Aortic Valve Replacement
The Influence of Prosthesis-Patient Mismatch
for Left Ventricular Remodeling,
Cardiac Function and Survival
Shahab Nozohoor, M.D.
Department of Cardiothoracic Surgery
Faculty of Medicine
Lund University, 2009
Doctoral Dissertation
Department of cardiothoracic Surgery
Faculty of Medicine
Lund University
SE-221 85 Lund
SWEDEN
© Shahab Nozohoor, 2009 (pages 1-80)
Lund University
Printed by Media-Tryck, Lund, 2009
ISBN 978-91-86253-87-5
2
Dedicated to Ann and Saga,
the noor of my eyes
3
"A Parisian tailor, not yet old, having dined and left his house had walked hardly 40
paces when he suddenly fell to the ground and expired. His body was opened and no
disease found except that the three semilunar cusps leading to the aorta were bony".
Théofile Bonet, 1679
4
LIST OF PUBLICATIONS ................................................................................. 7
ABSTRACT ....................................................................................................... 8
ABBREVIATIONS ............................................................................................. 9
INTRODUCTION ............................................................................................. 10
1.1 Prosthesis-patient mismatch – the concept .......................................................... 10
1.2 Classification of PPM .......................................................................................... 10
1.3 Determinants of prosthesis-patient mismatch ..................................................... 11
1.4 Hemodynamic impact of prosthesis-patient mismatch ....................................... 11
1.5 The clinical influence of prosthesis-patient mismatch ........................................ 14
1.5.1 Survival ...................................................................................................... 14
1.5.2 Prosthesis-patient mismatch and morbidity ............................................... 15
1.5.3 Prosthesis-patient mismatch and BMI ....................................................... 16
1.5.4 Prosthesis-patient mismatch and in vivo EOA .......................................... 16
1.5.5 Severe prosthesis-patient mismatch ........................................................... 18
1.5.6 Homogeneity and propensity scoring ........................................................ 18
1.5.7 Prosthesis-patient mismatch and left ventricular mass regression ............ 19
1.5.8 Prosthesis-patient mismatch quality of life ............................................... 20
1.5.9 Prosthesis-patient mismatch and aortic valve insufficiency ...................... 20
1.6 Postoperative heart failure ................................................................................... 20
1.7 Diastolic dysfunction in patients with aortic valve disease ................................. 21
1.8 Brain-type natriuretic peptide .............................................................................. 22
1.8.1 Preoperative measurement of brain-type natriuretic peptide in aortic valve
stenosis ................................................................................................................ 22
1.8.2 Measurement of brain-type natriuretic peptide following aortic valve
replacement ......................................................................................................... 23
1.9 Aortic valve stenosis............................................................................................ 23
1.9.1 Pathophysiology ........................................................................................ 23
1.10 Aortic valve insufficiency ................................................................................. 24
1.10.1 Acute aortic valve insufficiency .............................................................. 24
1.10.2 Chronic aortic valve insufficiency ........................................................... 25
1.11 Aortic valve replacement ................................................................................... 25
1.12 The small aortic root and alternative surgical strategies ................................... 27
AIMS OF THIS RESEARCH ........................................................................... 29
MATERIAL AND METHODS .......................................................................... 30
3.1 Patients................................................................................................................. 30
3.2 Study design ........................................................................................................ 30
3.2.1 Paper I ........................................................................................................ 30
5
3.2.2 Paper II ....................................................................................................... 31
3.2.3 Paper III ..................................................................................................... 31
3.2.4 Paper IV ..................................................................................................... 31
3.3 Anesthetic management....................................................................................... 32
3.4 Surgical management .......................................................................................... 32
3.5 Triage® BNP test ................................................................................................ 32
3.6 Echocardiography ................................................................................................ 33
3.7 Definitions ........................................................................................................... 34
3.8 Statistical analyses ............................................................................................... 34
3.9 Ethical aspects ..................................................................................................... 35
RESULTS ........................................................................................................ 36
4.1 Impact of patient-prosthesis mismatch on in-hospital complications ................. 36
