**Clinical and Hemodynamic Performance of the Sorin Mitroflow Pericardial Bioprosthesis**

W. R. E. Jamieson1, C. A. Yankah2, R. Lorusso3,

O. Benhameid1, R. I. Hayden1, R. Forgie4 and H. Ling1

*1University of British Columbia, Vancouver, 2Berlin, 3Brescia, 4Saint John, 1,4Canada 2Germany 3Italy* 

## **1. Introduction**

The Mitroflow aortic pericardial bioprosthesis has been available worldwide since 1982, except in the United States, Japan, and China. The original prosthesis was designated model 11, and the model 12, introduced in 1991, was approved in the United States in November 2007. The current model Mitroflow LX is available on the worldwide market, except for Japan and China.

The objective of this review is to document the clinical and hemodynamic performance of the Mitroflow pericardial bioprosthesis and to document the modifications of the Mitroflow LX model and the recently introduced calcium mitigation treatment of pericardial tissue.

## **2. Device specifications**

The Mitroflow pericardial bioprosthesis has had three design changes since its introduction in 1982 (Figure 1A-J).

There are the general specifications of all three models of the prosthesis. The prosthesis is formulated with a single unit acetal homopolymer stent that provides flexibility and strength at implantation without the risk of residual distortion. The stent is low-profile to afford clearance of the coronary ostia, and to avoid interfering with the sinotubular junction in narrow aortic roots. The stent is also creep resistant. The stent is covered with surgicalgrade polyester cloth and incorporates a tungsten impregnated radiopaque, medical-grade silicone sewing ring that is tiny and soft so it can be easily attached to the patient's tissue annulus. The silicone sewing ring also provides a secure hemostatic seal. The pericardium is mounted externally to maximize the flow area with wide, synchronous opening of the leaflets. The pericardium is used as a single component without critical stent-post sutures. The pericardial thickness is related to the size of the prosthesis. The pericardial tissue is selected for uniformity, and this tissue is sewn onto the external surface of the covered stent.

Clinical and Hemodynamic Performance of the Sorin Mitroflow Pericardial Bioprosthesis 167

The pericardial tissue undergoes leaflet formation in the model 11 and 12 prostheses, and then fixation in 0.5% glutaraldehyde. The difference between model 11 and model 12 was that the polyester cloth was reversed so that the ribbed side was external rather than

The distinctive features of the initial models of the Mitroflow prostheses are inclusive in the current LX model. The design features of the various models are important when evaluating the current LX model. Model LX is a variation of model 12 with manufacturing modifications. The differences between the two models are related to manufacturing processes and minor design variations, but the material components remain the same as in model 12. The changes are these: because model LX uses automatic machine sewing instead of manual sewing for the fabric tube seam in the covered stent, there is a change in the fabric orientation of the covered stent. The number of sewing cuff base seams has been reduced to one seam. Model LX has changed tissue fixation with 0.2% glutaraldehyde of the bovine pericardium from postfixation (after stent application) to prefixation (before stent application) to facilitate tissue application on the stent. This change is from a manual leaflet formation method to an automated leaflet formation method. These manufacturing process improvements for model LX were implemented to increase manufacturing efficiencies, not

The next major change of the Mitroflow pericardial bioprosthesis is the addition of calcium mitigation therapy. Mitroflow models 11 and 12 did not have calcium mitigation therapy incorporated in the manufacturing process. The manufacturing processes are to control or reduce degeneration of biological tissue, induced by calcification, tissue stress, or both. The major contributing factors in the degeneration of biological tissue (porcine or pericardium) are considered to be residual aldehydes and the presence of phospholipids. The major manufacturers of bioprostheses have used chemical formulations to control one or both of

The Sorin Group (Milan, Italy and Vancouver, Canada), manufacturer of the Mitroflow pericardial bioprosthesis, has recently completed an evaluation of incorporating calcium mitigation in the manufacturing process of the prosthesis and received market approval in Europe in July 2011 and subsequently in Canada. The Sorin Group has used methodology to control residual aldehydes in their other bioprostheses. This methodology is a detoxification process post-glutaraldehyde with homocysteic acid to neutralize unbound residual aldehydes. The methodology for the Mitroflow bioprosthesis is a chemical solution effective

The process has been named phospholipid reduction therapy (PRT), a patented chemical process that uses long-chain alcohol aqueous solutions to remove phospholipids from tissue materials. The process exposes the bovine pericardium to a buffered ethanolic solution containing long-chain aliphatic alcohol for specific times and temperatures. The PRT treatment is a sterile-filtered solution of 5% 1,2-Octanediol in ethanol and HEPES solutions. An evaluation of 5% 1,2-Octanediol in the rat subcutaneous model has revealed a very significant reduction of tissue calcium and phosphorus (Figure 2) (Pettenazzo et al., 2008). Incorporating PRT with homocysteic acid aldehyde control therapy is under consideration

The Sorin Group (2011) has documented in their product literature the specifications and *in vitro* effective orifice areas (EOA) by valve size. The reported internal diameter/EOA for size 19 was 15.4 mm/1.7 cm2; size 21, 17.3 mm/2.1 cm2; size 23, 19.0 mm/2.8 cm2; and size

in reducing the phospholipid content of bovine pericardium (Figure 2).

to control both known etiologies of tissue mineralization.

internal where there was a risk of abrasion.

to affect the design or performance of the prosthesis.

these etiologies since the early 1980s.

25, 21.0 mm/3.2 cm2.

Fig. 1. (A) Acetyl homopolymer stent. (B) Stent covered polyester cloth. (C) Pericardium mounted externally. (D) Silicone sewing ring. (E) Cutaway of Prosthesis. (F) Aortic aspect of prosthesis. (G) Aortic aspect leaflets open. (H) Complete prosthesis – titled profile. (I) Complete prosthesis – lateral profile. (J) Supra-annular implantation of the prosthesis. Model 12 - B,C,F and Model LX - G,H,I

(D) (E) (F)

(A) (B)

(G) (H) (I)

(J)

Model 12 - B,C,F and Model LX - G,H,I

Fig. 1. (A) Acetyl homopolymer stent. (B) Stent covered polyester cloth. (C) Pericardium mounted externally. (D) Silicone sewing ring. (E) Cutaway of Prosthesis. (F) Aortic aspect of prosthesis. (G) Aortic aspect leaflets open. (H) Complete prosthesis – titled profile. (I) Complete prosthesis – lateral profile. (J) Supra-annular implantation of the prosthesis.

(C)

The pericardial tissue undergoes leaflet formation in the model 11 and 12 prostheses, and then fixation in 0.5% glutaraldehyde. The difference between model 11 and model 12 was that the polyester cloth was reversed so that the ribbed side was external rather than internal where there was a risk of abrasion.

The distinctive features of the initial models of the Mitroflow prostheses are inclusive in the current LX model. The design features of the various models are important when evaluating the current LX model. Model LX is a variation of model 12 with manufacturing modifications. The differences between the two models are related to manufacturing processes and minor design variations, but the material components remain the same as in model 12. The changes are these: because model LX uses automatic machine sewing instead of manual sewing for the fabric tube seam in the covered stent, there is a change in the fabric orientation of the covered stent. The number of sewing cuff base seams has been reduced to one seam. Model LX has changed tissue fixation with 0.2% glutaraldehyde of the bovine pericardium from postfixation (after stent application) to prefixation (before stent application) to facilitate tissue application on the stent. This change is from a manual leaflet formation method to an automated leaflet formation method. These manufacturing process improvements for model LX were implemented to increase manufacturing efficiencies, not to affect the design or performance of the prosthesis.

The next major change of the Mitroflow pericardial bioprosthesis is the addition of calcium mitigation therapy. Mitroflow models 11 and 12 did not have calcium mitigation therapy incorporated in the manufacturing process. The manufacturing processes are to control or reduce degeneration of biological tissue, induced by calcification, tissue stress, or both. The major contributing factors in the degeneration of biological tissue (porcine or pericardium) are considered to be residual aldehydes and the presence of phospholipids. The major manufacturers of bioprostheses have used chemical formulations to control one or both of these etiologies since the early 1980s.

The Sorin Group (Milan, Italy and Vancouver, Canada), manufacturer of the Mitroflow pericardial bioprosthesis, has recently completed an evaluation of incorporating calcium mitigation in the manufacturing process of the prosthesis and received market approval in Europe in July 2011 and subsequently in Canada. The Sorin Group has used methodology to control residual aldehydes in their other bioprostheses. This methodology is a detoxification process post-glutaraldehyde with homocysteic acid to neutralize unbound residual aldehydes. The methodology for the Mitroflow bioprosthesis is a chemical solution effective in reducing the phospholipid content of bovine pericardium (Figure 2).

The process has been named phospholipid reduction therapy (PRT), a patented chemical process that uses long-chain alcohol aqueous solutions to remove phospholipids from tissue materials. The process exposes the bovine pericardium to a buffered ethanolic solution containing long-chain aliphatic alcohol for specific times and temperatures. The PRT treatment is a sterile-filtered solution of 5% 1,2-Octanediol in ethanol and HEPES solutions. An evaluation of 5% 1,2-Octanediol in the rat subcutaneous model has revealed a very significant reduction of tissue calcium and phosphorus (Figure 2) (Pettenazzo et al., 2008). Incorporating PRT with homocysteic acid aldehyde control therapy is under consideration to control both known etiologies of tissue mineralization.

The Sorin Group (2011) has documented in their product literature the specifications and *in vitro* effective orifice areas (EOA) by valve size. The reported internal diameter/EOA for size 19 was 15.4 mm/1.7 cm2; size 21, 17.3 mm/2.1 cm2; size 23, 19.0 mm/2.8 cm2; and size 25, 21.0 mm/3.2 cm2.

Clinical and Hemodynamic Performance of the Sorin Mitroflow Pericardial Bioprosthesis 169

published extensively on the Mitroflow pericardial bioprosthesis model 11 (Benhameid et al., 2008) and model 12 (Yankah, 2010; ISTHMUS Investigators, 2011, Lorusso, 2011 –

**Author Prosthesis Age Group Actuarial Actual (Years)** 

Mitroflow ≥60 85.2 ± 3.9\* 93.3 ± 1.8\* 12 ≥65 85.0 ± 4.0\* 94.2 ± 1.8\* 12 61-70 95.7 ± 4.3\* 97.4 ± 2.6\* 10

>70 83.2 ± 4.6\* 94.0 ± 1.9\* 12

≥65 71.8 ± 6.0\* 92.6 ± 4.6\* 20

 ≥70 84.8 ± 0.7\* 96.6 ± 0.8\* 20 Mitroflow 75.3 ± 6.8 <60 54.4 ± 3.4 60.9 ± 4.3 18 61-70 62.0 ± 2.6 68.3 ± 3.3 18 >70 78.2 ± 2.6 89.3 ± 2.5 18 <60 75.4 ± 2.9\*\* 87.4 ± 2.3\*\* 18 61-70 87.0 ± 1.6\*\* 92.9 ± 0.4\*\* 18

>70 94.6 ± 0.6\*\* 97.1 ± 0.5\*\* 18

*\*\* Reoperation, Autopsy & Echocardiography (non-prospective) Lorusso – Personal Communication 2011.* 

Benhameid et al. (2008) reported a satisfactory freedom from SVD after 15 years with model 11 for patients ≥70 years old. The majority of other publications provide information on the freedom from SVD in patient populations with model 11 (predominately) and 12 prostheses (Minami et al., 2006; Yankah et al., 2008). These reports provide support for use of the prosthesis in elderly patient populations. Yankah et al. (2008), documented in patients with predominately model 11 prostheses for 20 years, that freedom from SVD was 71.8 ± 6.0% for those ≥65 years old and 84.8 ± 0.7% for those ≥70 years old. Yankah et al. (2010) has since reported on 104 patients <60 years old (age range: 22-60 years) with a linearized rate of 1.9%/patient-year of SVD managed by reoperation with an actual risk of 12% at 10 years. Klieverik et al. (2007) concluded that the Mitroflow valve demonstrated an important complementary role to allograft and pulmonary autografts if implanted in appropriately

The predominant publication on Mitroflow model 12 is Jamieson et al. (2009) (Figure 3A-D). This report provides preliminary support for using the prosthesis in patients 61-70 years old, as well as in patients >70 years old. The 12-year freedom from SVD (actual/actuarial) at explant was 94.4%/85.2% for those ≥60 years old, 94.2%/85.0% for those ≥65 years old, and 94.0%/83.2% for those >70 years old. For patients 61-70 years old, at 10 years, the freedom

 **Mean Age Freedom from SVD (%) Time Interval** 

Personal Communication – ISTHMUS Investigators).

