**3. Pathogenesis**

Indications for aortic valve replacement are either aortic stenosis, or aortic insufficiency or combined lesions. It is important to distinguish between the indications for aortic valve due to the fact that aortic insufficiency is a risk factor in itself for worse outcome following surgery beyond the impact of reduced left ventricular function.

(Chaliki et al., 2002; Sionis et al., 2010)

34% of all the patients with valve pathologies referred to cardiac surgery are patients with aortic stenosis but only 10% are admitted with aortic insufficiency. (Vahanian et al. 2007 ESC, VHD Guidelines, 2007) Around 10% of the patients with aortic stenosis have combined lesions, but stenosis is the clinically predominant pathology in these cases and therefore these lesions are included into the statistics of aortic stenosis.

#### **3.1 Aortic regurgitation (AR)**

The literature regarding aortic valve replacement in patients with aortic insufficiency and impaired ejection fraction is extremely limited with very few patients studied.

Aortic insufficiency as compared to aortic stenosis turns out to be a significant predictor of both mortality and morbidity after aortic valve replacement. Chaliki et al. investigated 450 patients with aortic insufficiency. Only about 10% (n=43) of those patients had a severely impaired left ventricular function (<35%). A major finding of the study is that these patients constitute a high risk group even after successful surgery. The operative mortality rate in this group was excessive with 14% as compared to patients with moderately impaired and normal ejection fraction, with 6.7% and 3.7% mortality rates respectively. This difference becomes even more pronounced in the long term follow-up: At 10 years after surgery only 41% of the patients with low ejection fraction survived as opposed to 56% and 70% in patients with moderately impaired EF and normal EF respectively. Of note, aortic valve replacement for aortic insufficiency does not lead to any significant improvement in pumpfunction regardless of the preoperative ejection fraction. (Chaliki et al. 2002) (table 1)

In view of the high risk of AVR in patients with heart failure, surgery should ideally be performed before such a severe decrease in EF occurs. However, patients do remain asymptomatic for a long time even if the ejection fraction is already reduced. The decision to recommend operative intervention to asymptomatic patients with chronic, severe aortic regurgitation is very difficult because aortic valve replacement continues to entail immediate risk, and biologic and mechanical valves still have problems resulting in significant mortality and morbidity. (Scognamiglio, et al., 2005) On the other hand for patients who

define reduced left ventricular ejection fraction as <60%, which is in fact an unusual cut off

Sharony et al. included patients with an ejection fraction < 40% in their study on aortic valve replacement in patients with impaired ventricular function. (Sharony et al., 2003) Mihaljevic T. et al. used a more complex system including 5 subgroups according to cardiac pumpfunction. Impairment of LV function was graded qualitatively as follows: EF 50% or greater, none; EF 40% to 49%, mild EF 35-39% moderate; EF 26%-34% moderately severe, and EF 25% or less, severe. They demonstrated the prognostic value of this grading system in previous studies. (Mihaljevic T. et al., 2008) For the sake of clearness of this book chapter we include scientific studies with a cut off level of less than 40% and cite the exact values as

Indications for aortic valve replacement are either aortic stenosis, or aortic insufficiency or combined lesions. It is important to distinguish between the indications for aortic valve due to the fact that aortic insufficiency is a risk factor in itself for worse outcome following

34% of all the patients with valve pathologies referred to cardiac surgery are patients with aortic stenosis but only 10% are admitted with aortic insufficiency. (Vahanian et al. 2007 ESC, VHD Guidelines, 2007) Around 10% of the patients with aortic stenosis have combined lesions, but stenosis is the clinically predominant pathology in these cases and therefore

The literature regarding aortic valve replacement in patients with aortic insufficiency and

Aortic insufficiency as compared to aortic stenosis turns out to be a significant predictor of both mortality and morbidity after aortic valve replacement. Chaliki et al. investigated 450 patients with aortic insufficiency. Only about 10% (n=43) of those patients had a severely impaired left ventricular function (<35%). A major finding of the study is that these patients constitute a high risk group even after successful surgery. The operative mortality rate in this group was excessive with 14% as compared to patients with moderately impaired and normal ejection fraction, with 6.7% and 3.7% mortality rates respectively. This difference becomes even more pronounced in the long term follow-up: At 10 years after surgery only 41% of the patients with low ejection fraction survived as opposed to 56% and 70% in patients with moderately impaired EF and normal EF respectively. Of note, aortic valve replacement for aortic insufficiency does not lead to any significant improvement in pump-

impaired ejection fraction is extremely limited with very few patients studied.

