3.3 g/dl, age over 85, and falls in the last 6 months before TAVI. High-risk patients had a 1-year mortality rate of 36.6% compared to 12.3% in the low-risk group [31, 32].

Newer surgical approaches are minimally invasive surgical aortic valve replacement (MiAVR) and rapid-deployment AVR. MiAVR includes AVR through smaller incisions other than median sternotomy but still requiring cardiopulmonary bypass [37]. Preoperative CT imaging is required to ensure suitable anatomy.

Rapid-deployment or sutureless aortic valve prostheses are an evolution of standard bioprosthetic valves. During AVR, the diseased aortic valve is approached and excised; the valve prosthesis is implanted under direct vision without the need for circumferential sutures.

There are two rapid-deployment valves in clinical use. The Perceval (LivaNova, London, UK) is true sutureless, self-expanding a bovine pericardial valve; balloon may be used for full expansion within the annulus. The INTUITY valve is a bovine pericardial valve mounted within a balloon expandable; the valve is positioned with three guide sutures that are secured after deployment.

A recent meta-analysis has found that rapid-deployment valves allow shorter aortic cross-clamp and cardiopulmonary bypass times compared with standard bioprosthetic valves, but, similar to TAVI, there are higher rates of pacemaker implantation and paravalvular leak; there is no difference in early operative mortality [36]. Currently, rapid-deployment valves may be helpful for specific indication.

2.8 Resilient valves

The Inspiris Resilia bioprosthetic valve (Edwards Lifesciences) is the first in a new class of “resilient” valves designed for patients aged 60 years.

The leaflet tissue valve has been treated with a novel anticalcification treatment with the aim of achieving longer durability, avoiding the need for warfarin, and allowing another option for women of child-bearing age. The valve frame has also been engineered to facilitate valve-in-valve TAVI if required. There are no long-term clinical freedoms from structural valve degeneration [38].

2.9 Mechanical valves—lower intensity coagulation

The On-X valve (CryoLife, Kennesaw, GA, USA) is a bileaflet mechanical aortic prosthesis designed for lower intensity anticoagulation in younger patients. The On-X valve has been licensed for use in the USA with lower intensity warfarin plus aspirin.

The PROACT Xa study (Clinical Trials.gov identifier NCT04142658) is due to start recruitment soon. This study is a prospective randomized controlled trial comparing apixaban 2.5 or 5 mg daily (according to age, weight, and renal function0 with standard warfarin therapy (INR 2.0–3.0) in patients with an On-X AVR; favorable results may improve the acceptability and increase the usage of the On-X AVR in the future.

2.10 Choice of surgical valve prosthesis

The choice of valve prosthesis for an individual patient depends on several factors, including, most importantly, patient preference, age and life expectancy, metabolic factors predisposing to calcification and early structural valve deterioration (e.g., chronic kidney disease), any increased bleeding risk or contraindication to anticoagulation, expectation of pregnancy, previous infection, and risk of reoperation.

Biological or bioprosthetic valves for aortic valve replacement are made from glutaraldehyde-fixed porcine aortic leaflet or bovine pericardial tissue with a proprietary anticalcification treatment mounted in an alloy frame. Modern bileaflet mechanical valves are made from pyrolytic carbon and offer the advantage of excellent durability and lower intensity anticoagulation and the disadvantages of long-term anticoagulation to prevent thromboembolism and the associated risk of bleeding.

A mechanical prosthesis is recommended for patients <60 years and a bioprosthesis for patients >65 years or those in whom life expectancy is shorter than expected bioprosthetic valve durability. Freedom from reoperation due to structural valve deterioration for a modern bovine pericardial aortic bioprosthesis has been reported as 70.8% and 38.1% at 15 and 20 years for patients aged <60 years at implantation, compared with 98.1% at 15 years for patients aged >70 years [39]. There are no long-term outcome data for rapid-deployment or resilient valves.

Anticoagulation is required in all currently available mechanical aortic valve prostheses. The intensity of anticoagulation depends on prosthesis valve characteristics, e.g., bileaflet or tilting-disc, and patient factors such as a history of tromboembolism, atrial fibrillation, and LV systolic dysfunction (LVEF <35%): the target INR is 2.5 (range 2.0–3.0) for modern bileaflet mechanical aortic valve prostheses (e.g., Medtronic, St. Jude, Liva Nova) and 1.5 (warfarin plus aspirin 81 mg) for the On-X aortic valve in the absence of additional patient risk factors.

Calcific AS has many characteristics in common with atherosclerosis including hypercholesterolemia and intensive lipid lowering does not slow down the progression of AS, but cannot exclude a small reduction in major clinical end points. Significant CAD is present in 40–75% of patients undergoing TAVI. The management of subset of patients is particularly challenging because the AVA gradient discrepancy raises uncertainty about the actual stenosis severity and thus about the indication for AVR if the patient has symptoms of an LV dysfunction.

2.11 Medical treatment

In some elderly patients with symptomatic SAS, even minimally invasive treatment therapy can be harmful, and the only possible therapy remains palliative medical treatment. Their high mortality risk related to the intervention due to comorbiditis and less than 1 year life expectancy is no longer suitable for TAVI. In such patients, almost all cardiovascular drugs should be used as in other patients without SAS, but with caution due to the possibility of drug-induced hypotension and syncope [40, 41, 42].

2.12 General measures

The medical management of patients with symptomatic SAS begins with some lifestyle changes, limited physical activity; sodium intake should be restricted to 2 g/day. Knowing that the patients are afterload fixed and preload dependent, hypotension and dehydration should be avoided. All patients should be evaluated for CAD. According to recent finding, only in patients with a previous history of infectious, endocarditis prophylaxis is indicated.