Mitroflow 73.2 ± 0.22

Table 1. Freedom from Structural Valve Deterioration (SVD)

Jamieson et al. (2009)

Yankah et al. (2008)

ISTHMUS (2010)

*\* Reoperation,* 

selected patients.

from SVD at explant was 97.4%/95.7%.

Fig. 2. Results of Phospholipid Reduction Therapy (PRT) in subcutaneous rat model Pettenazzo et al Eur J Cardiothorac Surg 2008

## **3. Implantation technique**

The Mitroflow bioprosthesis can be implanted using either supra-annular or infra-annular techniques. The supra-annular technique is preferable to get the largest valve implanted and to optimize hemodynamic performance (Figure 1J). The supra-annular positioning facilitates a one-to-one annular match and optimal blood flow. The native annulus should be adequately debrided for placement of supra-annular suturing. Since the sewing cuff of the prosthesis is flat and non-scalloped, it may be optimal on some occasions, especially with bicuspid anatomy, to place non-pledgeted everting mattress sutures at the commissures and standard non-everting mattress sutures in the remainder of the annulus for supra-annular implantation.

## **4. Clinical performance**

The clinical performance of the Mitroflow aortic bioprosthesis is comparable to that of other marketed porcine and pericardial bioprostheses (Jamieson, 2011).

The clinical performance of the Mitroflow pericardial bioprosthesis has been reported by several investigative groups (Table 1) ( Benhameid et al., 2008; Minami et al., 2005; Yankah et al., 2008; Yankah et al., 2010; Jamieson et al., 2009; Alvarez et al., 2009; ISTHMUS investigators, 2011; Conte et al., 2010; Jamieson et al., 2009). Actuarial freedom from structural valve deterioration provides an assessment of durability while actual cumulative incidence analysis documents structural valve deterioration in patient groups, such as elderly patients, who are subject to competing risks of death. Actuarial freedom from structural valve deterioration (SVD) overestimates the incidence of SVD, while actual analysis provides the actual risk of failure in specific population groups.

Advancing life expectancy with the increased prevalence of aortic valve degenerative disease brings the need for an aortic bioprosthesis with excellent hemodynamic performance and comparable durability. The University of British Columbia and collaborating centers have published extensively on the Mitroflow pericardial bioprosthesis model 11 (Benhameid et al., 2008) and model 12 (Yankah, 2010; ISTHMUS Investigators, 2011, Lorusso, 2011 – Personal Communication – ISTHMUS Investigators).


*\* Reoperation,* 

168 Aortic Valve

Glutaraldehyde-fixed only Pericardium Phospholipid Reduction Treatment

The Mitroflow bioprosthesis can be implanted using either supra-annular or infra-annular techniques. The supra-annular technique is preferable to get the largest valve implanted and to optimize hemodynamic performance (Figure 1J). The supra-annular positioning facilitates a one-to-one annular match and optimal blood flow. The native annulus should be adequately debrided for placement of supra-annular suturing. Since the sewing cuff of the prosthesis is flat and non-scalloped, it may be optimal on some occasions, especially with bicuspid anatomy, to place non-pledgeted everting mattress sutures at the commissures and standard non-everting mattress sutures in the remainder of the annulus for supra-annular

The clinical performance of the Mitroflow aortic bioprosthesis is comparable to that of other

The clinical performance of the Mitroflow pericardial bioprosthesis has been reported by several investigative groups (Table 1) ( Benhameid et al., 2008; Minami et al., 2005; Yankah et al., 2008; Yankah et al., 2010; Jamieson et al., 2009; Alvarez et al., 2009; ISTHMUS investigators, 2011; Conte et al., 2010; Jamieson et al., 2009). Actuarial freedom from structural valve deterioration provides an assessment of durability while actual cumulative incidence analysis documents structural valve deterioration in patient groups, such as elderly patients, who are subject to competing risks of death. Actuarial freedom from structural valve deterioration (SVD) overestimates the incidence of SVD, while actual

Advancing life expectancy with the increased prevalence of aortic valve degenerative disease brings the need for an aortic bioprosthesis with excellent hemodynamic performance and comparable durability. The University of British Columbia and collaborating centers have

marketed porcine and pericardial bioprostheses (Jamieson, 2011).

analysis provides the actual risk of failure in specific population groups.

Pericardium

Fig. 2. Results of Phospholipid Reduction Therapy (PRT) in subcutaneous rat model

240

180

120

60

0

implantation.

Pettenazzo et al Eur J Cardiothorac Surg 2008

**3. Implantation technique** 

**4. Clinical performance** 

Calcium (mg/g) Phosphorus (mg/g)

*\*\* Reoperation, Autopsy & Echocardiography (non-prospective) Lorusso – Personal Communication 2011.* 

Table 1. Freedom from Structural Valve Deterioration (SVD)

Benhameid et al. (2008) reported a satisfactory freedom from SVD after 15 years with model 11 for patients ≥70 years old. The majority of other publications provide information on the freedom from SVD in patient populations with model 11 (predominately) and 12 prostheses (Minami et al., 2006; Yankah et al., 2008). These reports provide support for use of the prosthesis in elderly patient populations. Yankah et al. (2008), documented in patients with predominately model 11 prostheses for 20 years, that freedom from SVD was 71.8 ± 6.0% for those ≥65 years old and 84.8 ± 0.7% for those ≥70 years old. Yankah et al. (2010) has since reported on 104 patients <60 years old (age range: 22-60 years) with a linearized rate of 1.9%/patient-year of SVD managed by reoperation with an actual risk of 12% at 10 years. Klieverik et al. (2007) concluded that the Mitroflow valve demonstrated an important complementary role to allograft and pulmonary autografts if implanted in appropriately selected patients.

The predominant publication on Mitroflow model 12 is Jamieson et al. (2009) (Figure 3A-D). This report provides preliminary support for using the prosthesis in patients 61-70 years old, as well as in patients >70 years old. The 12-year freedom from SVD (actual/actuarial) at explant was 94.4%/85.2% for those ≥60 years old, 94.2%/85.0% for those ≥65 years old, and 94.0%/83.2% for those >70 years old. For patients 61-70 years old, at 10 years, the freedom from SVD at explant was 97.4%/95.7%.

Clinical and Hemodynamic Performance of the Sorin Mitroflow Pericardial Bioprosthesis 171

**SVD at Explant** 

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

331 297 275 253 233 193 150 114 86 53 31 16 11 4

(C) Fig. 3. Freedom from Structural Valve Deterioration (SVD) at Explant (A) ≥65 years, (B) 65-70

There always remains a concern about the true incidence of SVD unless there is a prospective echocardiographic program, because elderly patients may not be evaluated for prosthesis failure or presented for reoperation. The results in the 61-70 years old age group is encouraging, even though small in number, because patients with a failed prosthesis because of SVD in that age group would more likely to be referred for

In another recent report on the Mitroflow model 12, Alvarez et al. (2009) reported the freedom from SVD by reoperation, as well as the freedom from bioprosthesis degeneration determined from prospective echocardiographic assessment. These authors report their freedom from SVD at an advanced interval with a minimal number of patients at risk. The freedom from SVD at a more appropriate interval seems to be very similar to that documented in Jamieson et al. (2009). We believe that because Alvarez et al. (2009) did a prospective echocardiographic study, some patients had prophylactic

The most extensive published report is the multicenter ISTHMUS study (2011) on 1591 patients, of which 91% had model 12 prostheses. The study reported on SVD by actuarial analysis of echocardiographic diagnoses that used the American Association for Thoracic Surgery (AATS), Society of Thoracic Surgeons (STS), and European Association for Cardio-Thoracic Surgeons (EACTS) guidelines. Personal communication from the ISTHMUS

Years after Implant

Patients > 70 Years

100

90

 80 70 60

50

% Freedom from SVD at Explant

40

30

20

10

Patients at risk

 % Freedom Period Actuarial Actual 1 yr. 100.0±0.0 100.0±0.0 5 yr. 99.5±0.5 99.7±0.3 10 yr. 83.2±4.6 94.0±1.5 12 yr. 83.2±4.6 94.0±1.9

0

years, (C) >70 years

reoperative surgery.

reoperative surgery.

**SVD at Explant** 

(B)

**SVD at Explant** 

**SVD at Explant** 

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0 1 2 3 4 5 6 7 8 9 10

(B)

42 37 36 30 27 24 22 19 15 13 7

Years after Implant

 % Freedom Period Actuarial Actual 1 yr. 100.0±0.0 100.0±0.0 5 yr. 100.0±0.0 100.0±0.0 10 yr. 95.7±4.3 97.4±2.6

365 327 304 278 254 213 168 130 99 64 36 17 12 4

(A)

**SVD at Explant** 

Years after Implant

Patients ≥ 65 Years

Patients at risk

Patients 61-70 Years

Patients at risk

% Freedom from SVD at Explant

 % Freedom Period Actuarial Actual 1 yr. 100.0±0.0 100.0±0.0 5 yr. 99.6±0.4 99.7±0.3 10 yr. 85.0±4.0 94.2±1.4 12 yr. 85.0±4.0 94.2±1.8

% Freedom from SVD at Explant

## **SVD at Explant**

Fig. 3. Freedom from Structural Valve Deterioration (SVD) at Explant (A) ≥65 years, (B) 65-70 years, (C) >70 years

There always remains a concern about the true incidence of SVD unless there is a prospective echocardiographic program, because elderly patients may not be evaluated for prosthesis failure or presented for reoperation. The results in the 61-70 years old age group is encouraging, even though small in number, because patients with a failed prosthesis because of SVD in that age group would more likely to be referred for reoperative surgery.

In another recent report on the Mitroflow model 12, Alvarez et al. (2009) reported the freedom from SVD by reoperation, as well as the freedom from bioprosthesis degeneration determined from prospective echocardiographic assessment. These authors report their freedom from SVD at an advanced interval with a minimal number of patients at risk. The freedom from SVD at a more appropriate interval seems to be very similar to that documented in Jamieson et al. (2009). We believe that because Alvarez et al. (2009) did a prospective echocardiographic study, some patients had prophylactic reoperative surgery.

The most extensive published report is the multicenter ISTHMUS study (2011) on 1591 patients, of which 91% had model 12 prostheses. The study reported on SVD by actuarial analysis of echocardiographic diagnoses that used the American Association for Thoracic Surgery (AATS), Society of Thoracic Surgeons (STS), and European Association for Cardio-Thoracic Surgeons (EACTS) guidelines. Personal communication from the ISTHMUS

Clinical and Hemodynamic Performance of the Sorin Mitroflow Pericardial Bioprosthesis 173

authors (R Lorusso) has provided actual documentation incorporating clinical symptoms, explantation, echocardiographic examination, and autopsy assessment. The 18-year actual/ actuarial freedom from SVD incorporating clinical symptoms, explantation, echocardiographic examination and autopsy examination for patients <60 years old was 87.4%/75.4%, for patients 61-70 years old was 92.9%/87.0%, and for patients >70 years old was 97.1%/94.6%.

The hemodynamic performance of the Mitroflow aortic bioprosthesis is considered excellent

Author 19 mm 21 mm 23 mm 25 mm 27 mm

(2010) 1.05 1.22 1.37 1.60 1.82

and very important in optimizing management for the small aortic annulus (Table 2).

Size

(2008) 1.4 1.5 1.85

Table 2. Hemodynamic Orifice Areas (cm2) for Mitroflow Aortic Bioprostheses

(2009) 1.4 1.4 1.8 1.8

These three studies show excellent hemodynamic performance of the prosthesis. Jamieson et al. (2009) reported that the *in vivo* effective orifice areas by valve size provide the opportunity of avoiding obstructive characteristics for all valve sizes, including optimizing the management of the small aortic annulus. The EOA for the 19-mm and 21-mm prostheses is 1.4 cm2, and for the 23-mm and 25-mm prostheses is 1.8 cm2. These EOAs in the population reported prevented prosthesis-patient mismatch in all valve sizes with indexed

In their study on the hemodynamic performance of 1513 isolated aortic valve replacements, primarily model 11, Yankah et al. (2008) reported that the EOA for size 19-mm prosthesis

The Conte et al. (2010) study of the Mitroflow model 12 prosthesis reported very satisfactory hemodynamic performance. The effective orifice areas for the 19-mm prosthesis was 1.05 cm2; the 21-mm, 1.22 cm2; the 23-mm, 1.37 cm2; the 25-mm, 1.60 cm2; and the 27-mm, 1.82 cm2. The mean gradient for the 19-mm prosthesis was 13.4mm Hg.; the 21-mm, 11.5mm Hg.; the

The Mitroflow LX external mounted pericardial bioprosthesis will continue to provide optimization of hemodynamics regardless of valve size, especially in the small aortic annulus. The addition of anticalcification therapy to the manufacturing process will provide the opportunity to retard or prevent structural valve deterioration of the bioprosthesis and may improve its long-term durability; this prosthesis has clinically been shown to be comparable in durability to other bovine pericardial aortic bioprostheses (Jamieson et al.,

**4. Hemodynamic performance** 

Yankah et al.

