Prevalence and Causes
Degenerative aortic stenosis is the most common valvular heart disease in developed countries. Degeneration results from an active process over decades in a tricuspid or bicuspid valve, leading from mild sclerosis to calcific stenosis. It is characterised by lipid accumulation, inflammation, calcification and even bone formation, and has many similarities to atherosclerosis.1,2 In the past few years, it has become clear that degeneration and development of stenosis may be triggered by genetic and environmental factors such as smoking, diabetes, hyperlipidaemia and hypertension.3 As aortic valve calcification increases with age, the prevalence of aortic stenosis increases concomitantly. Prevalence estimates range from 1 to 2.5% in people 75 years of age to nearly 8% in people over 85 years of age.3,4 As the developed world population continues to age and the more widespread use of Doppler techniques results in detection of more (asymptomatic) patients, aortic stenosis constitutes a growing health burden. The global annual need for aortic valve replacement (AVR) is expected to triple to approximately 850,000 by 2050.5
Symptom variability is large: patients with only moderate stenosis may report symptoms, while others with a more severe stenosis may not. The classic and most frequent symptoms are angina, syncope and dyspnoea, often occurring in that order. Although approximately half of elderly patients undergoing AVR for aortic stenosis have significant concomitant coronary artery disease, angina can also occur in patients with a healthy coronary system.6 The left ventricle adapts to the high afterload caused by the stenosis, resulting in left ventricular hypertrophy. This leads to a higher oxygen demand and decreased capillary density. Furthermore, increased left ventricular pressure, decreased diastolic filling and decreased diastolic coronary perfusion time all contribute to ischaemia.7,8 Syncope can result from the inability of the heart to adapt to sudden vasodilatation causing blood pressure drops in cerebro on exertion or emotion. Dyspnoea results from pulmonary congestion, which in time can lead to pulmonary hypertension. The mean lifetime expectancy after onset of angina is reported to be 4.5 years, after syncope 2.6 years and after heart failure less than one year.9
Due to the gradual progression of the stenosis and the adaptation of the heart, patients often tend to deny the presence of symptoms, or they attribute them to the ageing process or other co-morbidities. When overt symptoms do occur, disease is generally more advanced and left ventricular diastolic and systolic dysfunction is already present. Symptoms can rapidly progress and 3% die within three to six months after onset of overt symptoms.10 Therefore, education of the patient to recognise and report symptoms is essential in improving prognosis.
As patients have difficulty in reporting symptoms, it would be useful to have better indicators of disease severity (not only ‘stenosis severity’) to be able to select those who are at risk of clinical deterioration and to determine the threshold at which surgery is indicated. Ideally, this cut-off point would be just before left ventricular dysfunction occurs.
Quality of Life
If disease causes symptoms, the resulting functional disability is frequently underestimated by physicians.11 Consequently, we conducted a study to investigate quality of life in patients with symptomatic severe aortic stenosis.12 The main finding was that symptoms result in both physical and emotional disability, with major effects on normal daily life and social functioning. Therefore, the decision to perform AVR should be based not only on expected gain in life expectancy, but also on the impaired quality of life that patients have with conservative treatment.
Echocardiography has become the major diagnostic tool to evaluate the degree and progression of stenosis, left ventricular function and hypertrophy and structural abnormalities of other cardiac valves. Cardiac catheterisation is still used to image the coronary tree if coronary artery disease is suspected, but it has lost its leading role in the assessment of isolated aortic stenosis.