function regardless of the preoperative ejection fraction. (Chaliki et al. 2002) (table 1)

In view of the high risk of AVR in patients with heart failure, surgery should ideally be performed before such a severe decrease in EF occurs. However, patients do remain asymptomatic for a long time even if the ejection fraction is already reduced. The decision to recommend operative intervention to asymptomatic patients with chronic, severe aortic regurgitation is very difficult because aortic valve replacement continues to entail immediate risk, and biologic and mechanical valves still have problems resulting in significant mortality and morbidity. (Scognamiglio, et al., 2005) On the other hand for patients who

level. (Ali et al., 2006)

**3. Pathogenesis** 

described in the respective publications.

(Chaliki et al., 2002; Sionis et al., 2010)

**3.1 Aortic regurgitation (AR)** 

surgery beyond the impact of reduced left ventricular function.

these lesions are included into the statistics of aortic stenosis.


have AR and already have severe LV dysfunction, an important issue to consider is whether AVR represents too high a risk and conservative treatment is preferable.

reprint from Chaliki HP, et al. 2002 with permission of Circulation

Table 1. Comparision of pre- and postoperative echocardiographic values (Chaliki et al. 2002)

Natural history studies have focused mainly on asymptomatic patients with normal function. In a recent study patients were stratified according to their ejection fraction and it was demonstrated that those with markedly lower EF had a higher rate of congestive heart failure than patients who had moderately reduced or normal EF before AVR.

The outcome of conservatively treated patients with even mild LV dysfunction is poor. Indeed, patients with either EF 55% or LV systolic dimension 25 mm/m2, even if asymptomatic at presentation, have excessive long-term mortality rates if treated conservatively. Although patients with severe LV dysfunction could not be analyzed specifically, the uniform risk increase with decreasing EF under conservative treatment suggests that such patients are at very high risk if not operated on and that an aggressive approach is justified.

Sionis et al. even evaluated if it is beneficial to offer these patients cardiac transplantation instead of performing aortic valve replacement. But they conclude from their data of only 27 patients that while the mortality of patients with aortic valve insufficiency and impaired ventricular function undergoing aortic valve replacement is high, it is not excessively high justifying listing for transplantation. Additionally a lot of these patients do not develop heart failure and therefore still benefit from AVR. (Sionis et al., 2010)

Conversely, although patients with a markedly low EF and severe AR are at high risk, their medium-term outcome is not uniformly ominous. The usual operative mortality rate reported for AVR ranges from 1% to 7%. Chaliki et al. show excessive operative mortality rates among patients with markedly low EF, but it is not overwhelming. A majority of patients remain free of heart failure 10 years after AVR. Therefore, a notable period of eventfree survival can be achieved in most patients after correction of AR despite their very low preoperative EF. The functional status of most patients improves after surgery, irrespective of preoperative EF. Thus, a markedly low EF (<35%) is not, in our judgment, a contraindication to AVR. (Chaliki 2002)

In light of the fact that patients with aortic insufficiency and reduced ejection fraction do not benefit from aortic valve replacement regarding pump function it would be necessary to reevaluate the guidelines for aortic valve replacement in those patients, since currently AVR in asymptomatic patients is only recommended when EF declines down to <50% or end-

Aortic Valve Surgery and Reduced Ventricular Function 155

study participants had aortic sclerosis (a thickening of the valve or calcification without significant obstruction). A slight predominance of the disorder was noted in men. 2% of all

A clear increase in prevalence of sclerosis was seen with age: 20% in patients aged 65–75 years, 35% in those aged 75–85 years, and 48% in patients older than 85 years. For the same

The only effective therapy is the mechanical relief of the obstruction. (Carabello, 2009) with operative replacement of the valve or transcatheter aortic valve implantation (TAVI) as treatment options. Therefore it is one of the clearest decisions for a doctor to recommend valve replacement for aortic stenosis. Balloon valvuloplasty plays an important role in the pediatric population but a very limited role in adults because its efficacy is low while

Fig. 2. Mean survival of patients with symptoms of aortic stenosis. (Carabello et al. 2009)

patients had frank aortic stenosis.

complication rates are high (>10%).