Jamieson et al.

Conte et al.

EOAs ranging from 0.8 to 1.0 cm2/m2.

was 1.4 cm2; the 21-mm, 1.5 cm2; and the 23-mm, 1.85 cm2.

2009; Alvarez et al., 2009; ISTHMUS Investigators, 2011).

23-mm, 10.6mm Hg.; the 25-mm, 8.6mm Hg.; and 27-mm, 7.3mm Hg.

Fig. 4. Freedom from Structural Valve Deterioration (SVD) by clinical relevant symptoms, explantation or autopsy. (A) Overall freedom from SVD Actuarial and Actual. (B) Actuarial freedom from SVD. (C) Actual freedom (cumulative incidence) from SVD. ISTHMUS Investigators – Lorusso (Personal Communication – 2011)

authors (R Lorusso) has provided actual documentation incorporating clinical symptoms, explantation, echocardiographic examination, and autopsy assessment. The 18-year actual/ actuarial freedom from SVD incorporating clinical symptoms, explantation, echocardiographic examination and autopsy examination for patients <60 years old was 87.4%/75.4%, for patients 61-70 years old was 92.9%/87.0%, and for patients >70 years old was 97.1%/94.6%.

## **4. Hemodynamic performance**

172 Aortic Valve

**SVD**

0.4 pt/yr (0.1-0.7)

0 1 5 10 15 18

Time (Years)

(A)

0 1 5 10 15 18

**< 60** 1.0 pt/yr (0.5-1.3) **61-70** 0.6 pt/yr (0.2-0.9) **> 70** 0.1pt/yr (0.08-0.2)

**Time (Years)**

0 1 5 10 15 18

**Time (Years)**

(C) Fig. 4. Freedom from Structural Valve Deterioration (SVD) by clinical relevant symptoms, explantation or autopsy. (A) Overall freedom from SVD Actuarial and Actual. (B) Actuarial freedom from SVD. (C) Actual freedom (cumulative incidence) from SVD. ISTHMUS

(B)

93.8 ± 0.7 85.3 ± 1.4

> Actuarial Actual

< 60 yrs 61-70 yrs > 70 yrs

< 60 yrs 61-70 yrs > 70 yrs

97.1 ± 0.5 92.9 ± 0.4 87.4 ± 2.3

94.6 ± 0.6 87.0 ± 1.6 75.4 ± 2.9

100

80

60

%

 40 20 0

100

80

60

%

40

20

0

100

80

60

%

40

20

0

Investigators – Lorusso (Personal Communication – 2011)

The hemodynamic performance of the Mitroflow aortic bioprosthesis is considered excellent and very important in optimizing management for the small aortic annulus (Table 2).


Table 2. Hemodynamic Orifice Areas (cm2) for Mitroflow Aortic Bioprostheses

These three studies show excellent hemodynamic performance of the prosthesis. Jamieson et al. (2009) reported that the *in vivo* effective orifice areas by valve size provide the opportunity of avoiding obstructive characteristics for all valve sizes, including optimizing the management of the small aortic annulus. The EOA for the 19-mm and 21-mm prostheses is 1.4 cm2, and for the 23-mm and 25-mm prostheses is 1.8 cm2. These EOAs in the population reported prevented prosthesis-patient mismatch in all valve sizes with indexed EOAs ranging from 0.8 to 1.0 cm2/m2.

In their study on the hemodynamic performance of 1513 isolated aortic valve replacements, primarily model 11, Yankah et al. (2008) reported that the EOA for size 19-mm prosthesis was 1.4 cm2; the 21-mm, 1.5 cm2; and the 23-mm, 1.85 cm2.

The Conte et al. (2010) study of the Mitroflow model 12 prosthesis reported very satisfactory hemodynamic performance. The effective orifice areas for the 19-mm prosthesis was 1.05 cm2; the 21-mm, 1.22 cm2; the 23-mm, 1.37 cm2; the 25-mm, 1.60 cm2; and the 27-mm, 1.82 cm2. The mean gradient for the 19-mm prosthesis was 13.4mm Hg.; the 21-mm, 11.5mm Hg.; the 23-mm, 10.6mm Hg.; the 25-mm, 8.6mm Hg.; and 27-mm, 7.3mm Hg.

The Mitroflow LX external mounted pericardial bioprosthesis will continue to provide optimization of hemodynamics regardless of valve size, especially in the small aortic annulus. The addition of anticalcification therapy to the manufacturing process will provide the opportunity to retard or prevent structural valve deterioration of the bioprosthesis and may improve its long-term durability; this prosthesis has clinically been shown to be comparable in durability to other bovine pericardial aortic bioprostheses (Jamieson et al., 2009; Alvarez et al., 2009; ISTHMUS Investigators, 2011).

**9** 

**Influence of Prosthesis-Patient Mismatch on** 

Prosthesis-patient mismatch (PPM) was first described over 30 years ago (Rahimtoola, 1978) for aortic valve replacement: when the *in vivo* effective orifice area (EOA) of the prosthetic valve is less than that of the native, non-diseased, human valve. Extensive documentation on the role of PPM after aortic valve replacement (AVR) particularly addresses left ventricular mass regression and patient survival. Controversy continues about the influence of PPM on patient survival, both early and late mortality. Many studies (Pibarot and Dumesnil, 2000; Muneretto et al., 2004; Mohty et al., 2006; Tasca et al., 2006; Moon et al., 2006; Florath et al., 2008; Mohty et al., 2009; Blais et al., 2003) report PPM to be an independent predictor of mortality while others (Jamieson et al., 2010; Kato et al., 2007; Vicchio et al., 2008; Mascherbauer et al., 2008; Monin et al., 2007) showed no significant effect of PPM on patient outcome. There is also debate about whether the control of PPM reduces congestive heart failure and regression of the left ventricular mass, thereby contributing to improved survival. Several Canadian centers have been actively involved in this area of research, namely the Laval University group led by P. Pibarot, J.G. Dumesnil and D. Mohty, the UBC group led by W.R.E. Jamieson, and the University of Ottawa group

PPM is categorized by Pibarot and Dumesnil (2000), Mohty et al. (2009), and Jamieson et al. (2010) as normal (EOA index (EOAI) of > 0.85 cm2 / m2), mild-to-moderate (> 0.65 cm2 / m2 to ≤ 0.85 cm2 / m2), and severe (≤ 0.65 cm2 / m2). Tasca et al. (2006) defined PPM as an EOAI of ≤ 0.80 cm2 / m2, Moon et al. (2006) as an EOAI of < 0.75 cm2 / m2, while Ruel et al. (2004), Kulik et al. (2006), Kato et al. (2007), and Monin et al. (2007) as EOAI of ≤ 0.85 cm2 / m2; Florath et al. (2008) and Vicchio et al. (2008) chose 0.60 cm2 / m2 as the cutoff between moderate and severe PPM. As can be seen, there is no clear consensus on the exact definition of PPM; this lack of consensus may contribute at least in part to the observed discrepancies in the conclusions of the studies. The studies also differ in the length of their patient followup. Jamieson et al. (2010) report survival to 15 years, Moon et al. (2006) and Mohty et al. (2009) to 12 years, and the majority of the other publications on the topic of PPM report survival from 4 to 8 years (Mothy et al. 2006; Tasca et al., 2006; Florath et al., 2008; Kato et al., 2007; Mascherbauer et al., 2008; Monin et al., 2007). These differences may also

**1. Introduction** 

led by M. Ruel and A. Kulik.

contribute to the different conclusions reached.

**Survival with Aortic Valve Replacement** 

Jennifer Higgins, Michael H. Yamashita and Jian Ye

W.R. Eric Jamieson, Charlie Zhang,

*University of British Columbia, Vancouver* 

*British Columbia,* 

*Canada* 

#### **5. References**


 <http://www.sorin.com/product/mitroflowreg-aortic-pericardial-heart-valve> Accessed 15 August 2011.


## **Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement**

W.R. Eric Jamieson, Charlie Zhang, Jennifer Higgins, Michael H. Yamashita and Jian Ye *University of British Columbia, Vancouver British Columbia, Canada* 

## **1. Introduction**

174 Aortic Valve

Pettenazzo E., Valente M., Thiene G. Octanediol treatment of glutaraldehyde fixed bovine

Sorin Group. Sorin Mitroflow – Aortic pericardial heart valve. Hemodynamics, durability and ease of implant in one valve. Sorin Group (Marketing Pamphlet). Available at:

<http://www.sorin.com/product/mitroflowreg-aortic-pericardial-heart-valve>

Jamieson WRE. Biological prostheses: current options and clinical performance. In:

Benhameid O, Pomar JL, Jamieson WRE, Germann E, Castella M, Pellerin M, Carrier M,

Yankah CA, Pasic M, Musci M, Stein J, Detschades C, Siniawski H, Hetzer R. Aortic valve

Yankah CA. Mitroflow pericardial aortic bioprosthesis in patients younger than 60 years.

Klieverik LM, Takkenberg JJ, Bekkers JA, Roos-Hesselink JW, Witsenburg M, Bogers AJ. The

Jamieson WRE, Koerfer R, Yankah CA, Dolman W, Zitterman A, Minami K, Hayden RI Ling

Alvarez RJ, Sierra J, Vega M, Adrio B, Martinez-Comendador J, Gude F, Martinez-Cerijo J,

ISTHMUS Investigators. The Italian study on the Mitroflow postoperative results

Conte J, Weissman N, Dearani JA, Bavaria J, Heimansohn D, Dembitsky W, Doyle D. A

Jamieson WRE, Forgie WR, Hayden RI, Langlois Y, Ling H, Stanford EA, Roberts KA,

aortic pericardial bioprosthesis. *Thorac Cardiovasc Surg* 2009;57:1-6.

Ross operation; a Trojan horse? *Eur Heart J* 2007;28(16):1993-2000.

in patients with ≥ 60 years of age. *Thorac Cardiovasc Surg.* 2008:56;1-5. Minami K, Zittermann A, Schulte-Eistrup S, Koertke H, Korfer R. Mitroflow Synergy

*Cardiothoracic Surgery Review*, Franco KL & Thourani VH (Eds.). Philadelphia, PA:

Brownlee RT. CarboMedics Mitroflow pericardial aortic bioprosthesis: performance

prostheses for aortic valve replacement: 19 years experience in 1,516 patients. *Ann* 

replacement with the Mitroflow pericardial bioprosthesis: durability results up to

H, Hetzer R. Mitroflow Aortic Pericardial Bioprosthesis– Clinical Performance. *Eur* 

Garcia J. Early calcification of the aortic Mitroflow pericardial bioprosthesis in the

(ISTHMUS): a 20-year, multicentre evaluation of Mitroflow pericardial bioprosthesis. *Eur J Cardiothorac Surg,* 2011 Jan;39(1):18-26; discussion 26. Epub 2010

North American, prospective, multicenter assessment of the Mitroflow aortic

Brownlee RT, Moon BC, Dolman WB. Hemodynamic evaluation of the Mitroflow

*Eur J Cardothorac Surg* 2008;34;418-422.

<http://www.sorin.com/product/mitroflowreg>

Lippincott Williams & Wilkins, 2011 (In Press).

21 years. *J Thorac Cardiovasc Surg* 2008;136:688-696.

elderly. *Interact Cardiovas Thorac Surg.,* 2009;9:842-846.

pericardial prosthesis. *Ann Thorac Surg* 2010;90:144-152.

*J Thorac Cardiovasc Surg* 2010;140;e83-e84.

*J Cardiothorac Surg.* 2009;36:818-824.

Jul 10.

Accessed 15 August 2011.

*Thorac Surg* 2005;80:1699-1705.

pericardium: evidence of anticalcification efficacy in the subcutaneous rat model.