Grading the severity of aortic stenosis is based on the echocardiographic measurement of multiple parameters. Severe stenosis is characterised by one of the following: peak aortic jet velocity >4.0m/second or peak gradient >64mmHg, mean aortic gradient >40mmHg, aortic valve area <1cm2 or aortic valve area adjusted for body surface area <0.6cm2/m2.13,14. As calculation of the aortic valve area can be subject to several measurement errors, it can underestimate the real valve opening and, therefore, exaggerate the degree of stenosis. An underestimation of the degree of stenosis can also occur, which is most frequently caused by a Doppler beam that is not exactly parallel to the aortic jet. In patients with left ventricular dysfunction suspected of low-flow/low-gradient stenosis, or in cases in which left ventricular outflow tract diameter cannot be measured precisely, it is advisable to calculate the ratio between the jet velocity (time integral) of the left ventricular outflow tract and the aortic valve opening. A ratio <0.25 indicates a severe stenosis.13 The rate of stenosis progression is related to the degree of valve calcification and presence of coronary artery disease, but it has large individual variability.15 The increase of the peak transaortic pressure gradient ranges from 7 to 15mmHg per year and the decrease of aortic valve area is 0.1–0.3cm2 per year.16–18
Patients with left ventricular dysfunction may not be capable of producing enough output to reach the established criteria for severe aortic stenosis, the so-called low-flow/low-gradient aortic stenosis. In order to determine whether stenosis is severe or only moderate, it may be useful to perform exercise or low-dose dobutamine infusion to compare the transvalvular pressure gradient at exercise with the baseline state. Stroke volume increases and patients with only moderate stenosis will have an increase in valve opening, resulting in no significant elevation of the gradient.19
Due to inactivity and gradual adjustment of daily activities to developing symptoms, many (elderly) patients tend to attribute symptoms to the ageing process. Exercise testing provokes symptoms in up to 37% of patients who claimed to be asymptomatic.20 Symptoms occurring during exercise testing are superior to echocardiography and clinical history in predicting the onset of symptoms in daily life.20
For many years, physicians have been reluctant to use exercise testing in severe aortic stenosis, even in asymptomatic patients, but it is safe under medical supervision.17,21 However, exercise testing is highly underused according to the European Heart Survey and recently it shifted from a class IIa to a class IIb recommendation in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of valvular heart disease.13,22
As the literature is inconsistent about the usefulness of exercise testing, we decided to evaluate its use in 44 asymptomatic patients with severe aortic stenosis. Approximately one-third were positive, one-third were negative and the rest were inconclusive (data as yet unpublished). From these preliminary results, exercise testing seems useful: although it has its limitations in an elderly population, it reveals more patients to have limiting symptoms than could have been established by questioning.
Currently, biomarkers are not routinely used for diagnosis and evaluation of patients with aortic stenosis. Recent studies have suggested several natriuretic peptides to be useful, such as B-type natriuretic peptide (BNP) and its precursor N-terminal prohormone BNP (Nt-proBNP). BNP is secreted in the left ventricle in reaction to increased intra-ventricular pressure or stretching.23 Nt-proBNP is biologically more stable than BNP and preferable in clinical practice. Both markers are weakly related to stenosis severity, but would be able to discriminate cardiac from non-cardiac dyspnoea and symptomatic from asymptomatic patients.24,25 Furthermore, they could perhaps be used to predict which asymptomatic patients will become symptomatic and to predict outcome in both medically and surgically treated patients.24,26 From our own Nt-proBNP study in patients with severe aortic stenosis, it seems that the first results are less encouraging than expected. Nt-proBNP measured on the log scale was only weakly related to aortic valve area, left ventricular function and symptomatic status. Although long-term follow-up data are not yet available, we doubt whether Nt-proBNP measurement is useful for individual patient assessment.
