Degenerative Aortic Valve Disease, its Mechanism on Progression, its Effect on the Left Ventricle and the Postoperative Results

The aortic valve has a deceivingly simple design. However, its macroscopic anatomy must be understood in relation to its function. This understanding also has a repercussion on the surgical treatment of aortic valve disease. A supporting structure of a valve prosthesis does not necessarily follow the line of attachment of the native leaflets.

The aortic root has to be defined properly. It is more than just a ring in a two dimensional plane. The attachment of the valvular leaflets possesses a three dimensional structure which changes in shape during the cardiac cycle.

The aortic annulus also needs full description. The diameters at the level of the STJ, the mid-sinusal level and the anatomic AVJ are part of this concept.

The microscopic and cell biological description of the aortic valve include

- The layers within the leaflets.

- The cells.

o Endothelial cells or EC and their function.

o Valvular interstitial cells or VIC and their function.

- The extracellular matrix.

o The fibers: collagen and elastin.

o The glycosaminoglycans or GAG.

A thorough description of these elements is needed for understanding of:

- The durability of the native valve during an entire human life span.

- The understanding of pathological processes.

- The construction of tissue engineered heart valves or TEHV.

The pathological changes in CAVS are much more than a simple age related “wear and tear”. There is some resemblance of CAVS with atherosclerosis, but important differences have also been authenticated. Both conditions share a number of risk factors, however

The mechanisms leading to the microscopically observable changes in CAVS include many molecules and pathways. There is a considerable “cross talk” between these mechanisms which makes their description difficult.

The unravelling of these pathways requires a description in layers.

The outer layer consists of the risk factors of which the most common are lipid disorders and hypertension.

The middle layer consists of the molecules and mediators involved. Some of these molecules are inflammatory, others are the result of mechanical or oxidative stress, still others play a role in the remodelling of the ECM.

The inner layer consists of the mechanisms, which are inflammation, calcification or ossification, angiogenesis, remodelling of the ECM and programmed cell death.

The unravelling of these processes in CAVS is an ongoing process and is still not completely understood. This understanding might have some consequences in terms of prevention or slowing down of the process.

Since several risk factors for the development of CAVS have been identified, it seemed reasonable to explore the effects of their medical targeting on the rate of progress of this disease.

Especially for lipid disorders and statins, hopes have been high. Statins have a proven value for the treatment of lipid disorders in atheromatosis, which shares some risk factors with CAVS. A proof of concept could also be derived from animal models.

Early non randomized and retrospective studies have seemed to confirm these hopes. With appearance of the more recent trails (SEAS, SALTIRE and ASTRONOMER) it has become clear that these hopes are unjustified. No difference in effect have been found between statins and placebo on the rate of progression of CAVS.

Reasons for these findings are probably:

- The composition of the population: it is unethical to deny patients with lipid disorders a treatment with statins. This limitation makes it difficult to compare certain populations.

- The stage of CAVS: statins might work only very early in the course of the disease, which is asymptomatic.

- The mechanisms of action: fibrosis of the aortic valve could be induced by statins. A fibrotic cap in atheromatosis has a protective effect; in contrast, fibrosis in CAVS could impair the mobility of the leaflets and worsens the disease.

Statins have probably also no role in the prevention of SVD of bioprostheses.

Other approaches such as ACE inhibitors, ATR blocking agents and endothelin receptor antagonists need still investigations. The “window” of “opportunity” for their action might be too short.

The evaluation of the aortic valve can be performed in several ways.

The main imaging techniques for heart valves are:

- Doppler-echocardiography.

- Catheter based investigation.

- Computer tomography.

- MRI-MRA.

Each of these techniques has its advantages and drawbacks.

Trans thoracic echocardiography or TTE remains the standard imaging technique. It is widely used due to its availability, low cost, non-invasive character and low radiation burden. Several modalities exists. Drawbacks of the technique are the operator dependency, difficult imaging in patients with obesity and in cases with extensive calcification. Trans-esophageal echocardiography or TEE might offer better imaging, but the technique is invasive.

The description of the valve, and calculation of hemodynamic parameters such as jet velocity, mean TVG and AVA are the important parameters to estimate the severity of CAVS. For some of thes parameters, the continuity equation can be used. These parameters allow the categorization of the severity of CAVS. Each of these parameter has its advantages and drawbacks. Flow dependency is an important issue to deal with.

In asymptomatic patients, it is useful to assess the rate of progress of CAVS. This can give an indication when AVR for a given patien might become necessary. Assessment of the LVF and LVM are also important parameters to take into account.

Catheter examination has the advantage of direct measurement of TVG. The technique is invasive and can be recommended when echocardiographic data are inconclusive or are in conflict with clinical data. Usually, there is good correlation with echocardiographic data. If the presence of CAD is suspected, coronarygraphy should be performed.

CT and CMR are valuable adjuncts in the assessment of AVA. CT also allows the scoring of the calcium load, which is an important indicator for the severity of CAVS. CMR allows the flow mapping and imaging of the LV.