**5. References** 

and

Prosthesis-patient mismatch (PPM) was first described over 30 years ago (Rahimtoola, 1978) for aortic valve replacement: when the *in vivo* effective orifice area (EOA) of the prosthetic valve is less than that of the native, non-diseased, human valve. Extensive documentation on the role of PPM after aortic valve replacement (AVR) particularly addresses left ventricular mass regression and patient survival. Controversy continues about the influence of PPM on patient survival, both early and late mortality. Many studies (Pibarot and Dumesnil, 2000; Muneretto et al., 2004; Mohty et al., 2006; Tasca et al., 2006; Moon et al., 2006; Florath et al., 2008; Mohty et al., 2009; Blais et al., 2003) report PPM to be an independent predictor of mortality while others (Jamieson et al., 2010; Kato et al., 2007; Vicchio et al., 2008; Mascherbauer et al., 2008; Monin et al., 2007) showed no significant effect of PPM on patient outcome. There is also debate about whether the control of PPM reduces congestive heart failure and regression of the left ventricular mass, thereby contributing to improved survival. Several Canadian centers have been actively involved in this area of research, namely the Laval University group led by P. Pibarot, J.G. Dumesnil and D. Mohty, the UBC group led by W.R.E. Jamieson, and the University of Ottawa group led by M. Ruel and A. Kulik.

PPM is categorized by Pibarot and Dumesnil (2000), Mohty et al. (2009), and Jamieson et al. (2010) as normal (EOA index (EOAI) of > 0.85 cm2 / m2), mild-to-moderate (> 0.65 cm2 / m2 to ≤ 0.85 cm2 / m2), and severe (≤ 0.65 cm2 / m2). Tasca et al. (2006) defined PPM as an EOAI of ≤ 0.80 cm2 / m2, Moon et al. (2006) as an EOAI of < 0.75 cm2 / m2, while Ruel et al. (2004), Kulik et al. (2006), Kato et al. (2007), and Monin et al. (2007) as EOAI of ≤ 0.85 cm2 / m2; Florath et al. (2008) and Vicchio et al. (2008) chose 0.60 cm2 / m2 as the cutoff between moderate and severe PPM. As can be seen, there is no clear consensus on the exact definition of PPM; this lack of consensus may contribute at least in part to the observed discrepancies in the conclusions of the studies. The studies also differ in the length of their patient followup. Jamieson et al. (2010) report survival to 15 years, Moon et al. (2006) and Mohty et al. (2009) to 12 years, and the majority of the other publications on the topic of PPM report survival from 4 to 8 years (Mothy et al. 2006; Tasca et al., 2006; Florath et al., 2008; Kato et al., 2007; Mascherbauer et al., 2008; Monin et al., 2007). These differences may also contribute to the different conclusions reached.

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 177

The results of Jamieson et al. (2010) (N = 3343) are compared with those of Molty et al. (2009) (N = 2576); J.G. Dumesnil and P. Pibarot, two of the more prominent investigators in the

> Severe PPM (N = 212)

Age, yrs 66 ± 11 69 ± 10 69 ± 12 68 ± 10 71 ± 9 69 ± 11 Female, % 29 36 57 33 50 67 BSA, m2 1.8 ± 0.2 1.9 ± 0.2 2.0 ± 0.3 1.8 ± 0.2 1.8 ± 0.2 1.9 ± 0.3 BMI, kg/m2 26 ± 4 28 ± 5 32 ± 8 26 ± 5 29 ± 5 32 ± 7 Hypertension 19 27 28 54 59 68

III/IV 77 75 68 61 68 67 LVEF < 50%, % 19 19 18 19 17 18

prosthesis, % 32 19 23 24 14 43

<sup>≤</sup>21mm, % 14 42 91 16 38 80

CABG 40 47 44 43 46 58 EOAI, cm2 / m2 0.99 ± 0.15 0.76 ± 0.05 0.60 ± 0.04 1.10 ± 0.20 0.80 ± 0.05 ± 0.04 NS = nonsignificant; PPM = prosthesis-patient mismatch (see text for description of the categories); BSA = body surface area; BMI = body mass index; NYHA = New York Heart Association; LVEF = left

Table 1. Descriptive preoperative and operative data of the two patient cohort studies:

early mortality in the same cohort had already been analyzed by Blais et al. (2003).

As can be seen, the preoperative and operative characteristics of both cohorts are quite comparable, with the exception of hypertension and female gender, both of which higher in the Mohty et al. cohort. Also, 46.3% of patients were classified as having no PPM, 47.4% as mild-to-moderate PPM, and 6.3% as severe PPM in the Jamieson et al. cohort, whereas 67.5% of the patients had no PPM, 30.9% had moderate PPM, and 1.6% had severe PPM in the Mohty et al. cohort. The Jamieson et al. data analysis was based primarily on overall survival (early + late), whereas Mohty et al. took only late mortality into account because

Jamieson et al. found no significant difference in early mortality between the EOAI categories (no PPM: 3.4%, mild-to-moderate PPM: 3.5%, and severe PPM: 2.8%), or in late mortality (no PPM: 33.0%, moderate PPM: 30.2%, and severe PPM: 29.2%). The freedom from cardiac death by EOAI categories was also not significant (no PPM: 68.7 ± 2.4%, moderate PPM: 68.9 ± 2.6%, and severe PPM: 58.9 ± 9.7%, p = 0.699). In addition, the freedom from valve-related mortality was not significantly different by EOAI categories (no

ventricular ejection fraction; CABG = coronary artery bypass grafting

Jamieson et al. 2010 (Overall) UBC Study Mohty et al. 2009 (Late) Laval Study

NS PPM (N = 1739) Moderate PPM (N = 797)

Severe PPM (N = 40)

area of PPM, were also authors of the 2009 study.

Moderate PPM (N = 1547)

PPM (N = 3343)

NS

**Pre-operative data** 

NYHA class

**Operative data**  Mechanical

Prosthesis size

Concomitant

Overall (2010) and Late (2009)

It should be noted that the indication for surgical management of aortic stenosis is symptomatic severe aortic stenosis (< 1.0 cm2 valve area). In the majority of patients, this is equivalent to an EOAI at or below the level of severe mismatch by our definition.

## **2. The influence of PPM on postoperative patient outcomes**

The objective of our study (Jamieson et al., 2010) on 3,343 patients having AVR for severe aortic stenosis or mixed aortic stenosis/insufficiency was to determine the predictors for all levels of PPM on mortality and to determine if there is a relationship between PPM and other predictors of survival. The prostheses used were contemporary stented bioprostheses (2493) and mechanical prostheses (850). More specifically, 667 patients had Carpentier-Edwards PERIMOUNT pericardial prostheses (Edwards Lifesciences, Irvine, CA), 1250 patients had Carpentier-Edwards supra-annular porcine prostheses, 576 patients had Medtronic Mosaic porcine prostheses (Medtronic, Minneapolis, MN), 462 patients had St. Jude Medical mechanical prostheses (St. Jude Medical, St. Paul, MN), and 388 patients had CarboMedics mechanical prostheses (Sorin-CarboMedics, Saluggia, Italy) (Figure 1). There is a misconception with the Carpentier-Edwards supra-annular aortic valve for the early version (prior to 1985) of the mitral valve failed because of stent-post dehiscence due to excessive trimming of the aortic wall; however, this failure mode was identified in only one aortic prosthesis before the manufacturing trimming was changed (Jamieson et al., 2005; Jamieson et al, 2009). The level of PPM was classified for each patient based on reference EOAs and size for each prosthesis in the published literature. The patients considered for the study had their first aortic valve replacement. Patients who had a subsequent valvular replacement were censored alive on the date of the reoperative procedures. This concept was to avoid a hemodynamically different prosthesis at the time of reoperative explantation.

Fig. 1. Contemporary prostheses used in Jamieson et al. (2010)

It should be noted that the indication for surgical management of aortic stenosis is symptomatic severe aortic stenosis (< 1.0 cm2 valve area). In the majority of patients, this is

The objective of our study (Jamieson et al., 2010) on 3,343 patients having AVR for severe aortic stenosis or mixed aortic stenosis/insufficiency was to determine the predictors for all levels of PPM on mortality and to determine if there is a relationship between PPM and other predictors of survival. The prostheses used were contemporary stented bioprostheses (2493) and mechanical prostheses (850). More specifically, 667 patients had Carpentier-Edwards PERIMOUNT pericardial prostheses (Edwards Lifesciences, Irvine, CA), 1250 patients had Carpentier-Edwards supra-annular porcine prostheses, 576 patients had Medtronic Mosaic porcine prostheses (Medtronic, Minneapolis, MN), 462 patients had St. Jude Medical mechanical prostheses (St. Jude Medical, St. Paul, MN), and 388 patients had CarboMedics mechanical prostheses (Sorin-CarboMedics, Saluggia, Italy) (Figure 1). There is a misconception with the Carpentier-Edwards supra-annular aortic valve for the early version (prior to 1985) of the mitral valve failed because of stent-post dehiscence due to excessive trimming of the aortic wall; however, this failure mode was identified in only one aortic prosthesis before the manufacturing trimming was changed (Jamieson et al., 2005; Jamieson et al, 2009). The level of PPM was classified for each patient based on reference EOAs and size for each prosthesis in the published literature. The patients considered for the study had their first aortic valve replacement. Patients who had a subsequent valvular replacement were censored alive on the date of the reoperative procedures. This concept was to avoid a hemodynamically different prosthesis at the time of reoperative explantation.

Carpentier-Edwards Carpentier-Edwards Medtronic Mosaic

CarboMedics

(Standard, HP & Regent) (Standard, R Series, Top Hat)

SAV Perimount

Fig. 1. Contemporary prostheses used in Jamieson et al. (2010)

equivalent to an EOAI at or below the level of severe mismatch by our definition.

**2. The influence of PPM on postoperative patient outcomes** 

St. Jude Medical


The results of Jamieson et al. (2010) (N = 3343) are compared with those of Molty et al. (2009) (N = 2576); J.G. Dumesnil and P. Pibarot, two of the more prominent investigators in the area of PPM, were also authors of the 2009 study.

NS = nonsignificant; PPM = prosthesis-patient mismatch (see text for description of the categories); BSA = body surface area; BMI = body mass index; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; CABG = coronary artery bypass grafting

Table 1. Descriptive preoperative and operative data of the two patient cohort studies: Overall (2010) and Late (2009)

As can be seen, the preoperative and operative characteristics of both cohorts are quite comparable, with the exception of hypertension and female gender, both of which higher in the Mohty et al. cohort. Also, 46.3% of patients were classified as having no PPM, 47.4% as mild-to-moderate PPM, and 6.3% as severe PPM in the Jamieson et al. cohort, whereas 67.5% of the patients had no PPM, 30.9% had moderate PPM, and 1.6% had severe PPM in the Mohty et al. cohort. The Jamieson et al. data analysis was based primarily on overall survival (early + late), whereas Mohty et al. took only late mortality into account because early mortality in the same cohort had already been analyzed by Blais et al. (2003).

Jamieson et al. found no significant difference in early mortality between the EOAI categories (no PPM: 3.4%, mild-to-moderate PPM: 3.5%, and severe PPM: 2.8%), or in late mortality (no PPM: 33.0%, moderate PPM: 30.2%, and severe PPM: 29.2%). The freedom from cardiac death by EOAI categories was also not significant (no PPM: 68.7 ± 2.4%, moderate PPM: 68.9 ± 2.6%, and severe PPM: 58.9 ± 9.7%, p = 0.699). In addition, the freedom from valve-related mortality was not significantly different by EOAI categories (no

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 179

However, Mohty et al. found survival to be significantly lower for patients with severe PPM (5-year survival: no PPM: 84 ± 1%, moderate PPM: 81 ± 2%, severe PPM: 74 ± 8%; 10-year survival: no PPM: 61 ± 2%, moderate PPM: 57 ± 3%, severe PPM: 40 ± 10%). Freedom from cardiovascular-related death was also found to be significantly lower in patients with severe PPM (5-year survival: no PPM: 93 ± 1%, moderate PPM: 90 ± 1%, severe PPM: 78 ± 7%; 10-

Late (Overall) Survival A Freedom From Cardiovascular

100

B

80

60

40

20

0

Fig. 3. Late overall survival and freedom from cardiovascular death (from Mohty et al., 2009). Brown line indicates nonsignificant prosthesis-patient mismatch (PPM); green line

The conclusion by Mohty et al. that severe PPM is an independent predictor of late mortality in patients undergoing AVR differs from the conclusion by Jamieson et al. that PPM is not a predictor of survival. It should be noted that the severe PPM group consisted of 40 patients (1.6%) in the Mohty cohort whereas it consisted of 212 patients (6.3%) in the Jamieson cohort. The very small percentage of patients with severe PPM in the Mohty et al. study could be attributed to the fact that [1] only patients who survived through the short-term period following AVR were included (whereas all patients undergoing AVR was included in the Jamieson et al. study), and [2] the short-term mortality was much higher in the Mohty cohort (7 out of 27 patients with severe PPM, 25.9%), compared with the Jamieson cohort (6 out of 212, 2.8%), and therefore not as many patients in the severe PPM survived past the early period to be included in the Mohty et al. study. The finding of severe PPM as a significant predictor of survival may be purely related to the small group size. In other words, if the group had consisted of more patients, severe PPM may not have been found to be an independent predictor. The discrepancy between the findings of these two studies

0 2 4 6 8 10 12 Years

Death (%)

P = 0.008 P < 0.0001

1286 898 561 329 175 77 594 444 294 159 78 35 29 22 15 11 8 2

year survival: no PPM: 81 ± 2%, moderate PPM: 77 ± 3%, severe PPM: 50 ± 11%).

