Asymptomatic Aortic Stenosis - Prognosis, Risk Stratification and Follow-Up

Due to an aging population and improved non-invasive cardiac imaging (mainly the wide use of transthoracic echocardiography), the number of patients with asymptomatic aortic stenosis (AS) is continuously increasing. Aortic stenosis is a progressive active disease which can be treated effectively by aortic valve implantation. Therefore, optimal timing of surgery is crucial demanding precise risk stratification to identify high-risk but still asymptomatic patients. Such patients should undergo close clinical follow-up examination or even elective aortic valve replacement. Whereas severe symptomatic aortic stenosis is a class I indication for valve replacement, the decision to operate on asymptomatic patients remains controversial. Accepted indications for aortic valve replacement for asymptomatic patients with severe aortic stenosis are (a) the need of cardiac surgery for any other reason such as coronary bypass grafting or surgery of the aorta ascendens and (b) if left ventricular systolic dysfunction defined by an ejection fraction below 50% occurs. The risk of sudden death in asymptomatic severe aortic stenosis without preceding symptoms is a matter of concern, although it is regarded as low (around 1% per year) and below the perioperative mortality of aortic valve replacement. Otherwise, there is a risk of irreversible myocardial damage due to left ventricular hypertrophy and myocardial fibrosis if surgery is performed too late. The strategy to wait for occurrence of symptoms before indicating aortic valve implantation is further challenged by an increased mortality in patients awaiting surgery after onset of symptoms, by late symptom reporting by many patients and a higher operative risk for more symptomatic patients. On the other hand, the immediate operative risk, the long-term morbidity and mortality related to the prosthetic aortic valve, and the potential need for re-operation have to be taken into account. Several risk factors for worse clinical outcome in patients with asymptomatic aortic stenosis have been established in the last years. Hemodynamic parameters such as a peak aortic jet velocity > 5m/s or a mean gradient > 60 mmHg are used to define very severe aortic stenosis, and an increase in peak aortic jet velocity > 0.3 m/s/year define a fast hemodynamic progression rate. Whether such highrisk patients should undergo elective aortic valve implantation even in the asymptomatic state is still a matter of debate and handled differently between European and American Guidelines. Furthermore, interest has


Introduction
Due to an aging population and improved non-invasive cardiac imaging (mainly the wide use of transthoracic echocardiography), the number of patients with asymptomatic aortic stenosis (AS) is continuously increasing.Aortic stenosis is a progressive active disease which can be treated effectively by aortic valve implantation.Therefore, optimal timing of surgery is crucial demanding precise risk stratification to identify high-risk but still asymptomatic patients.Such patients should undergo close clinical follow-up examination or even elective aortic valve replacement.Whereas severe symptomatic aortic stenosis is a class I indication for valve replacement, the decision to operate on asymptomatic patients remains controversial.Accepted indications for aortic valve replacement for asymptomatic patients with severe aortic stenosis are (a) the need of cardiac surgery for any other reason such as coronary bypass grafting or surgery of the aorta ascendens and (b) if left ventricular systolic dysfunction defined by an ejection fraction below 50% occurs.The risk of sudden death in asymptomatic severe aortic stenosis without preceding symptoms is a matter of concern, although it is regarded as low (around 1% per year) and below the perioperative mortality of aortic valve replacement.Otherwise, there is a risk of irreversible myocardial damage due to left ventricular hypertrophy and myocardial fibrosis if surgery is performed too late.The strategy to wait for occurrence of symptoms before indicating aortic valve implantation is further challenged by an increased mortality in patients awaiting surgery after onset of symptoms, by late symptom reporting by many patients and a higher operative risk for more symptomatic patients.On the other hand, the immediate operative risk, the long-term morbidity and mortality related to the prosthetic aortic valve, and the potential need for re-operation have to be taken into account.Several risk factors for worse clinical outcome in patients with asymptomatic aortic stenosis have been established in the last years.Hemodynamic parameters such as a peak aortic jet velocity > 5m/s or a mean gradient > 60 mmHg are used to define very severe aortic stenosis, and an increase in peak aortic jet velocity > 0.3 m/s/year define a fast hemodynamic progression rate.Whether such high-risk patients should undergo elective aortic valve implantation even in the asymptomatic state is still a matter of debate and handled differently between European and American Guidelines.