Tissue Doppler Imaging
Tissue Doppler imaging (TDI) is a relatively new ultrasound technique. Instead of high-frequency, low-amplitude signals from moving blood cells in conventional echocardiography, it quantifies high-amplitude, low-velocity signals of myocardial tissue motion.27,28 TDI provides an objective means of quantifying global and regional left and right ventricular function, and improves the accuracy and reproducibility of conventional echocardiography studies.28
In a series of over 160 patients with severe aortic stenosis, we performed TDI together with standard echocardiographic evaluation, and found little evidence that it could predict clinical deterioration. TDI could be valuable in establishing early diastolic dysfunction in asymptomatic patients, but this has yet to be determined. More studies are needed to investigate whether it is useful to add TDI to the standard echocardiographic evaluation of patients with severe aortic stenosis.27
Guidelines and Common Daily Practice
For asymptomatic patients with severe aortic stenosis, the optimal treatment strategy remains a matter of debate. Truly asymptomatic patients have a much better prognosis compared with symptomatic patients and a low incidence of sudden death.17,29 According to the AHA/ACC guidelines, asymptomatic patients should not be confronted with the risks associated with AVR unless they have left ventricular dysfunction.13 By contrast, recent reports have documented a grim prognosis in asymptomatic severe aortic stenosis, suggesting that diastolic dysfunction, interstitial fibrosis and secondary pulmonary hypertension already exist before symptoms occur.29–32 Survival free of developing symptoms or having AVR is only 33% at four to five years.29,31 These reports suggest that the threshold for performing AVR could be lowered to asymptomatic patients.30–32 Agreement on treatment does exist in symptomatic patients with severe aortic stenosis: AVR prevents sudden death and deterioration of left ventricular function.13 Prognosis of symptomatic patients is poor when treated conservatively, and patients should be referred for AVR without delay when they become symptomatic.9,32
In daily practice, a considerable proportion of patients (30–60%) with symptomatic severe aortic stenosis are not referred for surgery.33–36 From our own experience in 179 symptomatic patients with severe aortic stenosis, 56% did not have AVR within a mean follow-up of 17 months.37 Operative risk is often deemed too high due to co-morbidities or advanced age, and misclassification of both haemodynamic severity and symptomatic status occurs relatively frequently.37 Therefore, the number of patients who could potentially benefit from an aortic valve replacement is underestimated.
Microsimulation modelling can be used to predict long-term outcome after AVR.38–40 Based on the data of patients who have received AVR, this computer application can calculate age- and gender-specific long-term outcomes after AVR. It not only provides insight into survival, but also produces estimates of (event-free) life expectancy and occurrence of valve-related events for the individual patient. In this way, the lifetime event risks between different types of valve prosthesis can be compared, which can help in patient and prosthesis selection and in counselling.
Symptoms can be relieved by diuretics and treatment of systemic or pulmonary hypertension and atrial fibrillation. In order to prevent endocarditis, each patient with structural valve abnormalities should receive prophylactic antibacterial treatment before starting non-sterile surgical procedures. As aortic stenosis is an inflammatory process, some drugs may interfere with the progression of aortic stenosis. Statins and angiotensin-converting enzyme (ACE) inhibitors have been suggested to have a beneficial effect, but recent trials showed no effect on the progression of moderate to severe aortic stenosis.41,42 An inhibiting effect of these prescriptions in the earlier phases of the disease cannot be ruled out.
Conventional Aortic Valve Replacement
In 1954, the first aortic valve prosthesis was implanted by Hufnagel in the descending aorta to correct aortic regurgitation.43 Shortly thereafter, extracorporeal circulation was developed and AVR became common practice. To date, it is the only long-lasting treatment option for patients with aortic stenosis.
In recent years, improvements in cardiac anaesthesia and post-operative care have led to an increased willingness among surgeons to operate on elderly or high-risk patients. Nowadays, operative results are acceptable even in octogenarians, with an operative mortality of around 8% for a single AVR.44 Operative mortality in younger patients is approximately 1%.45 Several types of prosthesis are available, each with its own advantages and limitations. The most frequently used valve prostheses are mechanical and biological prostheses. Mechanical prostheses have long-lasting durability but necessitate anticoagulation, leading to increased risk of bleeding. Bioprostheses do not require anticoagulation, but are subject to structural valve deterioration, which in the long term increases the risk of re-operation. Other valve-related events that can occur are paravalvular leakage, prosthetic valve endocarditis and valve thrombosis.