100

80

60

40

20

0

0 2 4 6 8 10 12 Years

warrants further investigation.

1286 898 561 329 175 77 594 444 294 159 78 35 29 22 15 11 8 2

indicates moderate PPM; orange line shows severe PPM

PPM: 84.3 ± 2.0%, moderate PPM: 85.7% ± 1.9%, and severe PPM: 76.8 ± 9.6%, p = 0.998). The overall (early + late) survival, at 15 years, was 38.1 ± 2.1% for no PPM, 37.0 ± 2.2% for mildmoderate PPM, and 22.1 ± 6.5% for severe PPM (no PPM versus severe PPM: p=0.040) (Figure 2).

Fig. 2. Freedom from late and overall mortality by three effective orifice area index (EOAI) groups (N = 3343) (Jamieson et al., 2010). E1 (solid line), not significant; E2 (long-dash line), mild to moderate; and E3 (short-dash line), severe. (AVR = aortic valve replacement; BP = bioprosthesis; MP = mechanical prosthesis)

PPM: 84.3 ± 2.0%, moderate PPM: 85.7% ± 1.9%, and severe PPM: 76.8 ± 9.6%, p = 0.998). The overall (early + late) survival, at 15 years, was 38.1 ± 2.1% for no PPM, 37.0 ± 2.2% for mildmoderate PPM, and 22.1 ± 6.5% for severe PPM (no PPM versus severe PPM: p=0.040)

**Patient Prosthesis Mismatch AVR (BP & MP)**

 **Freedom from Late Mortality**

 **3 EOAI Groups n=3343**

**1547 892 E1 428 100**

 **212 99 E3 23 5**

**1547 892 E1 428 100**

 **212 99 E3 23 5**

 **Log Rank Statistic Overall p=0.122 E1 vs E2 p=0.227 E1 vs E3 p=0.040 E2 vs E3 p=0.240**

bioprosthesis; MP = mechanical prosthesis)

 **Log Rank Statistic Overall p=0.079 E1 vs E2 p=0.250 E1 vs E3 p=0.020 E2 vs E3 p=0.148**

**%**

**%**

**1584 768 E2 325 82 1**

**Patient Prosthesis Mismatch AVR (BP & MP)**

 **Freedom from Overall Mortality**

 **3 EOAI Groups n=3343**

**0 3 6 9 12 15 18 21 Years**

Fig. 2. Freedom from late and overall mortality by three effective orifice area index (EOAI) groups (N = 3343) (Jamieson et al., 2010). E1 (solid line), not significant; E2 (long-dash line), mild to moderate; and E3 (short-dash line), severe. (AVR = aortic valve replacement; BP =

**1584 768 E2 325 82 1**

**0 3 6 9 12 15 18 21 Years**

> **%±SE@15yrs E1 ≥0.85 Not Sign 39.5±2.1 E2 >65; <85 Mild-Mod 38.5±2.3 E3 ≤0.65 Severe 22.9±6.7**

**E1 E2 E3**

> **E1 E2 E3**

 **%±SE@15yrs E1 ≥0.85 Not Sign 38.1±2.1 E2 >65; <85 Mild-Mod 37.0±2.2 E3 ≤0.65 Severe 22.1±6.5**

(Figure 2).

However, Mohty et al. found survival to be significantly lower for patients with severe PPM (5-year survival: no PPM: 84 ± 1%, moderate PPM: 81 ± 2%, severe PPM: 74 ± 8%; 10-year survival: no PPM: 61 ± 2%, moderate PPM: 57 ± 3%, severe PPM: 40 ± 10%). Freedom from cardiovascular-related death was also found to be significantly lower in patients with severe PPM (5-year survival: no PPM: 93 ± 1%, moderate PPM: 90 ± 1%, severe PPM: 78 ± 7%; 10 year survival: no PPM: 81 ± 2%, moderate PPM: 77 ± 3%, severe PPM: 50 ± 11%).

Fig. 3. Late overall survival and freedom from cardiovascular death (from Mohty et al., 2009). Brown line indicates nonsignificant prosthesis-patient mismatch (PPM); green line indicates moderate PPM; orange line shows severe PPM

The conclusion by Mohty et al. that severe PPM is an independent predictor of late mortality in patients undergoing AVR differs from the conclusion by Jamieson et al. that PPM is not a predictor of survival. It should be noted that the severe PPM group consisted of 40 patients (1.6%) in the Mohty cohort whereas it consisted of 212 patients (6.3%) in the Jamieson cohort. The very small percentage of patients with severe PPM in the Mohty et al. study could be attributed to the fact that [1] only patients who survived through the short-term period following AVR were included (whereas all patients undergoing AVR was included in the Jamieson et al. study), and [2] the short-term mortality was much higher in the Mohty cohort (7 out of 27 patients with severe PPM, 25.9%), compared with the Jamieson cohort (6 out of 212, 2.8%), and therefore not as many patients in the severe PPM survived past the early period to be included in the Mohty et al. study. The finding of severe PPM as a significant predictor of survival may be purely related to the small group size. In other words, if the group had consisted of more patients, severe PPM may not have been found to be an independent predictor. The discrepancy between the findings of these two studies warrants further investigation.

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 181

The influence of BMI was further evaluated (Yamashita et al., personal communication). Overweight or mild-to-moderately obese patients had a lower risk of early mortality, while underweight and severely obese patients had a higher risk of late mortality. When patients were analyzed as normal/underweight or overweight/obese, those with a normal EOAI had better 15-year survival than those with severe PPM. After adjusting for EOAI, age > 60 years and EF ≤ 50% indicated a higher risk of overall (early + late) mortality within BMI categories. These results suggest that BMI is associated with survival after AVR and that

EOAI was also evaluated as a continuous variable (along with other variables except EF), as well as a categorical variable, which revealed that EOAI was not an independent risk factor for late (> 30 days) or overall mortality. The predictors, otherwise, were not different from the categorical modeling except for the elimination of valve size and the addition of BMI for early mortality. Valve type was eliminated for late mortality and

The survival curves in Jamieson et al. show that severe PPM (EOAI of ≤ 0.65 cm2/m2) reduces survival for patients > 60 years old but not for patients ≤ 60 years old, that severe PPM reduces survival for patients with a BMI ≥ 25kg/m2 but not for those with a BMI < 25 kg/m2, and that severe PPM reduces survival for patients with an ejection fraction > 50% but not for those with an EF ≤ 50% (Figure 5). In comparison, Mohty et al. found that severe PPM was associated with increased mortality in patients < 70 years old but not in older patients, and that it significantly affected survival in patients with a BMI < 30kg/m2 but not in those with a BMI ≥ 30kg/m2 (Figure 6A, 6B, 6C, 6D). They also found moderate-to-severe PPM to be an independent predictor of late mortality in patients with a pre-operative LVEF < 50% but not in those with preserved LV systolic function (Figure 6E, 6F). With regard to these discrepancies, it is worth noting that there were only 21 patients in the Jamieson et al. BMI < 25 kg/m2 severe PPM group and 39 patients in the LVEF ≤ 50% severe PPM group, while for the severe PPM subset of the Mohty cohort, there were fewer than 20 patients in each of the < 70 years old, ≥ 70 years old, BMI < 30 kg/m2, and BMI ≥ 30kg/m2 subgroups. We therefore believe that the discrepancies in the above results may be purely due to random variations in the small data sets, and that if given an adequate number of cases in each of the categories, there may be no differences in the results between the Jamieson et al.

Ruel et al. (2006) found that PPM primarily affected patients with impaired left ventricular function at the time of AVR, and patients in whom PPM was associated with decreased overall long-term survival, lower freedom from heart failure, and diminished left ventricular mass regression. Also, an EOAI ≤ 0.85 cm2 / m2 did not have a significantly detrimental effect in patients with normal preoperative left ventricular function. However, the authors pointed out that PPM might have been found to have a significant effect in the normal LV function cohort had they evaluated cases with severe mismatch (≤ 0.65 cm2 / m2). An earlier study by Ruel et al. (2004) had shown that although PPM had significant effects on cardiac end points (occurrence of congestive heart failure, etc), it had no effect on overall survival after AVR. Kulik et al. (2006) found that patients with low-gradient aortic stenosis (LGAS, defined as an aortic valve area of < 1.2cm2, a mean transvalvular pressure gradient of < 40 mmHg, and a LVEF of < 50%) have worse long-term outcomes after AVR, and that PPM further adversely affects the long-term outcomes of LGAS patients and should

PPM may modify the effect.

and the Mohty et al. groups.

therefore be avoided in this population.

overall mortality.

In Jamieson et al., age, NYHA class III/IV, concomitant CABG, renal failure and dialysis, and emergent preoperative status were found to be predictors of early mortality (114/3343, 3.4%) on multivariate analysis. Because a univariate analysis of the various EOAI categories showed no significance in early mortality, there was no need for a multivariate analysis on PPM versus early mortality. A study by Blais et al. (2003) revealed LVEF < 40%, infectious endocarditis, emergent status, cardiopulmonary bypass time, chronic lung disease, and moderate-severe PPM to be independent predictors of early mortality (58/1266, 4.6%). Again, the short-term mortality in the severe PPM category was much higher in Blais et al. (7 out of 27 patients with severe PPM, 25.9%) than in Jamieson et al. (6 out of 212 patients, 2.8%), which may have contributed to the significant finding by Blais et al. that severe PPM was an independent predictor of survival (Figure 4). It is not clear why early mortality was so high in Blais et al.

Fig. 4. Relative risk ratio for short-term mortality according to the presence and severity of valve prosthesis-patient mismatch (from Blais et al., 2003). Numbers above the bars indicate the relative risk ratio for mortality compared with the group with nonsignificant mismatch

The predictors for late mortality, identified in a multivariate analysis in Jamieson et al. were age, male gender, NYHA functional class III/IV, concomitant coronary artery bypass, LVEF < 35%, BMI < 18, BMI > 35, bioprosthesis, preoperative congestive heart failure, diabetes mellitus, renal failure, and chronic obstructive pulmonary disease. In comparison, Mohty et al. (2009) found age, coronary artery disease, diabetes, renal failure, chronic lung disease, mechanical prosthesis, and severe PPM to be multivariate predictors of late mortality.

Jamieson et al. found EOAI to have no predictive effect on survival, whether early, late, or overall, despite the survival curves differing by EOAI categories (38.1 ± 2.1% 15-year overall survival for no PPM, 37.0 ± 2.2% for mild-to-moderate PPM, and 22.1 ± 6.5% for severe PPM). The reasons for the differences in survival curves are related to the complexity of the patients in the three categories, especially the category of severe PPM for ≤ 60 years and ejection fraction ≤ 50%, rather than a direct contribution from PPM.

Survival was adjusted in Jamieson et al. to determine the effect of covariates (EOAI, age, BMI, and EF). Severe EOAI had no relationship on adjusted survival for the evaluated covariates, except for very low level of significance for EF > 50%.

The influence of BMI was further evaluated (Yamashita et al., personal communication). Overweight or mild-to-moderately obese patients had a lower risk of early mortality, while underweight and severely obese patients had a higher risk of late mortality. When patients were analyzed as normal/underweight or overweight/obese, those with a normal EOAI had better 15-year survival than those with severe PPM. After adjusting for EOAI, age > 60 years and EF ≤ 50% indicated a higher risk of overall (early + late) mortality within BMI categories. These results suggest that BMI is associated with survival after AVR and that

PPM may modify the effect.