History
Aortic stenosis proves the outstanding diagnostic power of a well-taken clinical history.Classical symptoms of aortic stenosis are angina pectoris, heart failure, severe cardiac arrhythmia such as ventricular tachycardia and syncope.However, these symptoms are often preceded by a decreased exercise tolerance or dyspnoe on exertion.It is the skill and clinical experience of the physician to discover and interpret these changes correctly in patients who may have a low physical activity also for other reasons (e.g.frailty, pulmonary disease, obesity, de-conditioning).
Patients with congenital valvular stenosis may give a history of a murmur since childhood or infancy.Those with rheumatic stenosis may have a history of rheumatic fever.The influence of sex on the outcome of asymptomatic aortic stenosis is a matter of debate as well.Some studies found that female gender is independently predictive of the midterm development of symptoms (Monin et al., 2009), but guidelines recommendations so far do not differ between genders.

Physical findings
As usual, anamnesis is followed by physical examination.Typical for aortic stenosis is a systolic ejection murmur, with a maximum in the 2 nd ICR right parasternal with radiation in the carotids.In patients with a loud systolic murmur, an echocardiography is indicated.
Arterial hypertension is present in many patients and imposes additional load on the left ventricle by increased vascular resistance.This results in lower transvalvular gradients and possible underestimation of stenosis severity, whereas clinical symptoms might occur earlier.

Echocardiography
Transthoracic echocardiography supplies the most important information for risk stratification of adults with aortic stenosis yielding information about valve anatomy and

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hemodynamics, the left ventricular response to chronic pressure overload, aortic dilatation and associated valve disease.Only in certain circumstances, a transoesophageal or a 3Dechocardiography is needed, e.g. for improved analysis of valve anatomy (bicuspid valve, planimetry of valve area) or preoperative measurements needed in transcatheter aortic valve implantation (TAVI).On 2D echocardiography, a stenotic aortic valve is thickened and calcified, with restricted opening of the cusps.Three basic parameters are routinely used to assess the hemodynamic severity of aortic stenosis: jet velocity, mean transaortic pressure gradient and valve area.
The aortic jet velocity is measured with continuous wave Doppler from several transducer windows, to obtain the signal most parallel with the direction of stenotic jet flow yielding the highest velocity signal (Figure 2).For this, color-flow imaging may be helpful to guide Doppler beam alignment.Sometimes it is necessary that the patient has to move to a rightsupine position using a right parasternal window and a smaller nonimaging continuouswave Doppler transducer (so-called pencil-probe) which is easier to manipulate between the ribs.In very small or very tall adults, valve area should be indexed for body size, e.g. to avoid that a small person with only a moderate obstruction get the misdiagnosis of a severe aortic stenosis.
Fig. 3. Using an apical five-chamber view, transvalvular continuous Doppler shows a severe to very severe aortic stenosis, with mean/peak systolic gradients of 69 and 98 mmHg, respectively, and a peak systolic velocity of 4.9 m/s.
There are some caveats in the assessment of aortic stenosis by transthoracic echocardiography.The measurement of the left ventricular outflow tract diameter has to be thoroughly performed from a systolic freeze-frame in the parsternal long-axis view, defined by the distance from where the anterior (right aortic) cusp meets the ventricular septum to the point where the posterior (noncoronary) cusp meets the anterior mitral leaflet.This may be difficult because of heavy calcifications.Furthermore, in patients with atrial fibrillation or flutter, velocities should be averaged from 5 to 10 cardiac cycles.Whereas systolic left ventricular dysfunction occurs very late in the disease process (mainly in symptomatic patients with very severe aortic stenosis who do not undergo valve replacement for whatever reason), left ventricular diastolic dysfunction is frequently found in an early phase of aortic stenosis.Left ventricular hypertrophy can be found in most cases of severe aortic stenosis.AVA (cm²) -> 1.5 1.0 -1.5 < 1.0 < 0.6 Indexed AVA (cm²/m²) -> 0.9 0.6 -0.9 < 0.6 -Table 1. Categories of aortic stenosis severity, according to ESC (Vahanian et al., 2007) and ACC/AHA (Bonow et al., 2008)