In some patients with CAVS, it can be difficult to decide if referral of AVR is warranted. There are several reasons for this.

In the low flow – low gradient conundrum, a conventional parameter, such as AVA, is insufficient to distinguish a truly severe CAVS from pseudo-severe CAVS. Additional diagnostic procedures such as a stress-echocardiography can be necessary.

In patients referred for CABG, a mild to moderate CAVS might be detected coincidentally. Must this valve be replaced? To answer this question, the outcome of a concomitant AVR must be carefully balanced against the outcome of isolated CABG and the risk of a second cardiac operation on short or mid-term.

In elderly patients, especially in those with co-morbid conditions, it can be notoriously difficult to assess the symptomatic status and to ascertain the valvular origin of their symptoms. Nevertheless, this is of vital importance in the decision making for referral of AVR. A stress test can also be useful.

The rate of progression of CAVS varies widely. Nevertheless, it can be useful to identify asymptomatic patients with a rapid progressing CAVS. Once these patients become symptomatic, they will need an AVR and the symptomatic phase of the disease should be kept as short as possible. Conventional echocardiography might offer some clues.

The referral pattern is determined, not only by the severity of CAVS, but also by age, LVF and the presence of co-morbid conditions. Nevertheless, denial of AVR is not always appropriate.

Aortic valve replacement has been applied for over half a century. Two classes of devices have been developed: mechanical and biological valve prostheses. For biological devices, autografts, homografts and xenografts (porcine and pericardial) have been developed. For mechanical devices, cage ball, tilted disc and bi-leaflet valves have been designed.

For BHV, the main drawback is a limited durability, the main advantage is the low rate for TE events, which obviates the need for peroral anticoagulation. Age is a major determinant for durability. In contrast, MHV are very durable, but they require a lifelong anticoagulation with all their side effects. The choice for a valve in each individual patients depends on several factors: age and life expectancy are the main factors.

In difficult situations, i.e. an age between 55 and 70 years, results of comparative studies might be helpful in the decision making. Comparison should include contemporary devices and techniques. Use of historical series are confounded by changes and improvements in peri and postoperative care. A RCT remains the gold standard, but these are few in numbers.

The only recent RCT did not change much: the outcome is still more dependent on patient related factors than on the type of the valve, except 1) for bleeding, which is more common with MHV and 2) for SVD, which is observed with BHV. These observations are hardly surprising.

Results for a twenty-year follow-up might be needed. The preference of physician and patients for the choice of a valve is important. The dilemma between anticoagulation related bleeding and SVD remains for the time being.

Follow-up studies have been performed for several reasons. There are minimal requirements for data collection and for follow-up techniques. These include enrolment of patients, type, frequency and mode of data acquisition. A risk profile of the preoperative patient population also allows an individual risk assessment an evaluation of the quality of care for any given institution.

The preoperative EuroSCORE has been developed as tool for such risk assessments. However, the additive as well as the logistic model tended to overestimate the risk for operative mortality. One of the reasons could be the improvements of the care since the development of this score, which have not yet been taken into account. The STS score seems more adequate, but still overestimates the operative risk.

Apart from mortality, postoperative adverse events have been listed and defined. It is, even today, not always possible to make a distinction between valve related complications and non-valvular events.

Short-term events can be represented as percentages. For long-term events, a linearized rate is usually not sufficient since the occurrence of events is not necessarily linear. Actual and actuarial analysis have to be performed.

For a risk analysis, proper statistical methods have to be applied. Identification of independent preditors for hospital events, requires the multivariate logistic regression analysis. For long-term events, this is the Cox’ proportional hazard analysis.

The study of postoperative results in patient series can have several purposes. This goes from a simple description of a device or a technique to the identification of risk factors and the comparison between several devices and between different techniques. RCT can be considered as the “gold standard”, but even non randomized prospective and retrospective series have been used.

The main outcomes under scrutiny are:

- Hospital mortality.

- Long term mortality.

- Valve related events:

º TE.

º Bleeding.

º SVD.

º PVE.

º PPVL.

º Reoperation.

- Other cardiac events:

º CHF.

º CD.

º AF.

- Non-cardiac events:

º Pulmonary.

º Renal.

For these outcomes, it is useful to make a search for risk factors and independent predictors.

The life expectancy in the Western societies has increased steadily. CAVS is usually occurring at a higher age, therefore its incidence is also rising. However, the diagnosis of CAVS in elderly is not always easy: the disease might be overlooked because its symptoms sometimes are not recognized. Moreover, ascertaining the valvular origin of the symptoms in elderly patients might be a challenge.

If the presence of a symptomatic CAVS has been established in an elderly patient, the optimal treatment still has to be decided. Age, frailty, co-morbid conditions and LVF all have played a role in this decision making. It has become clear that there were and still are different approaches of cardiologists in regard to the referral policy.

Unto recently, about one third of the patients has been denied AVR unjustly. The EuroSCORE overestimates the postoperative mortality, especially in high risk patients, and should be used with great caution.