Reprinted with permission of the Lancet

age-groups, 1.3%, 2.4%, and 4% had frank aortic stenosis.

diastolic diameter increases >70 mm or end-systolic diameter increases > 50mm (or >25 mm/m2 body surface area)

However it is difficult to schedule patients with aortic insufficiency and normal EF for surgery because often these patients remain asymptomatic until the pump-function is markedly reduced. When EF is significantly impaired the outcome of surgery is worse but on the other hand the mortality rate of asymptomatic AR patients is rather low and surgery does not improve quality of life. So it remains a matter of debate if the time point of surgery has to be delayed in a later stage if the surgical outcome becomes worse or if surgery should be performed as soon as possible even in asymptomatic patients as long as left ventricular function is still normal

Scognamiglio et al. showed that patients with AR and reduced LVEF can benefit from an unloading therapy with Nifedipine, so that the need for surgery can be delayed by prolonging the asymptomatic period while preserving LVEF (Scognamiglio 2005)

From the data from the literature we conclude that patients with AI and impaired EF should be considered at high risk, carefully evaluated and if suitable scheduled for surgical intervention as soon as possible.

#### **3.2 Aortic stenosis (AS)**

In developed countries, aortic stenosis is the most prevalent of all valvular heart diseases. It is primarily a manifestation in patients with advanced age. The disorder is becoming more frequent as the average age of the population is increasing. Symptomatic severe AS is a lethal disease if left untreated. (Figure 1, Figure 2, Carabello, 2009)

Aortic valvular abnormalities are quite frequent in old patients. In the Cardiovascular Health Study, in which 5201 men and women older than 65 years were examined, 26% of

Reprinted with permission of the Lancet

Fig. 1. Survival of patients with aortic stenosis over time. After a long latent asymptotic period. during witch time survival is nearly normal, survival declines precipitously once symptoms develop. Adapted with permission from Ross and colleagues (Carabello et al. 2009)

diastolic diameter increases >70 mm or end-systolic diameter increases > 50mm (or >25

However it is difficult to schedule patients with aortic insufficiency and normal EF for surgery because often these patients remain asymptomatic until the pump-function is markedly reduced. When EF is significantly impaired the outcome of surgery is worse but on the other hand the mortality rate of asymptomatic AR patients is rather low and surgery does not improve quality of life. So it remains a matter of debate if the time point of surgery has to be delayed in a later stage if the surgical outcome becomes worse or if surgery should be performed as soon as possible even in asymptomatic patients as long as left ventricular

Scognamiglio et al. showed that patients with AR and reduced LVEF can benefit from an unloading therapy with Nifedipine, so that the need for surgery can be delayed by

From the data from the literature we conclude that patients with AI and impaired EF should be considered at high risk, carefully evaluated and if suitable scheduled for surgical

In developed countries, aortic stenosis is the most prevalent of all valvular heart diseases. It is primarily a manifestation in patients with advanced age. The disorder is becoming more frequent as the average age of the population is increasing. Symptomatic severe AS is a

Aortic valvular abnormalities are quite frequent in old patients. In the Cardiovascular Health Study, in which 5201 men and women older than 65 years were examined, 26% of

Fig. 1. Survival of patients with aortic stenosis over time. After a long latent asymptotic period. during witch time survival is nearly normal, survival declines precipitously once symptoms

develop. Adapted with permission from Ross and colleagues (Carabello et al. 2009)

prolonging the asymptomatic period while preserving LVEF (Scognamiglio 2005)

lethal disease if left untreated. (Figure 1, Figure 2, Carabello, 2009)

mm/m2 body surface area)

function is still normal

intervention as soon as possible.

Reprinted with permission of the Lancet

**3.2 Aortic stenosis (AS)** 

study participants had aortic sclerosis (a thickening of the valve or calcification without significant obstruction). A slight predominance of the disorder was noted in men. 2% of all patients had frank aortic stenosis.

A clear increase in prevalence of sclerosis was seen with age: 20% in patients aged 65–75 years, 35% in those aged 75–85 years, and 48% in patients older than 85 years. For the same age-groups, 1.3%, 2.4%, and 4% had frank aortic stenosis.