Biomarkers
Natriuretic peptides are secreted from the heart as response to pressure overload.Whereas atrial natriuretic peptide (ANP) is produced in the atria, B-type natriuretic peptide (BNP) is mainly derived from ventricular myocardium.Obviously, increased intraventricular pressure due to significant aortic stenosis is accompanied by elevated plasma levels of BNP and its derivatives such as N-terminal pro BNP.Such an elevation of natriuretic peptides predict adverse clinical outcome, such as occurrence of symptoms in still asymptomatic patients or higher operative mortality or worse post-operative outcome (Bergler-Klein et al., 2004;Pedrazzini et al., 2008).Systemic inflammation, expressed by elevated plasma CRP levels, influence the clinical outcome in advanced stages of aortic stenosis whereas no correlation to the progression from aortic sclerosis to aortic stenosis could be found in the Cardiovascular Health Study (Galante et al., 2001;Novaro et al., 2007).

Exercise test
An exercise test may be considered for patients with severe AS and equivocal symptoms or for asymptomatic, physically active patients with severe AS and slow progression.A stress test can unmask signs like dyspnoea, angina pectoris, and inadequate rise in blood pressure, complex ventricular arrhythmias or repolarisation abnormalities, and dizziness.Patients suffering from symptoms during exercise have an event-free survival rate of lower than 20% within 2 years, whereas patients with a normal exercise tolerance have a survival rate of over 80% at 5 years (Iung, 2011).A positive exercise test is associated with a 7 times higher clinical event rate (Amato et al., 2001).
The exercise test should be interrupted for limiting dyspnoea and fatigue, any angina or dizziness, > 2mm ST depression, any decrease in systolic blood pressure (> 20 mmHg or a fall compared to baseline), and complex ventricular ectopy.The exercise test should be considered abnormal if exercise tolerance is < 80% according to age-and sex-adjusted levels.
The type of exercise test-induced symptom is important for the outcome.Patients with dizziness on exertion have an 83% probability for proximate developing of symptoms, whereas with breathlessness or chest tightness it is only 54%, respectively 50% (Dal-Bianco et al., 2008).

Cardiac catherization
The role of invasive assessment of aortic stenosis severity has decreased in the last decades, mainly due to the diagnostic power of echocardiography.Passage through a stenotic valve may lead to peripheral embolism.The main indication of cardiac catherization is nowadays to perform coronary angiography at symptom onset.Multislice computed tomography may be used in young patients with a low probabilty of coronary artery disease instead, but this method is limited in older patients because of coronary calcification causing blooming artefacts.Using specific catheters, simultaneous evaluation of the proximal aortic and left ventricular pressures yields the most accurate data.It is important to distinguish the maximum instantenous gradient from the mean and peak-to-peak gradients, when comparing to echocardiographic measurements.Right heart catherization is often performed to assess cardiac output by either the Fick principle or the indicator dilution technique, which allows aortic valve area calculation by the Gorlin formula.

Chest X-ray
Poststenotic dilatation of the aorta ascendens is often the main chest X-ray finding in patients with aortic stenosis, whereas cardiac silhouette shows no or only minor enlargement.Calcification of the aortic valve is hardly seen on chest X-ray, in contrast to flouroscopy or electron-beam / multislice computed tomography (see below).

Cardiac multislice computed tomography and cardiac magnetic resonance
Although limited by the exposure to radiation, its availibity and its use in patients with high heart rate or atrial fibrillation, multislice computed tomography (MSCT) may be helpful in certain clinical situations in patients with aortic stenosis, e.g.diagnosis of coronary artery disease (Figure 3) or better assessment of aortic dilatation / aneurysm.Although lipidlowering therapy does not halt progression of moderate aortic stenosis, it is certainly indicated in the majority of patients because of concomitant coronary artery disease, as shown in the SEAS study and discussed below.MSCT is superior to quantify aortic valve calcification, although no cut-off point has been established yet influencing clinical decision making.It may also diagnose bicuspid valve morphology, and may even be helpful in assessment of valve area (Feuchtner et al., 2006).Cardiac MRI has been used in patients with asymptomatic aortic stenosis as well, but is not suitable for detection of concomitant coronary disease.Both MSCT and MRI have the limitation that they measure the anatomic and not the functional effective AVA, so the AS severity is often underrated.The velocity-encoded phase contrast imaging is a new magnetic resonance imaging technique, which allows aortic valve area quantification with the continuity equation imitating echocardiographic Doppler quantification.It is helpful in patients with poor echochardiographic windows, obesity, lung disease, or heavily calcified aortic valve (Dal-Bianco et al., 2008).