The renin-angitensin system (RAS) is upregulated in AS and has been shown to be involved in aortic valve calcification in experimental and clinical evidence. Angiotensin converting enzyme inhibitors (ACEI) and ARB prevent the hemodynamic impairment of AS. ARBs appear to be effective in reducing LV mass and slowing the progression of calcification of the aortic valve. Dahl et al. [43] studied 114 patients with symptomatic SAS and LVEF >40%, randomized after AVR to Candesartan up to 32 mg/day or conventional therapy for 1 year. Mortality and hospitalization did not differ between groups, but there was a significant improvement of echocardiographic parameters in the active treatment group.

Calcium channel blockers should be used with caution (nifedipine should be avoided) because of the risk of hypotension, induced coronary hypoperfusion [44], and aggravation of heart failure. Patients with SAS on calcium channel blockers for arterial hypertension, compared to those not on this drug, had a sevenfold increased hazard ratio for all-cause mortality and significantly lower event-free interval (20.5% versus 5.6%, P < 0.001), independent of age, diabetes, LV ejection fraction, and AVA [44].

Diuretics must be used with caution because patients with SAS are preload dependent, and they can develop a low cardiac output and arterial hypotension with peripheral hypoperfusion. Eplerone was studied in 33 patients with asymptomatic moderate-to-severe AS and LVEF higher than 50% versus 32 controls, followed up for 15–25 months. There were no significant differences between groups regarding the LV mass index and LV end-systolic volume index [44].

Beta blockers in patients with SAS because of the risk of negative inotropic effect in the presence of LV outflow tract obstruction are difficult to manage [45, 46, 47, 48]. They are indicated in symptomatic SAS with heart failure in low doses, for rate control in patients with atrial fibrillation or in hypertension. However, some studies reported more promising data. Metoprolol 100 ± 53 mg/day versus placebo for 22 weeks reduces myocardial oxygen consumption, aortic peak and mean gradient, as well as heart rate and increases systolic ejection time. Thus, the study suggests a favorable hemodynamic profile of beta blocker use in moderate-to-severe AS. Rossi et al. [46] evaluated the treatment with beta blockers in a retrospective analysis of 113 patients with symptomatic SAS who did not undergo surgery and demonstrated a 62% reduction in all-cause mortality. The association of moderate-to-severe aortic regurgitation is contraindication for the treatsment with beta blockers, which can aggravate aortic regurgitation by prolonging ventricular diastole.

Digoxin is indicated for rate control in concomitant atrial fibrillation. There are no randomized trial data about survival rates in patients with symptomatic SAS treated with digoxin.

Nitrate derivatives are not recommended in patients with SAS as long-term therapy but can be used in decompensated states with proper hemodynamic monitoring. Nitroprusside significantly increases the cardiac index and right ventricular stroke volume and decreases the mean arterial pressure, systemic vascular resistance, and pulmonary vascular resistance at 6 and 24 h compared with baseline, without causing any clinically significant hypotension.

Despite some promising results in observational studies on aortic calcification rate, statins are not useful to improve the evolution of AS, except for the coexistence of other indications [49, 50, 51, 52]. Experimental studies showed that phosphodiesterase type 5 (PDE5) inhibition improves left ventricular function and pulmonary venous hypertension, but there are no data regarding their effects in patients with SAS.

Positive inotropic agents should be used with caution in the setting of acute heart failure because they may induce tachycardia, with subsequently reduced cardiac output by decreased diastolic ventricular filling, and also myocardial ischemia.

Antihypertensive treatment previously in symptomatic SAS was considered a relative contraindication. However, recent studies have shown that antihypertensive medical treatment may be beneficial and safe reducing the progression of LV remodeling and even the progression of AS. Concomitant arterial hypertension must be treated with the usual drug classes, but with careful titration of doses and rigorous blood pressure monitoring. Calcium channel blockers, especially nifedipine, must be used with caution [53].

Atrial fibrillation develops in 25% of the patients, which worsens heart failure. Therefore, every effort must be made to restore sinus rhythm by antiarhythmics or electrical cardioversion, and successful log-term cardioversion is uncommon in SAS patients. Rate control may be obtained with beta blockers ore digitalis. Chronic anticoagulation is decided according to the CHA2DS2-VASc and HAS BLED scores.

Acute and chronic decompensated heart failure in SAS positive inotropic agents, vasodilatators like nitroprusside, emergency balloon aortic dilatation, and emergency TAVI can be tried in such clinical cases. However, the improvement of the hymodinamic state is very difficult to achieve [54]. Balloon aortic dilatation can be useful, but acute complications, such as myocardial infarction, stroke, and acute aortic regurgitation, can occur in 10–20% cases, and progressive restenosis can appear in 6–12 months. Therefore, balloon aortic dilatation is indicated, especially as bridging to TAVI or SAVR.

Significant CAD is present in 40–75% of patients with symptomatic SAS. The indication of TAVI or SAVR requires concomitant coronary artery bypass graft (CABG), but often the interventional risks are too high [37].

In patients who are not eligible for coronary revascularization, the medical treatment should be used with caution due to the risk of coronary hypoperfusion. From this point of view, it is better to limit the chronic administration of nitrats and calcium channel blockers and to use low doses of beta blockers. Antiaggregant and anticoagulation therapy should be used according to the guidelines while taking into account the comorbidities of the patient.

Chronic heart failure patients with SAS may be treated with low doses of diuretics, ACEI or Ang receptor blockers (ARB), with caution dose increases. Beta blockers must be used very carefully or even avoided.