The only effective therapy is the mechanical relief of the obstruction. (Carabello, 2009) with operative replacement of the valve or transcatheter aortic valve implantation (TAVI) as treatment options. Therefore it is one of the clearest decisions for a doctor to recommend valve replacement for aortic stenosis. Balloon valvuloplasty plays an important role in the pediatric population but a very limited role in adults because its efficacy is low while complication rates are high (>10%).

Fig. 2. Mean survival of patients with symptoms of aortic stenosis. (Carabello et al. 2009)

Aortic Valve Surgery and Reduced Ventricular Function 157

Reprinted with permission of the Journal of Thoracic and cardiovascular surgery

Reprinted with permission of the Journal of Thoracic and cardiovascular surgery

ventricular dysfunction (EF<40%) (Mihaljevic et al. 2008)

Fig. 5. Long term (> 1 year) survival of patients undergoing AVR with and without

respectively. (Hannan et al. 2009)

Fig. 4. Hannan and coworkers investigated the survival after aortic valve replacement with concomitant CABG according to cardiac riskfactors. The Dashed line is the survival of ageand sex-matched population. Solid and dash-dotted lines represent survival for aortic valve re- placement patients with and without concomi- tant coronary artery bypass grafting,

Reprinted with permission of the Lancet

Fig. 3. Survival of asymptomatic patients with severe aortic stenosis versus age-matched US population. (Carabello et al. 2009)

In asymptomatic patients with aortic stenosis survival is comparable to an aged matched population (figure 3). Therefore there is no point in treating asymptomatic patients. As soon as those patients develop symptoms, survival is markedly reduced (Grossi et al. 2008) However one of the problems are asymptomatic patients with severe stenosis and reduced ejection fraction at time of surgery. It is recommended to perform aortic valve replacement in patients with asymptomatic severe aortic stenosis and an ejection fraction <50 (class of recommendation I) however the level of evidence is only C. (Vahanian 2007 ESC Guidelines) According to the paper by Hannan E. and colleagues, as soon as the aortic valve is replaced in these patients risk adjusted survival returns to level that is not statistically different to the survival of people from the general population who are age and sex matched to this group. As with aortic regurgitation reduced ejection fraction emerges as one of the most significant risk factors of early and late mortality (Figure 4, Hannan et al. 2009).

Michaljevic and coworkers showed that among other risk factors like older age, greater degree of aortic stenosis, greater LV mass index, smaller standardized prosthesis-patient size, in addition LV dysfunction and advanced symptoms influence the long term survival of patients undergoing aortic valve replacement (Figure 5, Mihaljevic et al. 2008)

Fig. 3. Survival of asymptomatic patients with severe aortic stenosis versus age-matched US

In asymptomatic patients with aortic stenosis survival is comparable to an aged matched population (figure 3). Therefore there is no point in treating asymptomatic patients. As soon as those patients develop symptoms, survival is markedly reduced (Grossi et al. 2008) However one of the problems are asymptomatic patients with severe stenosis and reduced ejection fraction at time of surgery. It is recommended to perform aortic valve replacement in patients with asymptomatic severe aortic stenosis and an ejection fraction <50 (class of recommendation I) however the level of evidence is only C. (Vahanian 2007 ESC Guidelines) According to the paper by Hannan E. and colleagues, as soon as the aortic valve is replaced in these patients risk adjusted survival returns to level that is not statistically different to the survival of people from the general population who are age and sex matched to this group. As with aortic regurgitation reduced ejection fraction emerges as one of the most significant

Michaljevic and coworkers showed that among other risk factors like older age, greater degree of aortic stenosis, greater LV mass index, smaller standardized prosthesis-patient size, in addition LV dysfunction and advanced symptoms influence the long term survival

of patients undergoing aortic valve replacement (Figure 5, Mihaljevic et al. 2008)

risk factors of early and late mortality (Figure 4, Hannan et al. 2009).