The available postoperative results seem to justify a referral of octogenarians with symptomatic CAVS for AVR. Hospital and long-term adverse events in these elderly patients are more frequent, compared to their younger counterparts. There is, however, a considerable variation in postoperative results, which is probably due to differences in the baseline characteristics of the patients. This finding applies for patients of all ages, including octogenarians.

The study of risk factors has revealed that need for urgent surgery has a dominant effect on the postoperative results. This factor is more present in elderly, indicating that poor postoperative results in elderly could be a self fulfilling prophecy. Long-term postoperative results in octogenarians show that, compared to the general population, a normal age and gender matched survival might be reached, with an acceptable quality of life.

The problem of VPPM needs to be addressed in patients with small aortic annuli. The options for such patients are implantation of stentless valves or of homografts. The enlargement of the aortic root could also be performed. These techniques, however, can be very demanding. The implantation of a stented valve is easier but carries the risk for VPPM.

The type of stentless valves and their implantation techniques are described very briefly. Of more importance are the postoperative results. These are difficult to compare for two reasons:

1) Stentless valves do no form a homogenous group.

2) Patients series can differ in age, co-morbid conditions and other characteristics.

Therefore, patients baseline characteristics should be described as completely as possible. The postoperative results for stentless valves seemed to be comparable with those of stented counterparts. For both, stented ans stentless devices, patient related factors have the most impact on the outcome.

The presence or absence of VPPM could be related to hemodynamic parameters, such as EOAI and TVG. This relationship, however, is not straightforward. Moreover, VPPM needs to be defined and graded properly. VPPM seems only to be clinically relevant in patients with a decreased LVF. In patients with a normal LVF, VPPM does not seem to affect the postoperative outcome in terms of survival, LVM regression and freedom of CHF.

The development of SVD could be held responsible for a recurrent hemodynamic burden on the LV. This burden could play a role in reappearance of LVH. SVD was thought to occur less in stentless valves, since turbulence and hence stress on the leaflets would be reduced. In some stentless devices this seems not to be the case.

Availability of 15 year results is needed, but this is not easy to obtain since the median age in patient series is rather high.

For patients deemed unfit to undergo AVR, BAV has been tried as a less traumatic alternative. Recurrence of stenosis within months has been observed, however. BAV has been abandoned, and alternatives have been explored.

Implantation of a valve through a catheter has proven experimentally feasible and has been performed for the first time in a patient in 2003. The more cumbersome transseptal technique has been replaced by the trans-arterial technique. This procedure has not always been applicable in patients with atheromatosis of the femoral and iliac arteries or of the aorta. As alternative, a trans-apical approach has been developed. TAVI might also become attractive as “valve-in-valve” procedure, for patients with a degenerated BHV.

The current procedure needs an elaborate imaging system, with a pre-procedural study of the anatomy of the aortic root. Interference with anatomical structures such as the coronary arteries and the conduction system needs to be avoided. Attachment and anchoring systems needs to be adequate, to avoid secondary displacement.

The selection of patients is problematic: the EuroSCORE tends to overestimate operative mortality of conventional AVR, especially in high risk patients. Such patients might be denied this operation unjustly. A RCT, comparing TAVI with medical treatment and with conventional AVR might seem desirable.

The early clinical and hemodynamic results in terms of TVG and AVA seem acceptable but PPVL could be a problem. A recently published RCT, which compared medical treatment or BAV with TAVI, showed superior clinical and hemodynamic results for the latter. PPVL has been considered as acceptable and has not worsened after one year. Vascular complications, bleeding an stroke have been troubling. Technical improvements with smaller delivery systems might offer relief. A second RCT has shown the non inferiority of TAVI, compared to conventional AVR, at least for the first postoperative year. TAVI offers the advantage of being less traumatic, compared to open surgery.

These results make clear that TAVI is here to stay.

The development of tissue engineered heart valves has seemed promising: with its development, a living tissue, capable of growth, repair and remodelling would cure the valve disease. Nevertheless, TEHV will have to compete with well established procedures and devices such as pericardial BHV.

The release of a device that can compete with currently available valves will take probably many more years. The development of TEHV is complex and requires several steps.

First, the scaffold has to be chosen: a synthetic and biodegradable device or a decellularized scaffold from biological origin. For the latter, many decellularization protocols exist, all with their pro’s and con’s.

Second, the decision for cell reseeding has to be made. The source for the cells has its importance. Differentiated cells of the same type but from a different region (vascular EC vs. valvular EC) can behave differently. Autologous mesenchymal stem cells derived from bone marrow and progenitor cells from other sources seem promising.

After reseeding, culturing in a bioreactor can improve the biomechanical properties of the device. Much depends however on the mechanical loading protocols and on the biochemical composition of the culture medium. Small differences in such protocols lead to a great variety of tissues.

It seems that the “silver bullet”, leading to the desired differentiation of the seeded cells, which are capable of remodelling an repairing the ECM, still has to be found. Moreover, long-term animal studies, in vivo evaluation of the device and bench-to-bed series are still lacking. Attempts to implant TEHV in young patients with congenital heart disease were and still are not promising.