Minimally Invasive Surgery
Several approaches have been used in order to avoid median sternotomy in an attempt to reduce wound-associated morbidity and mortality and to improve cosmetic results. Some of the possibilities are a partial upper ministernotomy, a reversed ‘C’ ministernotomy (in which the upper and lower part of the sternum remain intact retaining thoracic stability), a small right anterior thoracotomy in the second/third intercostal space or a right anterior submammarian minithoracotomy.46,47 A significant reduction in morbidity and mortality has not yet been established in larger studies. Some suggest faster recovery, fewer complications and less chest pain, resulting in more patient satisfaction, less rehabilitation and fewer costs.48–50 Others find no difference.51,52 The only truly established improvement is the better cosmetic result, which is mostly appreciated by younger patients.51,52
For patients who are not suitable candidates for conventional or minimally invasive surgery, other less invasive treatment modalities have been developed. In the mid-1980s, a technique for percutaneous aortic balloon valvuloplasty was introduced by Cribier.53 Although this dilatation provides some temporary relief for a selected group of patients, it has only limited effect on aortic valve area.54
Mortality (3.5–13.5%) and complication (20 –25%) rates are quite high, but are partly related to the critical conditions of the selected patients. For the same reason, long-term survival was also unfavourable, with 35% surviving at two years and 23% at three years.55 These limitations and the high frequency of early re-stenosis are the main reasons the technique has largely been abandoned.
Transcatheter Valve Implantation
In the last few years, transcatheter valve implantation techniques have been evolving rapidly. With this technique, a biological tri-leaflet valve, suspended in an expandable stent, can be placed in the aortic position after (balloon) dilatation of the stenotic aortic valve, which can be approached in several ways. In 2002, Cribier initiated the antegrade approach: a catheter was inserted through the femoral vein up to the right atrium, then through a puncture hole in the atrial septum and through the mitral valve towards the aorta. After balloon dilatation of the native calcified aortic valve, the folded stent with the prosthetic valve was introduced, positioned and deployed.56 As the device crosses the less diseased – ventricular – surface of the aortic valve, the risk of producing emboli is low. The main disadvantages of the antegrade approach are the transseptal puncture-related complications and the risk of mitral valve damage resulting in incompetence. At our centre, we use the retrograde femoral and the transapical antegrade approach. In the retrograde approach, the femoral artery is either opened under direct vision or punctured in case of a truly percutaneous procedure.57 The delivery device is inserted and shifted upward through the iliofemoral vessels and descending aorta to the aortic position. Downsides are the risk of producing emboli in the aortic arch or at the surface of the diseased aortic valve. Complications of the iliac or femoral vessels occur relatively frequently and include rupture, dissection, pseudo-aneurysm, bleeding, thrombus formation and stenosis.
Transapical valve implantation, also called ‘direct access valve replacement’, requires a left mini-thoracotomy, after which the pericardium is opened and a transmyocardial incision or puncture is made in the cardiac apex to provide entry of the cardiac cavity.58–60 The native aortic valve is then dilated by balloon valvuloplasty, and the delivery device with the valve prosthesis together with the balloon for valve expansion is brought into the aortic position. During rapid pacing the valve is deployed.
After removal of the device, the apex is closed using sutures with pledgets. The main advantage of the transapical route is easier access, without the risk of damaging the often diseased peripheral vessels. The mitral valve is avoided and, furthermore, there is less risk of damage to the aortic arch, resulting in lower risk of emboli. As the delivery system can have a larger diameter, it is stronger, which improves handling and insertion of the device.
In the antegrade, retrograde and transapical transcatheter procedures, extracorporeal circulation through the groin could be used as an extra safety measure in difficult cases to unload the ventricle and ease positioning of the valve. Intracardial ultrasound can be used to improve visualisation. The main disadvantages of transcatheter valve implantation are paravalvular leakages due to insufficient apposition of the valve in the calcified annulus. Also, cerebral complications are not uncommon, and the native (calcified) leaflets can fold upwards and be compressed into the coronary orifices occluding part of the coronary system.61
Although experience with the transcatheter techniques remains rather limited, their potential seems not to be limited to treating native aortic valve disease. In an experimental pig model, the transapical technique was used to successfully replace a deteriorated biological prosthesis.62 In the near future, this so-called ‘valve-in-valve’ concept could reduce (re-)operative morbidity and mortality in high-risk subsets of patients, and may therefore offer a solution for the treatment of elderly patients who experience structural valve deterioration after implantation of a biological valve prosthesis.