180 Aortic Valve

In Jamieson et al., age, NYHA class III/IV, concomitant CABG, renal failure and dialysis, and emergent preoperative status were found to be predictors of early mortality (114/3343, 3.4%) on multivariate analysis. Because a univariate analysis of the various EOAI categories showed no significance in early mortality, there was no need for a multivariate analysis on PPM versus early mortality. A study by Blais et al. (2003) revealed LVEF < 40%, infectious endocarditis, emergent status, cardiopulmonary bypass time, chronic lung disease, and moderate-severe PPM to be independent predictors of early mortality (58/1266, 4.6%). Again, the short-term mortality in the severe PPM category was much higher in Blais et al. (7 out of 27 patients with severe PPM, 25.9%) than in Jamieson et al. (6 out of 212 patients, 2.8%), which may have contributed to the significant finding by Blais et al. that severe PPM was an independent predictor of survival (Figure 4). It is not clear why early mortality was

> **Non significant Moderate Severe Valve prosthesis-patient mismatch**

Fig. 4. Relative risk ratio for short-term mortality according to the presence and severity of valve prosthesis-patient mismatch (from Blais et al., 2003). Numbers above the bars indicate the relative risk ratio for mortality compared with the group with nonsignificant mismatch The predictors for late mortality, identified in a multivariate analysis in Jamieson et al. were age, male gender, NYHA functional class III/IV, concomitant coronary artery bypass, LVEF < 35%, BMI < 18, BMI > 35, bioprosthesis, preoperative congestive heart failure, diabetes mellitus, renal failure, and chronic obstructive pulmonary disease. In comparison, Mohty et al. (2009) found age, coronary artery disease, diabetes, renal failure, chronic lung disease, mechanical prosthesis, and severe PPM to be multivariate predictors of late mortality. Jamieson et al. found EOAI to have no predictive effect on survival, whether early, late, or overall, despite the survival curves differing by EOAI categories (38.1 ± 2.1% 15-year overall survival for no PPM, 37.0 ± 2.2% for mild-to-moderate PPM, and 22.1 ± 6.5% for severe PPM). The reasons for the differences in survival curves are related to the complexity of the patients in the three categories, especially the category of severe PPM for ≤ 60 years and

Survival was adjusted in Jamieson et al. to determine the effect of covariates (EOAI, age, BMI, and EF). Severe EOAI had no relationship on adjusted survival for the evaluated

 **2.1 (p = 0.01)**  **11.4 (p < 0.001)**

so high in Blais et al.

**Mortality risk ratio**

**18**

**15**

**12**

 **9**

 **6**

 **3**

**1.0**

ejection fraction ≤ 50%, rather than a direct contribution from PPM.

covariates, except for very low level of significance for EF > 50%.

 **0**

EOAI was also evaluated as a continuous variable (along with other variables except EF), as well as a categorical variable, which revealed that EOAI was not an independent risk factor for late (> 30 days) or overall mortality. The predictors, otherwise, were not different from the categorical modeling except for the elimination of valve size and the addition of BMI for early mortality. Valve type was eliminated for late mortality and overall mortality.

The survival curves in Jamieson et al. show that severe PPM (EOAI of ≤ 0.65 cm2/m2) reduces survival for patients > 60 years old but not for patients ≤ 60 years old, that severe PPM reduces survival for patients with a BMI ≥ 25kg/m2 but not for those with a BMI < 25 kg/m2, and that severe PPM reduces survival for patients with an ejection fraction > 50% but not for those with an EF ≤ 50% (Figure 5). In comparison, Mohty et al. found that severe PPM was associated with increased mortality in patients < 70 years old but not in older patients, and that it significantly affected survival in patients with a BMI < 30kg/m2 but not in those with a BMI ≥ 30kg/m2 (Figure 6A, 6B, 6C, 6D). They also found moderate-to-severe PPM to be an independent predictor of late mortality in patients with a pre-operative LVEF < 50% but not in those with preserved LV systolic function (Figure 6E, 6F). With regard to these discrepancies, it is worth noting that there were only 21 patients in the Jamieson et al. BMI < 25 kg/m2 severe PPM group and 39 patients in the LVEF ≤ 50% severe PPM group, while for the severe PPM subset of the Mohty cohort, there were fewer than 20 patients in each of the < 70 years old, ≥ 70 years old, BMI < 30 kg/m2, and BMI ≥ 30kg/m2 subgroups. We therefore believe that the discrepancies in the above results may be purely due to random variations in the small data sets, and that if given an adequate number of cases in each of the categories, there may be no differences in the results between the Jamieson et al. and the Mohty et al. groups.

Ruel et al. (2006) found that PPM primarily affected patients with impaired left ventricular function at the time of AVR, and patients in whom PPM was associated with decreased overall long-term survival, lower freedom from heart failure, and diminished left ventricular mass regression. Also, an EOAI ≤ 0.85 cm2 / m2 did not have a significantly detrimental effect in patients with normal preoperative left ventricular function. However, the authors pointed out that PPM might have been found to have a significant effect in the normal LV function cohort had they evaluated cases with severe mismatch (≤ 0.65 cm2 / m2). An earlier study by Ruel et al. (2004) had shown that although PPM had significant effects on cardiac end points (occurrence of congestive heart failure, etc), it had no effect on overall survival after AVR. Kulik et al. (2006) found that patients with low-gradient aortic stenosis (LGAS, defined as an aortic valve area of < 1.2cm2, a mean transvalvular pressure gradient of < 40 mmHg, and a LVEF of < 50%) have worse long-term outcomes after AVR, and that PPM further adversely affects the long-term outcomes of LGAS patients and should therefore be avoided in this population.

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 183

**Freedom from Overall Mortality**

 **BMI < 25**

 **21 13 E3 5 1**

**0 3 6 9 12 15 18 21**

**Freedom from Overall Mortality**

**0 3 6 9 12 15 18 21**

**Years**

 **826 466 E1 214 45 1142 541 E2 236 58 191 85 E3 17 4**

**721 425 E1 213 54 1 442 226 E2 88 23 3**

> **%±SE@15yrs E1 ≥0.85 Not Sign 36.7±2.7 E2 >65; <85 Mild-Mod 31.0±3.9 E3 ≤0.65 Severe 12.7±10.9**

 **%±SE@15yrs E1 ≥0.85 Not Sign 38.4±3.2 E2 >65; <85 Mild-Mod 39.7±2.6 E3 ≤0.65 Severe 24.5±7.7**

**Years**

**100**

 **80**

 **60**

 **40**

**%**

 **20**

 **0**

 **80**

 **60**

 **40**

**%**

 **20**

 **0**

 **Log Rank Statistic Overall p=0.357 E1 vs E2 p=0.523 E1 vs E3 p=0.169 E2 vs E3 p=0.282**

 **Log Rank Statistic Overall p=0.089 E1 vs E2 p=0.114 E1 vs E3 p=0.031 E2 vs E3 p=0.339**

**100 BMI ≥ 25**

**E1 E2 E3**

**Freedom from Overall Mortality**

 **≤60 Years**

**450 319 E1 166 42**

**37 25 E3 10 4**

 **>60 Years <sup>100</sup>**

 **Log Rank Statistic Overall p=0.128 E1 vs E2 p=0.432 E1 vs E3 p=0.025 E2 vs E3 p=0.139**

**0 3 6 9 12 15 18 21**

**Years**

**Freedom from Overall Mortality**

**0 3 6 9 12 15 18 21 Years**

**1097 572 E1 261 57 1 1292 560 E2 196 43 1**

 **175 73 E3 12 1**

 **%±SE@15yrs E1≥0.85 Not Sign 63.5±3.9 E2 >65; <85 Mild-Mod 69.8±4.5 E3 ≤0.65 Severe 85.0±7.0**

 **%±SE@15yrs E1 ≥0.85 Not Sign 27.2±2.3 E2 >65; <85 Mild-Mod 26.6±2.4 E3 ≤0.65 Severe 4.2±3.9**

**292 207 E2 128 38 1**

**100**

 **80**

 **60**

 **40**

**%**

 **20**

 **0**

 **80**

 **60**

 **40**

**%**

 **20**

 **0**

 **Log Rank Statistic Overall p=0.171 E1 vs E2 p=0.090 E1 vs E3 p=0.301 E2 vs E3 p=0.662**

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 185

100

80

60

40

20

0

100

80

60

40

20

0

0 2 4 6 8 10 12 Years

3 BMI ≥30 kg/m

P = NS P < 0.001

0 2 4 6 8 10 12 Years

 232 154 83 46 23 9 212 160 107 61 30 17 16 11 8 6 5 2

Age ≥70 yrs

Late (Overall) Survival (%)

585 404 234 114 51 17 354 250 155 80 39 16 19 13 8 6 4 1

Late (Overall) Survival (%)

3

P = NS

703 495 328 216 125 61 241 194 140 81 40 20 15 11 10 8 6 4

C BMI <30 kg/m D Late (Overall) Survival (%)

0 2 4 6 8 10 12 Years

0 2 4 6 8 10 12 Years

1055 745 479 284 153 68 383 285 187 99 49 20 14 12 8 5 4 1

Age <70 yrs

100

80

60

40

20

0

100

80

60

40

20

0

Late (Overall) Survival (%) A B

P = 0.02

Fig. 5. Freedom from overall mortality in various subdivisions of the three effective orifice area index (EOAI) groups (Jamieson et al., 2010, and Jamieson, Personal Communication). E1 (solid line), not significant; E2 (long-dash line), mild to moderate; and E3 (short-dash line), severe. (EF = ejection fraction; BMI = body mass index)

**Freedom from Overall Mortality**

**0 3 6 9 12 15 18 21**

**Freedom from Overall Mortality**

**0 3 6 9 12 15 18 21**

Fig. 5. Freedom from overall mortality in various subdivisions of the three effective orifice area index (EOAI) groups (Jamieson et al., 2010, and Jamieson, Personal Communication). E1 (solid line), not significant; E2 (long-dash line), mild to moderate; and E3 (short-dash

**1251 781 E1 386 90 1 1282 677 E2 296 78 3**

 **174 87 E3 20 4**

**302 90 E2 28 3 1**

**296 110 E1 41 9**

 **38 11 E3 2 1**

 **%±SE@15yrs E1 ≥0.85 Not Sign 28.6±5.3 E2 >65; <85 Mild-Mod 16.8±5.9 E3 ≤0.65 Severe 14.2±12.9**

 **%±SE@15yrs E1 ≥0.85 Not Sign 39.5±2.3 E2 >65; <85 Mild-Mod 39.7±2.3 E3 ≤0.65 Severe 22.8±7.8**

**100 EF ≤ 50%**

 **Log Rank Statistic Years**

**<sup>100</sup> EF > 50%**

**Years Log Rank Statistic**

line), severe. (EF = ejection fraction; BMI = body mass index)

**Overall p=0.080 E1 vs E2 p=0.251 E1 vs E3 p=0.018 E2 vs E3 p=0.161**

**Overall p=0.813 E1 vs E2 p=0.553 E1 vs E3 p=0.905 E2 vs E3 p=0.763**

 **80**

 **60**

 **40**

**%**

 **20**

 **0**

 **80**

 **60**

 **40**

**%**

 **20**

 **0**

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 187

documented finding that AVR does not provide the same age/gender matched survival as in the general population allows this lower age threshold for bioprostheses in AVR (van Geldrop et al., 2009). This earlier failure threshold may be related to residual systolic dysfunction and more likely related to diastolic dysfunction concomitant with PPM

Because the negative impact of severe PPM on postoperative survival, it is crucial to avoid leaving patients with severe PPM after valvular surgery. Pibarot and Dumesnil (2000) presented a 3-step approach for preventing PPM: [1] calculate the patient's body surface area from weight and height; [2] using a BSA versus EOAI table, find the minimal valve EOA (in cm2) that will allow a given patient to have proper (ideally > 0.85 cm2 / m2) EOAI after surgery; and [3] select the type and size of prosthesis that has EOA reference values equal to or greater than the minimal valve EOA value obtained in step 2. The occurrence and severity of postoperative PPM can also be predicted before the operation from the patient's BSA and the reference EOA value of the selected prosthesis (Pibarot et al., 2001;

In agreement with the above, despite failing to find severe PPM (< 0.65 cm2 / m2) as an independent predictor of early, late, or overall mortality after AVR, we recommend that surgeons do not leave patients with a severe mismatch (especially for bioprostheses, which may develop degenerative changes over time that would further reduce the EOAI). Surgeons should maintain a prospective strategy of implanting an adequately sized aortic prosthesis that will preclude patients from being in the category of severe mismatch (near equivalent to indications for intervention in severe aortic stenosis). However, a significant portion of patients undergoing AVR will have some level of mild-to-moderate PPM owing to the intrinsic obstructive nature of most prostheses, and Jamieson et al. (2010) should provide some confidence to surgeons and cardiologists that mild-to-moderate PPM is

 Other than selecting a prosthesis with sufficient EOA, as described above, there are several more intraoperative options available to surgeons to prevent the occurrence of severe PPM. Aortic root enlargement may be considered in patients with an elevated risk of developing moderate-to-severe PPM at time of valvular replacement surgery (Mohty et al., 2006). Kulik et al. (2008) were able to insert larger prosthetic valves and achieve lower PPM by doing aortic root enlargement (ARE) at the time of AVR. They reported that the addition of an ARE to AVR increased the aortic cross-clamp time by 9.9 minutes, on average, and that there was no significant increase in perioperative morbidity or mortality associated with the added ARE. However, the lower incidence of PPM did not significantly affect long-term outcomes in their AVR + ARE cohort, once again coming back to the question of whether PPM significantly affects survival. The third option is a total aortic root replacement. Compared with a traditional stented bioprosthesis, total root replacement allows for optimal hemodynamics with no significant aortic regurgitation, improved regression of the LV mass, and less PPM in the small aortic root (Kon et al., 2002; Kincaid et al., 2007); however, total aortic root replacement comes at the cost of increased operative mortality, and a longer learning process. Several biological valves that allow for this procedure are the Medtronic

(Nozohoor et al., 2008).