Reprinted with permission of the Lancet

population. (Carabello et al. 2009)

Reprinted with permission of the Journal of Thoracic and cardiovascular surgery

Fig. 4. Hannan and coworkers investigated the survival after aortic valve replacement with concomitant CABG according to cardiac riskfactors. The Dashed line is the survival of ageand sex-matched population. Solid and dash-dotted lines represent survival for aortic valve re- placement patients with and without concomi- tant coronary artery bypass grafting, respectively. (Hannan et al. 2009)

Reprinted with permission of the Journal of Thoracic and cardiovascular surgery

Fig. 5. Long term (> 1 year) survival of patients undergoing AVR with and without ventricular dysfunction (EF<40%) (Mihaljevic et al. 2008)

Aortic Valve Surgery and Reduced Ventricular Function 159

A more recent paper by Clavel et. al. used a slightly different definition with an aortic valve area of <1.2 cm2 and <40% ejection fraction however a mean gradient of <40 mmHg. (Clavel, et al. 2008) This multicenter study showed that patients with low flow low gradient AS are a high risk population with an operative mortality of 18% and 3-year survival rates

In a best evidence topic of Subramanian et al. performed a meta analysis of the current literature on severe aortic stenosis but poor left ventricular function with no contractile reserve. To discuss whether it is ever worth contemplating aortic valve replacement in this setting. Out of the 251 papers screened for this analysis 14 presented the best evidence to

The conclusion of the study was that patients with severe aortic stenosis and a contractile reserve of <20% improvement in stroke volume on dobutamine stress testing have a very poor prognosis of only 10-20% at two years. Heart transplant would offer the best chance of survival to those eligible but for those not eligible, a surgical option should not be discounted for selected patients. The American Heart Association guidelines state that prognosis is very poor for either medical or surgical treatment, but the European Society of Cardiology guidelines state that surgery can be performed in these patients but should take into account the clinical condition of the patient. The operative mortality is around 30% and the French Multicentre study on low gradient aortic stenosis has shown that if the patient survives there is likely to be an improvement in symptoms and ejection fraction. Thus, absence of contractile reserve on stress testing does not exclude myocardial recovery after surgery, although it is a strong predictor for operative mortality. (Subramanian et al;

As stated above poor left ventricular function is a negative prognostic factor after aortic valve Replacement regardless the type of the aortic valve disease. Therefore it is important to find objective prognostic variables to identify patients who benefit the most from a

Several studies have reported various approaches to improve postoperative outcome in

Biomarkers, especially pro-BNP have been associated with heart failure and poor

Pro-BNP might be an objective prognostic variable for outcome after surgical aortic valve

NT pro-BNP levels have been to be elevated in patients with aortic valve stenosis. And has already been suggested to monitor the progression of the disease non-invasively as well as to time surgery for aortic stenosis optimally. Further more pro-BNP correlates with

At our department it has become standard of care to administer a 24 hour infusion course of levosimendan 3 days prior to surgery in patients with low EF and high proBNP levels, in order to precondition patients for surgery (data not yet published). In our experience pro-

surgical intervention and to exclude patients with an excessively high operative risk.

**4.1 B-Type natriuretic peptide as a predictor of heart failure following aortic valve** 

of only 57%.

2008)

theses patients.

ventricular function.

replacement. (Nozohoor et al. 2009)

endsystolic wallstress in patients with aortic stenosis.

BNP decrease more than 50% on average due to this treatment.

**surgery** 

answer this question.

**4. Strategies for improved outcome** 

Since AS is a disease of elderly patients the outcome depends on comorbidities and concomitant surgical procedures (CABG). Onset of dyspnoea and other symptoms of heart failure presage the worst outlook for the patient with aortic stenosis. Whereas concentric hypertrophy helps to maintain systolic performance, increased wall thickness impairs diastolic function. The percentage of patients with low ejection fraction in the surgical population of AS ranges from 10-15%

As in aortic insufficiency, valve replacement for stenosis has become a routine procedure and again patients with reduced ejection fraction represent a challenge for the cardiac surgeon. Low ejection fraction has been identified as a significant risk factor for both reduced early and late mortality after AVR.