Prognosis
The natural history of asymptomatic patients with moderate to severe aortic stenosis is not benign.One half of patients with mild-to-moderate aortic stenosis develop severe outflow obstruction within 6 years (Rosenhek et al., 2004).A large prospective study of asymptomatic patients with severe aortic stenosis showed that freedom from cardiovascular death or aortic valve replacement at 1, 2 and 5 years were only 80%, 63% and 20%, respectively.(Pellikka et al., 2005).This is particularly true for patients with very severe aortic stenosis, whose eventfree survival is only 64%, 36%, 25% and 12% at 1, 2, 3 and 4 years, respectively (Rosenhek et al., 2009).Furthermore, patients with a peak systolic velocity > 5.5 m/s not referred to elective surgery present with severe symptom onset (defined by NYHA functional class > II), which is associated with a worse perioperative outcome.
A survival analysis from 1968 from Ross and Braunwald showed that patients with aortic stenosis who had developed angina and syncope survived 3 years, patients with dyspnoea 2 years, and patients with heart failure survived only 1 to 2 years.This study included symptomatic patients with heterogeneous AS etiology, thus not only calcific aortic stenosis.

Noncardiac surgery risk
Aortic stenosis is a risk factor for perioperative mortality and nonfatal myocardial infarction, but it is unclear whether aortic valve surgery should precede noncardiac surgery.Complication rates are depending on the severity of aortic stenosis and the type of noncardiac surgery performed.Perioperative complications may occurr in up to 11% of patients with moderate aortic stenosis and 31% of patients with severe aortic stenosis, as compared to 2% in matched patients without aortic stenosis (Kertai et al., 2004).In experienced centers, low or intermediate risk noncardiac surgery can be performed safely even in patients with severe asymptomatic aortic stenosis with a low myocardial infarction rate of around 3%, if there is prompt vasopressor therapy for hypotensive episodes (Calleja et al., 2010).

Endocarditis prophylaxis
In 2009, the ESC guidelines concerning antibiotic endocarditis prophylaxis have changed limiting its use to only high-rik patients, such as patients with prosthetic valves, previous infective endocarditis or certain congenital heart disease.Degenerative aortic stenosis is not an indication for antibiotic endocarditis prophylaxis, even if a bicuspid aortic valve is present (Habib et al., 2009).

Aggressive cardiovascular risk factor intervention
As mentioned above, arterial hypertension puts additional load to the left ventricle in patients with aortic stenosis, and should be carefully treated.However, hypotensive episodes have to be avoided, and regular blood pressure measurements are mandatory.
Retrospective studies suggested that lipid-lowering with statins might slow the progression of aortic stenosis, but prospective studies such as SALTIRE (Cowell et al., 2005) or SEAS (Rossebo et al., 2008) could not confirm such a positive effect on aortic valve events in patients with a LDL cholesterol below 140 mg/dl.Nevertheless, the majority of the patients with aortic stenosis need statins because of three reasons:  concomitant coronary artery disease: in SEAS, intensive lipid-lowering therapy with simvastin 40 mg and ezetimibe 10 mg/d daily reduced cardiovascular ischemic events even in patients with baseline LDL cholesterol below 140 mg/dl, mainly driven by a significant reduction in the need of additional bypass grafting when aortic valve replacement became mandatory; notably, LDL cholesterol were reduced by 61.3% to mean 55 mg/dl. hypercholesterolemia: RAAVE, the only prospective study showing a slowing effect on the hemodynamic progression of aortic stenosis, was performed in hypercholesterolemic patients, defined by a LDL cholesterol above 160 mg/dl (Moura et al., 2007); therefore, such patients should receive statin therapy. early stage of the disease: a retrospective analysis of 1046 patients (Antonini-Canterin, et al., 2008) could show that statin therapy slowed hemodynamic progression in the early stages of the disease process, e.g.aortic sclerosis or mild aortic stenosis.However, this effect disappeared in patients with more advanced aortic stenosis (defined by a baseline peak aortic velocity between 3 and 4 m/s).