**3. A suggested approach to PPM** 

Urso et al., 2010; Dumesnil and Pibarot, 2010).

unlikely to be detrimental to survival.

Fig. 6. Impact of prosthesis-patient mismatch on late overall survival (from Mohty et al. 2009, Figure 2). (A) Patients < 70 years old, (B) Patients ≥ 70 years old, (C) Body mass index (BMI) < 30 kg/m2, (D) BMI ≥ 30 kg/m2, (E) Pre-operative left ventricular ejection fraction (LVEF) < 50%, (F) LVEF ≥ 50%. Brown line indicates nonsignificant prosthesispatient mismatch (PPM); green line indicates moderate PPM; orange line shows severe PPM

In the Jamieson et al. cohort of 3343 patients, an additional study (Higgins et al., 2011) that evaluated the influence of gender on early, late, and overall survival reported that the predictors of mortality after AVR for aortic stenosis differed between male and female patients. Female gender was a predictor of early mortality while male gender was a predictor of late (but not early or overall) mortality. Male gender increased the risk of late mortality, and a valve size ≤ 21 mm increased the risk of early and overall mortality among male patients only. These differences need to be taken into consideration preoperatively and require consideration during operative management.

The Jamieson et al. analysis indicated that severe PPM identified with an EOAI < 0.65 cm2/m2 is not an independent predictor of early mortality, late mortality, or overall mortality after AVR. These findings have been discussed in perspective with other studies that have and have not provided evidence of PPM as an independent predictor of survival. The independent influence of bioprostheses as a risk factor of late and overall mortality also needs extensive evaluation because currently bioprostheses are recommended for patients ≥ 60 years old to minimize serious valve-related morbidity and provide a relatively acceptable degree of valve-related reoperation for structural valve deterioration. Valve-related mortality is not influenced by valve type (bioprosthesis or mechanical prosthesis). The documented finding that AVR does not provide the same age/gender matched survival as in the general population allows this lower age threshold for bioprostheses in AVR (van Geldrop et al., 2009). This earlier failure threshold may be related to residual systolic dysfunction and more likely related to diastolic dysfunction concomitant with PPM (Nozohoor et al., 2008).

## **3. A suggested approach to PPM**

186 Aortic Valve

100

80

60

40

20

0

Fig. 6. Impact of prosthesis-patient mismatch on late overall survival (from Mohty et al. 2009, Figure 2). (A) Patients < 70 years old, (B) Patients ≥ 70 years old, (C) Body mass index (BMI) < 30 kg/m2, (D) BMI ≥ 30 kg/m2, (E) Pre-operative left ventricular ejection fraction (LVEF) < 50%, (F) LVEF ≥ 50%. Brown line indicates nonsignificant prosthesispatient mismatch (PPM); green line indicates moderate PPM; orange line shows severe

In the Jamieson et al. cohort of 3343 patients, an additional study (Higgins et al., 2011) that evaluated the influence of gender on early, late, and overall survival reported that the predictors of mortality after AVR for aortic stenosis differed between male and female patients. Female gender was a predictor of early mortality while male gender was a predictor of late (but not early or overall) mortality. Male gender increased the risk of late mortality, and a valve size ≤ 21 mm increased the risk of early and overall mortality among male patients only. These differences need to be taken into consideration preoperatively and

The Jamieson et al. analysis indicated that severe PPM identified with an EOAI < 0.65 cm2/m2 is not an independent predictor of early mortality, late mortality, or overall mortality after AVR. These findings have been discussed in perspective with other studies that have and have not provided evidence of PPM as an independent predictor of survival. The independent influence of bioprostheses as a risk factor of late and overall mortality also needs extensive evaluation because currently bioprostheses are recommended for patients ≥ 60 years old to minimize serious valve-related morbidity and provide a relatively acceptable degree of valve-related reoperation for structural valve deterioration. Valve-related mortality is not influenced by valve type (bioprosthesis or mechanical prosthesis). The

0 2 4 6 8 10 12 Years

1059 744 473 283 151 68 527 398 263 147 75 31

LVEF ≥50 %

Late (Overall) Survival (%)

P = NS

LVEF <50 %

0 2 4 6 8 10 12 Years

356 265 168 120 65 27 150 112 81 51 25 13

require consideration during operative management.

100

80

60

40

20

0

PPM

Late (Overall) Survival (%) E F

P = 0.007

Because the negative impact of severe PPM on postoperative survival, it is crucial to avoid leaving patients with severe PPM after valvular surgery. Pibarot and Dumesnil (2000) presented a 3-step approach for preventing PPM: [1] calculate the patient's body surface area from weight and height; [2] using a BSA versus EOAI table, find the minimal valve EOA (in cm2) that will allow a given patient to have proper (ideally > 0.85 cm2 / m2) EOAI after surgery; and [3] select the type and size of prosthesis that has EOA reference values equal to or greater than the minimal valve EOA value obtained in step 2. The occurrence and severity of postoperative PPM can also be predicted before the operation from the patient's BSA and the reference EOA value of the selected prosthesis (Pibarot et al., 2001; Urso et al., 2010; Dumesnil and Pibarot, 2010).

In agreement with the above, despite failing to find severe PPM (< 0.65 cm2 / m2) as an independent predictor of early, late, or overall mortality after AVR, we recommend that surgeons do not leave patients with a severe mismatch (especially for bioprostheses, which may develop degenerative changes over time that would further reduce the EOAI). Surgeons should maintain a prospective strategy of implanting an adequately sized aortic prosthesis that will preclude patients from being in the category of severe mismatch (near equivalent to indications for intervention in severe aortic stenosis). However, a significant portion of patients undergoing AVR will have some level of mild-to-moderate PPM owing to the intrinsic obstructive nature of most prostheses, and Jamieson et al. (2010) should provide some confidence to surgeons and cardiologists that mild-to-moderate PPM is unlikely to be detrimental to survival.

 Other than selecting a prosthesis with sufficient EOA, as described above, there are several more intraoperative options available to surgeons to prevent the occurrence of severe PPM. Aortic root enlargement may be considered in patients with an elevated risk of developing moderate-to-severe PPM at time of valvular replacement surgery (Mohty et al., 2006). Kulik et al. (2008) were able to insert larger prosthetic valves and achieve lower PPM by doing aortic root enlargement (ARE) at the time of AVR. They reported that the addition of an ARE to AVR increased the aortic cross-clamp time by 9.9 minutes, on average, and that there was no significant increase in perioperative morbidity or mortality associated with the added ARE. However, the lower incidence of PPM did not significantly affect long-term outcomes in their AVR + ARE cohort, once again coming back to the question of whether PPM significantly affects survival. The third option is a total aortic root replacement. Compared with a traditional stented bioprosthesis, total root replacement allows for optimal hemodynamics with no significant aortic regurgitation, improved regression of the LV mass, and less PPM in the small aortic root (Kon et al., 2002; Kincaid et al., 2007); however, total aortic root replacement comes at the cost of increased operative mortality, and a longer learning process. Several biological valves that allow for this procedure are the Medtronic

Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 189

more consistent; therefore, proactive measures should be taken to prevent its occurrence. For other levels of PPM, it is reasonable to evaluate each patient on an individual basis (i.e., moderate PPM being more acceptable for a sedentary elderly patient, but less so for someone who is younger and more active), and for surgical and postoperative management

[1] Rahimtoola SH. The problem of valve prosthesis-patient mismatch. *Circulation.*

[2] Pibarot P, Dumesnil JG. Hemodynamic and clinical impact of prosthesis-patient

[3] Muneretto C, Bisleri G, Negri A, Manfredi J. The concept of patient-prosthesis mismatch.

[4] Mohty D, Malouf JF, Girard SE, Schaff HV, Grill DE, Enriquez-Sarano ME, Miller FA Jr.

[5] Tasca G, Mhagna Z, Perotti S, Centurini PB, Sabatini T, Amaducci A, Brunelli F, Cirillo

[6] Moon MR, Pasque MK, Munfakh NA, Melby SJ, Lawton JS, Moazami N, Codd JE,

[7] Florath I, Albert A, Rosendahl U, Ennker IC, Ennker J. Impact of valve prosthesis-

[8] Mohty D, Dumesnil JG, Echahidi N, Mathieu P, Dagenais F, Voisine P, Pibarot P. Impact

[9] Blais C, Dumesnil JG, Baillot R, Simard S, Doyle D, Pibarot P. Impact of valve prosthesis-

[10] Jamieson WRE, Ye J, Higgins J, Cheung A, Fradet GJ, Skarsgard P, Germann E, Chan

[11] Kato Y, Suehiro S, Shibata T, Sasaki Y, Hirai H. Impact of valve prosthesis-

in patients with pure aortic stenosis. *Circulation.* 2006;113:570-6

mismatch in the aortic valve position and its prevention. *J Am Coll Cardiol.*

Impact of prosthesis-patient mismatch on long-term survival in patients with small St Jude Medical mechanical prostheses in the aortic position. *Circulation.*

M, Tomba MD, Quiani E, Troise G, Pibarot P. Impact of prosthesis-patient mismatch on cardiac events and midterm mortality after aortic valve replacement

Crabtree TD, Barner HB, Damiano RJ Jr. Prosthesis-patient mismatch after aortic valve replacement: impact of age and body size on late survival. *Ann Thorac Surg.*

patient mismatch estimated by echocardiographic-determined effective orifice area on long-term outcome after aortic valve replacement. *Am Heart J.*

of prosthesis-patient mismatch on long-term survival after aortic valve

patient mismatch on short-term mortality after aortic valve replacement.

F, Lichtenstein SV. Effect of prosthesis-patient mismatch on long-term survival with aortic valve replacement: assessment to 15 years. *Ann Thorac Surg.*

patient mismatch on long-term survival and left ventricular mass regression after aortic valve replacement for aortic stenosis. *J Cardiovasc Surg.* 2007;

options to be dependent on the individualized assessment.

*J Heart Valve Dis.* 2004;13:S59-S62

**4. References** 

1978;58:20-4

2000;36:1131-41

2006;113:420-6

2006;81:481-9

2008;155:1135-42

2010;89:51-9

22:314-9

*Circulation.* 2003;108:983-8

replacement. *J Am Coll Cardiol.* 2009;53:39-47

Freestyle (porcine, stentless), Edwards Prima Plus (porcine, stentless), and Sorin Pericarbon Freedom (pericardial, stentless) (Jamieson, 2010). Finally, a myectomy and a myotomy of the hypertrophied muscle are options for dealing with a small aortic root or a left ventricular outflow tract obstruction; they are safe and effective procedures without additional complications when done concomitantly with AVR (Kayalar et al., 2010). Myectomy-myotomy also has improved left ventricular mass regression after AVR for pure aortic stenosis (Tasca et al., 2003).

Among the three available intraoperative options available to surgeons to prevent the occurrence of severe PPM, the first option to consider for any patient should be to look for a valve with larger a EOAI and better hemodynamics. The On-X valve and the St. Jude Medical (SJM) Regent valve are mechanical valves with improved hemodynamics. The On-X valve by On-X Life Technologies Inc. also has improved hemodynamics (Palatianos et al., 2007; Chambers et al., 2005) and excellent postoperative EOA and transvalvular gradients (Moidl et al., 2002). The On-X valve was also designed to address the problems of occasional incidents of unexplained hemolytic anemia, tissue interference, excessive pannus overgrowth, and thrombotic complications (Moidl et al., 2002). The SJM Regent valve is an improvement on the SJM conventional valve, and has a wider valve area than the SJM HP valve (Sezai et al., 2010). With its supra-annular placement, several studies have suggested that using the Regent valve practically circumvents the need for root enlargement (Bach et al., 2002; Petracek, 2002). In a recent study (Okamura et al., 2010) in which 50 patients were given a small-sized (17-mm or 19-mm) St. Jude Regent mechanical valve, all patients improved to NYHA functional class II or better. Several biological valves with improved hemodynamics are the Carpentier-Edwards PERIMOUNT Magna Ease (pericardial), SJM Epic Supra (porcine), Sorin Soprano Armania (pericardial), and Medtronic Mosaic Ultra (porcine) valves (Jamieson, 2010). The Sorin Mitroflow (pericardial) and the St Jude Medical Trifecta (pericardial) (approved 2007 and 2010, respectively by the USFDA) are externally mounted pericardial bioprostheses and not amenable to increased diameter design.