#### **3.2.1 Low gradient low flow aortic stenosis**

Low gradient low flow AS is defined as aortic stenosis with an effective aortic area <1cm2, LVEF <40% and a mean transaortic pressure gradient of < 30 mmHg. Assessment is usually performed by dobutamine stress testing. This is neccessary to confirm that the reduced effective orifice area is in fact severe rather than an effect of low flow on a mild or moderately stenosed valve (2) Contractile reserve on dobutamine stress testing is defined by an increase in the systolic velocity integral or stroke volume by at least 20% during dobutamine infusion. Aortic valve replacement is recommended by the AHA for patients with low gradient low flow aortic stenosis with contractile reserve (Class1: level of evidence C) (Monin, et al. 2003)

Especially patients without contractile reserve represent a high risk group (figure 6). Monin and colleagues showed that patients with contractile reserve have better prognosis than those without contractile reserve. Both groups of patients have much better life expectancies when the diseased valve is replaced in comparison to medical treatment only. (figure 6)

Reprint with permission of Circulation

Fig. 6. Monin et al. showed that patients without contractile reserve (group II) perform worse than those with contractile reserve (group I). Nevertheless for both groups valve replacement has much better results than medical treatment alone

Since AS is a disease of elderly patients the outcome depends on comorbidities and concomitant surgical procedures (CABG). Onset of dyspnoea and other symptoms of heart failure presage the worst outlook for the patient with aortic stenosis. Whereas concentric hypertrophy helps to maintain systolic performance, increased wall thickness impairs diastolic function. The percentage of patients with low ejection fraction in the surgical

As in aortic insufficiency, valve replacement for stenosis has become a routine procedure and again patients with reduced ejection fraction represent a challenge for the cardiac surgeon. Low ejection fraction has been identified as a significant risk factor for both

Low gradient low flow AS is defined as aortic stenosis with an effective aortic area <1cm2, LVEF <40% and a mean transaortic pressure gradient of < 30 mmHg. Assessment is usually performed by dobutamine stress testing. This is neccessary to confirm that the reduced effective orifice area is in fact severe rather than an effect of low flow on a mild or moderately stenosed valve (2) Contractile reserve on dobutamine stress testing is defined by an increase in the systolic velocity integral or stroke volume by at least 20% during dobutamine infusion. Aortic valve replacement is recommended by the AHA for patients with low gradient low flow aortic stenosis with contractile reserve (Class1: level of evidence

Especially patients without contractile reserve represent a high risk group (figure 6). Monin and colleagues showed that patients with contractile reserve have better prognosis than those without contractile reserve. Both groups of patients have much better life expectancies when the diseased valve is replaced in comparison to medical treatment only. (figure 6)

Fig. 6. Monin et al. showed that patients without contractile reserve (group II) perform worse than those with contractile reserve (group I). Nevertheless for both groups valve

replacement has much better results than medical treatment alone

population of AS ranges from 10-15%

C) (Monin, et al. 2003)

Reprint with permission of Circulation

reduced early and late mortality after AVR.

**3.2.1 Low gradient low flow aortic stenosis** 

A more recent paper by Clavel et. al. used a slightly different definition with an aortic valve area of <1.2 cm2 and <40% ejection fraction however a mean gradient of <40 mmHg. (Clavel, et al. 2008) This multicenter study showed that patients with low flow low gradient AS are a high risk population with an operative mortality of 18% and 3-year survival rates of only 57%.

In a best evidence topic of Subramanian et al. performed a meta analysis of the current literature on severe aortic stenosis but poor left ventricular function with no contractile reserve. To discuss whether it is ever worth contemplating aortic valve replacement in this setting. Out of the 251 papers screened for this analysis 14 presented the best evidence to answer this question.

The conclusion of the study was that patients with severe aortic stenosis and a contractile reserve of <20% improvement in stroke volume on dobutamine stress testing have a very poor prognosis of only 10-20% at two years. Heart transplant would offer the best chance of survival to those eligible but for those not eligible, a surgical option should not be discounted for selected patients. The American Heart Association guidelines state that prognosis is very poor for either medical or surgical treatment, but the European Society of Cardiology guidelines state that surgery can be performed in these patients but should take into account the clinical condition of the patient. The operative mortality is around 30% and the French Multicentre study on low gradient aortic stenosis has shown that if the patient survives there is likely to be an improvement in symptoms and ejection fraction. Thus, absence of contractile reserve on stress testing does not exclude myocardial recovery after surgery, although it is a strong predictor for operative mortality. (Subramanian et al; 2008)