Recommended intervals for follow-up examinations
For asymptomatic patients with aortic stenosis, close follow-up is imperative.Clinical evaluation should be performed once a year in patients with mild or moderate aortic stenosis and every 6 months in patients with severe aortic stenosis.Patients need to be questioned thoroughly about symptoms and exercise levels, along with the assessment and treatment of cardiovascular risk factors.Any change in symptoms should prompt the physician to perform a transthoracic echocardiography.Otherwise, intervals between echocardiography examinations are 3 -5 years in patients with mild aortic stenosis, 1 -2 years in patients with moderate aortic stenosis and 6 months to 1 year in patient with severe stenosis.In patients with severe asymptomatic aortic stenosis, exercise testing and measurement of natriuretic peptide levels may be helpful.

Bicuspid aortic valve disease
Bicuspid aortic valve is the most common inherited valve abnormality, affecting 1 -2% of all individuals.There is a genetic component which may justify familiy testing.Around 40% of patients with bicuspid Aortic valves often suffer from dilatation of the ascending aorta as well, independent of the severity of aortic stenosis and/or insufficiency.A major risk of aortic dilation in these patients is aortic dissection, being 9 times higher for patients with a bicuspid aortic valve than for patients with a tricuspid valve.If the maximum diameter is ≥ 5 cm with a fast progression rate above 0.5 cm 2 /year, surgery may be considered even in asymptomatic patients (Class IIaC indication according to ESC guidelines).Therefore, echocardiography should always include measurement of the diameter of the ascending aorta.If dilatation predominates above the sinotubular junction, diagnosis can be missed by transthoracic echocardiography and additional imaging techniques should be considered.Otherwise, management of bicuspid aortic valve disease is similar to that of tricuspid valve disease.If a watchful waiting strategy is chosen, the patient should be educated and advised to selfreport onset of new symptoms to physician immediately.Patients often reduce subconsciously their physical activity, and so only a stress testing can uncover symptoms.

The comorbid and elderly patient -considerations on transcatheter aortic valve implantation
A third of patients with severe symptomatic aortic stenosis are not referred for valve replacement.This is mainly a problem for elderly patients, because many physcians ignore the fact that age itself is not a contra-indication to aortic valve implantation.The EuroSCORE or the STS-PROM score are commonly used to estimate the preoperative risk for cardiac surgery.Both scores incorporate various comorbidities such as chronic pulmonary disease and renal insufficiency; if a patient has too grave comorbidities he might be deemed inoperable.The approach to comorbid symptomatic patients is solid risk evaluation in experienced medical centers with a high surgery volume ("heart team").
Interventional cardiologist more and more challenge heart surgeons by the introduction of transcatheter aortic valve implantation (TAVI), and the years to come will show if this new procedure may play a role also in younger patients with moderate preoperative risk.
On the basis of current clinical outcome data, for symptomatic patients with severe aortic stenosis and a life expectancy over 1 year, indications for TAVI are definite contraindications to surgery or when surgery is estimated very high risk and if there are no barriers to TAVI.
The results of TAVI are preliminary and any conclusions carry limitations.It seems that TAVI is practicable and present acceptable clinical and hemodynamic results up to 3 years.However, there are still major limitations for TAVI, e.g.paravalvular leaks causing significant aortic insufficiency, a higher postoperative need for pacemaker implantation or vascular complications.Bicuspid aortic valve morphology is not suitable for TAVI as well.
The access for transcatheter aortic valve implantation is retrograde via the femoral or the subclavian artery or antegrade through a transapical approach.

Conclusions
Besides coronary artery disease and arterial hypertension, aortic stenosis is the third most common cardiovascular disorder in the Western World, affecting more than four percent of the population above 75 years.It is easy to diagnose by auscultation and subsequent transthoracic echocardiography.Surgical aortic valve implantation (SAVI) offers a very good therapeutic option for symptomatic patients with severe valve obstruction which has a dismal prognosis if left untreated.In contrast, the decision to operate on asymptomatic patients remains a controversity.Unfortunately, there is still no medical therapy available to prevent the development or to delay the progression of aortic stenosis.Probably, medical intervention would be most effective in early stages of the disease, even before obstruction of the left ventricular outflow occurs.This condition called aortic sclerosis is present in 25% of adults over 65 years of age.Currently, around 15% of these patients progress to hemodynamically significant aortic stenosis, and it would be of great importance to stop this active process more effectively in these patients.