For patients who have already developed moderate or severe postoperative PPM, reoperation may be an option to improve long-term survival (Girard et al., 2001). In Girard et al., there were no 30-day deaths for reoperations on 12 patients with isolated, severe PPM. However, 5 of the 9 patients who underwent concomitant major cardiac procedures at the time of valvular replacement died in-hospital, so there is a risk to reoperation. The benefit of relief from PPM must be weighed carefully against the risks of reoperation, and must be assessed on a patient-by-patient basis. When evaluating patients with mild-to-moderate PPM for the possibility of reoperation, we suggest that surgeons take into account the Jamieson et al. (2010) finding of the unlikelihood of mild-to-moderate PPM contributing to worse survival.

From the accumulated data from published literature, it is easy to see that the topic of prosthesis-patient mismatch remains controversial. The issue is further complicated by the fact that there are several levels of PPM (nonsignificant, mild, moderate, or severe), with different studies showing different outcomes for each level of PPM. There is also currently no clear consensus on the exact definitions of PPM and its categories.

A sensible approach to the issue of PPM is that we should avoid generalizations for any given level of PPM except for severe PPM, for which the data in the existing literature is more consistent; therefore, proactive measures should be taken to prevent its occurrence. For other levels of PPM, it is reasonable to evaluate each patient on an individual basis (i.e., moderate PPM being more acceptable for a sedentary elderly patient, but less so for someone who is younger and more active), and for surgical and postoperative management options to be dependent on the individualized assessment.

## **4. References**

188 Aortic Valve

Freestyle (porcine, stentless), Edwards Prima Plus (porcine, stentless), and Sorin Pericarbon Freedom (pericardial, stentless) (Jamieson, 2010). Finally, a myectomy and a myotomy of the hypertrophied muscle are options for dealing with a small aortic root or a left ventricular outflow tract obstruction; they are safe and effective procedures without additional complications when done concomitantly with AVR (Kayalar et al., 2010). Myectomy-myotomy also has improved left ventricular mass regression after AVR for pure

Among the three available intraoperative options available to surgeons to prevent the occurrence of severe PPM, the first option to consider for any patient should be to look for a valve with larger a EOAI and better hemodynamics. The On-X valve and the St. Jude Medical (SJM) Regent valve are mechanical valves with improved hemodynamics. The On-X valve by On-X Life Technologies Inc. also has improved hemodynamics (Palatianos et al., 2007; Chambers et al., 2005) and excellent postoperative EOA and transvalvular gradients (Moidl et al., 2002). The On-X valve was also designed to address the problems of occasional incidents of unexplained hemolytic anemia, tissue interference, excessive pannus overgrowth, and thrombotic complications (Moidl et al., 2002). The SJM Regent valve is an improvement on the SJM conventional valve, and has a wider valve area than the SJM HP valve (Sezai et al., 2010). With its supra-annular placement, several studies have suggested that using the Regent valve practically circumvents the need for root enlargement (Bach et al., 2002; Petracek, 2002). In a recent study (Okamura et al., 2010) in which 50 patients were given a small-sized (17-mm or 19-mm) St. Jude Regent mechanical valve, all patients improved to NYHA functional class II or better. Several biological valves with improved hemodynamics are the Carpentier-Edwards PERIMOUNT Magna Ease (pericardial), SJM Epic Supra (porcine), Sorin Soprano Armania (pericardial), and Medtronic Mosaic Ultra (porcine) valves (Jamieson, 2010). The Sorin Mitroflow (pericardial) and the St Jude Medical Trifecta (pericardial) (approved 2007 and 2010, respectively by the USFDA) are externally mounted pericardial bioprostheses and not

For patients who have already developed moderate or severe postoperative PPM, reoperation may be an option to improve long-term survival (Girard et al., 2001). In Girard et al., there were no 30-day deaths for reoperations on 12 patients with isolated, severe PPM. However, 5 of the 9 patients who underwent concomitant major cardiac procedures at the time of valvular replacement died in-hospital, so there is a risk to reoperation. The benefit of relief from PPM must be weighed carefully against the risks of reoperation, and must be assessed on a patient-by-patient basis. When evaluating patients with mild-to-moderate PPM for the possibility of reoperation, we suggest that surgeons take into account the Jamieson et al. (2010) finding of the unlikelihood of mild-to-moderate PPM contributing to

From the accumulated data from published literature, it is easy to see that the topic of prosthesis-patient mismatch remains controversial. The issue is further complicated by the fact that there are several levels of PPM (nonsignificant, mild, moderate, or severe), with different studies showing different outcomes for each level of PPM. There is also currently

A sensible approach to the issue of PPM is that we should avoid generalizations for any given level of PPM except for severe PPM, for which the data in the existing literature is

no clear consensus on the exact definitions of PPM and its categories.

aortic stenosis (Tasca et al., 2003).

amenable to increased diameter design.

worse survival.


Influence of Prosthesis-Patient Mismatch on Survival with Aortic Valve Replacement 191

[24] Urso S, Sadaba R, Monleón-Getino T, Aldamiz-Echevarría G. Moderate patient-

[25] Dumesnil JG, Pibarot P. Prevention of moderate prosthesis-patient mismatch: individualization versus generalization. *Rev Esp Cardiol.* 2010;63(4):387-9 [26] Kulik A, Al-Saigh M, Chan V, Masters RG, Bedard P, Lam BK, Rubens FD, Hendry PJ,

[27] Kon ND, Riley RD, Adair SM, Kitzman DW, Cordell AR. Eight-year results of aortic

[28] Kincaid EH, Cordell AR, Hammon JW, Adair SM, Kon ND. Coronary insufficiency after

[29] Jamieson WRE. Update on technologies for cardiac valvular replacement, transcatheter

[30] Kayalar N, Schaff HV, Daly RC, Dearani JA, Park SJ. Concomitant septal myectomy at

[31] Tasca G, Amaducci A, Parrella PV, Troise G, Dalla Tomba M, Magna Z,

[32] Palatianos GM, Laczkovics AM, Simon P, Pomar JL, Birnbaum DE, Greve HH,

[33] Chambers J, Roxburgh J, Blauth C, O'Riordan J, Hodson F, Rimington H. A randomized

[34] Moidl R, Simon P, Wolner E. The On-X prosthetic heart valve at five years. *Ann Thorac* 

[35] Sezai A, Kasamaki Y, Abe K, Hata M, Sekino H, Shimura K, Minami K. Assessment of

[37] Petracek MR. Assessing options for the small aortic root. *J of Heart Valve Dis.*

dobutamine stress echocardiography. *Ann Thorac Sur.* 2010;89(1):87-92 [36] Bach DS, Sakwa MP, Goldbach M, Petracek MR, Emery RW, Mohr FW. Hemodynamics

valve replacement [Spanish]. *Rev Esp Cardiol.* 2010;63:409-14

replacement: is there a benefit? *Ann Thorac Surg.* 2008;85(1)94-100

2010. San Francisco: Universal Medical Press; pp. 255-281

events. *J Thorac Cardiov Sur.* 2005;130(3):759-64

valve. *Ann Thorac Surg.* 2002;74(6):2003-9

*Thorac Surg.* 2002;73:1817-21

2007;83:964-968

2010;89:459-64

2003;4:865-71

2007;83(1):40-6

2002;S1:S50-5

*Surg.* 2002;74(4):S1312-7

prosthesis mismatch has no independent effect on 30-day mortality after isolated

Mesana TG, Ruel M. Enlargement of the small aortic root during aortic valve

root replacement with the freestyle stentless porcine aortic root bioprosthesis. *Ann* 

stentless aortic root replacement: risk factors and solutions. *Ann Thorac Surg.*

innovations, and reconstructive surgery. In: Szabó, Z., Coburg, A.J., Reich, H., Yamamoto, M., Brem, H., Hartwin, S.F. (Eds.) *Surgical Technology International, XX.*

the time of aortic valve replacement for severe aortic stenosis. *Ann Thorac Surg.*

Quaini E. Myectomy-myotomy associated with aortic valve replacement for aortic stenosis: effects on left ventricular mass regression. *Ital Heart J.*

Haverich A. Multicentered European study on safety and effectiveness of the On-X prosthetic heart valve: intermediate follow-up. *Ann Thorac Surg.* 

comparison of the MCRI On-X and CarboMedics Top Hat bileaflet mechanical replacement aortic valves: early postoperative hemodynamic function and clinical

the St Jude Medical Regent prosthetic valve by continuous-wave Doppler and

and early clinical performance of the St. Jude Medical Regent mechanical aortic


[12] Vicchio M, Della Corte A, De Santo LS, De Feo M, Caianiello G, Scardone M, Cotrufo M.

[13] Mascherbauer J, Rosenhek R, Fuchs C, Pernica E, Klaar U, Scholten C, Heger M,

[14] Monin JL, Monchi M, Kirsch ME, Petit-Eisenmann H, Baleynaud S, Chauvel C, Metz

[15] Ruel M, Rubens FD, Masters RG, Pipe AL, Bedard P, Hendry PJ, Lam BK, Burwash IG,

[16] Kulik A, Burwash IG, Kapila V, Mesana TG, Ruel M. Long-term outcomes after valve replacement for low-gradient aortic stenosis. *Circulation*. 2006;114:I553-8 [17] Jamieson WRE, Burr LH, Miyagishima RT, Germann E, Macnab JS, Stanford E, Chan F,

[18] Jamieson WRE, Gudas VM, Burr LH, Janusz MT, Fradet GJ, Ling H, Germann E,

[19] Ruel M, Al-Faleh H, Kulik A, Chan K, Mesana TG, Burwash IG. Prosthesis-patient

[20] Higgins J, Jamieson WRE, Benhameid O, Ye J, Cheung A, Skarsgard P, Germann E,

[21] van Geldorp MW, Jamieson WRE, Kappetein AP, Ye J, Fradet GJ, Eijkemans MJ,

[22] Nozohoor S, Nilsson J, Luhrs C, Roijer A, Sjogren J. Influence of prosthesis-patient

[23] Pibarot P, Dumesnil JG, Cartier PC, Metras J, Lemieux MD. Patient-prosthesis mismatch can be predicted at the time of operation. *Ann Thorac Surg.* 2001;71:S265-8

and quality of life. *Ann Thorac Surg.* 2008;86:1791-7

long-term mortality. *Heart.* 2008;94:1639-45

*J Thorac Cardiov Sur.* 2004;127:149-59

2007;28(21):2620-6

2005;130(4):994-1000

110

44

601

2009;137(4):881-6,

2008;85:1310-8.

Prosthesis-patient mismatch in the elderly: survival, ventricular mass regression,

Wollenek G, Maurer G, Baumgartner H. Moderate patient-prosthesis mismatch after valve replacement for severe aortic stenosis has no impact on short-term and

D, Adams C, Quere JP, Gueret P, Tribouilloy C. Low-gradient aortic stenosis: impact of prosthesis-patient mismatch on survival. *Eurn Heart J.*

Goldstein WG, Brais MP, Keon WJ, Mesana TG. Late incidence and predictors of persistent or recurrent heart failure in patients with aortic prosthetic valves.

Janusz MT, Ling H. Carpentier-Edwards supra-annular aortic porcine bioprosthesis: clinical performance over 20 years. *J Thorac Cardiov Sur.*

Lichtenstein SV. Mitral valve disease: if the mitral valve is not reparable/failed repair, is bioprosthesis suitable for replacement? *Eur J Cardio-thorac.* 2009;35(1):104-

mismatch after aortic valve replacement primarily affects patients with preexisting left ventricular dysfunction: impact on survival, freedom from heart failure, and left ventricular mass regression. *J Thorac Cardiov Sur.* 2006;131:1036-

Chan F, Lichtenstein SV. Influence of patient gender on mortality after aortic valve replacement for aortic stenosis. *J Thorac Cardiov Sur.* 2011;142:595-

Grunkemeier GL, Bogers AJ, Takkenberg JJ. Patient outcome after aortic valve replacement with a mechanical or biological prosthesis: weighing lifetime anticoagulant-related event risk against reoperation risk. *J Thorac Cardiov Sur.*

mismatch on diastolic heart failure after aortic valve replacement. *Ann Thorac Surg.*


**Part 6** 

**Transcatheter Aortic Valve Implantation** 