Fig. 4 .
Fig. 4. Left ventricular hypertrophy and restricted aortic cusp movement.Four echo parameters permit the classification of aortic stenosis severity.Unfortunately, the European Society of Cardiology (ESC) and the American College of Cardiology/ American Heart Association (ACC/AHA) differrently interpret mean gradients, as shown in Table1(values in brackets are advised from ACC/AHA).A shortcoming of this classification is that one patient may fall in two different categories, e.g. if he has an aortic jet velocity from 3.1 and an AVA from 1.6 cm 2 .Notably, guidelines are based on physiological valve area, as measured by continuity equation, which differs from anatomical valve area.Additional echo parameters who are not yet used in clinical routine are stroke-work loss and left ventricular strain analysis.Stroke-work loss is the ratio of mean gradient and left ventricular pressure, and a stroke-work loss > 26% results in a major clinical event rate > 30% within the following three months(Bermejo et al., 2003).Patients with systolic dysfunction and small valve area present with low transvalvular gradients.It is important to differentiate those with a low gradient due to low stroke volume

Fig. 6 .
Fig. 6.Invasive assessment of aortic stenosis.Simultaneous measurement of left ventricular and aortic pressures (left side), showing a significant pressure gradient indicating severe aortic stenosis.This gradient disappears after pull-back of the tip of the catheter into the aorta ascendens (right side).

Fig. 7 .
Fig. 7. Cardiac MSCT showing severe aortic valve calcification.On the left panel, poststenotic dilatation of the ascending aorta can be seen, whereas concomitant coronary artery calcification can be detected on the right panel.LCA denotes left coronary artery; RCA denotes right coronary artery.

Fig. 8 .
Fig. 8. Cardiac MSCT examinations showing the effects of newly initiated statin treatment on concomitant coronary artery disease.MPR denotes multiplanar reformation; VRT denotes volume-rendering technique; N denotes non-calcified atherosclerotic plaque; YOM denotes year old man.

Fig. 9 .
Fig. 9. Using transesophageal echocardiography in a patient with calcific aortic stenosis, a biscupid valve morphology is detected and planimetry of the aortic valve area can be reliably performed.

Table 2 .
(Vahanian et al., 2007;Bonow et al., 2008)lacement in asymptomatic patients(Vahanian et al., 2007;Bonow et al., 2008).AVR is recommended in class I indications.AVR is reasonable in class IIa and may be considered in class IIb indications.Note that most indications are based only on a level of evidence C. EF denotes ejection fraction; CABG denotes coronary artery bypass grafting; BP denotes blood pressure; CAD denotes coronary artery disease; BAV denotes balloon aortic valvuloplasty.57(low-gradient,low-flow AS) from those with a cardiomyopathy and concomitant only moderate AS.Dobutamin challenge for low-gradient aortic stenosis and left ventricular dysfunction may result in three pattern of responsiveness: fixed aortic stenosis, relative aortic stenosis and absence of contractile reserve.A fixed aortic stenosis is characterized by an increase in peak velocity > 4 m/s and a mean systolic gradient > 40 mmHg with no change in aortic valve area.These patients may still benefit from valve replacement despite increased perioperative rsik.In contrast, relative aortic stenosis is characterized by a significant increase in calculated aortic valve area (> 0.3 cm 2 ) without a significant increase in peak velocity or systolic gradients, whereas no variable changed significantly in patients without contractile reserve (lack of increase > 20% of stroke volume).
(Dal-Bianco et al., 2008)ing ECG in severe aortic stenosis usually shows signs of left ventricular hypertrophy, often accompanied by repolarisation abnormalities (ST-T-wave changes).Left ventricular hypertrophy is an independent predictor for the development of symptoms in asymptomatic severe aortic stenosis.However, the sensitivity for detecting left ventricular hypertrophy by the electrocardiogram is only 40%(Dal-Bianco et al., 2008).Conduction abnormalities are common ranging from first-degree atrio-ventricular block or bundle branch block.Atrial fibrillation is not a typical sign of aortic stenosis and may indicate concomitant mitral valve disease.