4.2 Risk factors for postoperative neurological events ............................................. 36
4.3 Left ventricular mass regression and diastolic dysfunction ................................ 37
4.4 Left ventricular remodeling following AVR for severe aortic valve insufficiency
................................................................................................................................... 39
4.5 Predictors of postoperative heart failure.............................................................. 41
4.6 Impact of PPM on early mortality ....................................................................... 41
4.7 Impact of PPM on late mortality ......................................................................... 43
4.8 Postoperative appearance of BNP and the relation between BNP and PPM ...... 44
DISCUSSION .................................................................................................. 45
5.1 Postoperative morbidity....................................................................................... 45
5.2 Impact of PPM on early mortality ....................................................................... 46
5.3 Postoperative heart failure ................................................................................... 47
5.4 Impact of PPM on diastolic heart failure ............................................................. 48
5.5 Stented bioprostheses for supra-annular implantation ........................................ 49
5.6 Impact of PPM on LV remodeling in aortic valve insufficiency ........................ 50
5.7 Impact of PPM on mortality ................................................................................ 51
5.8 General discussion ............................................................................................... 53
5.9 Limitations ........................................................................................................... 55
FUTURE PERSPECTIVES.............................................................................. 56
CONCLUSIONS .............................................................................................. 57
POPULÄRVETENSKAPLIG SAMMANFATTNING (SUMMARY IN SWEDISH)
......................................................................................................................... 58
ACKNOWLEDGEMENTS ............................................................................... 61
REFERENCES ................................................................................................ 63
PAPERS I-IV ................................................................................................... 81
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List of Publications
This thesis is based on the following papers, which are referred to in the text by their
Roman numerals:
I. Nozohoor S, Nilsson J, Lührs C, Roijer A, Sjögren J. The Influence of PatientProsthesis Mismatch on In-hospital Complications and Early Mortality after Aortic
Valve Replacement. Journal of Heart Valve Disease 2007;16:475-482.
II. Nozohoor S, Nilsson J, Lührs C, Roijer A, Algotsson L, Sjögren J. B-type
Natriuretic Peptide as a Predictor of Postoperative Heart Failure following Aortic
Valve Replacement. Journal of Cardiothoracic and Vascular Anesthesia
2009;23:161-165.
III. Nozohoor S, Nilsson J, Lührs C, Roijer A, Sjögren J. Influence of ProsthesisPatient Mismatch on Diastolic Heart Failure after Aortic Valve Replacement. The
Annals of Thoracic Surgery 2008;85:1310-1317.
IV. Nozohoor S, Nilsson J, Lührs C, Roijer A, Sjögren J. Influence of ProsthesisPatient Mismatch on Left Ventricular Remodeling in Severe Aortic Insufficiency.
European Journal of Cardiothoracic Surgery, online publication: 19-AUG-2009;
DOI: 10.1016/j.ejcts.2009.07.009
7
Abstract
Valve substitution due to aortic valve disease corrects anatomical defects, promotes
regression of myocardial hypertrophy, recovery of left ventricular performance, and
remission of symptoms. However, the best valve substitute in terms of hemodynamic
performance, durability, incidence of complications, and survival remains the subject
of much debate. It has been suggested that valve performance is influenced by the
potentially modifiable variable prosthesis-patient mismatch (PPM). PPM has been
reported to be detrimental for survival and symptom resolution mainly due to the
promotion of unfavorable prosthesis hemodynamics with secondary impaired left
ventricular remodeling. Nevertheless, an increasing number of studies with various
study designs and outcomes present conflicting results. Thus, there is no convincing
evidence for PPM’s detrimental effects.
The aims of this research were to evaluate the impact of PPM on in-hospital
complications and survival, to analyze whether postoperative heart failure can be
detected using brain-type natriuretic peptide (BNP) as a predictive biomarker, to
investigate the influence of PPM in bioprostheses with respect to recovery of left
ventricular diastolic function and left ventricular mass regression, and to evaluate the
influence of prosthesis-patient mismatch on left ventricular remodeling following
aortic valve replacement for severe valve insufficiency.
The present work demonstrated that PPM was not associated with low cardiac output
syndrome, but rather an independent risk factor for a neurological event during the
postoperative period after valve replacement. This finding probably reflects a more
cumbersome surgical procedure in a small aortic root with extensive calcification,
commonly observed in patients with native valvular stenosis. PPM had no impact on
either early or late mortality. Postoperative heart failure following AVR was
associated with a high early postoperative mortality and was predicted by elevated
BNP levels on arrival in the ICU although the discriminatory ability of the biomarker
was poor. PPM did not impair left ventricular mass regression or the recovery of
diastolic function. PPM was surprisingly common in patients with severe aortic
insufficiency undergoing AVR. In these patients, left ventricular remodeling was
initiated regardless of preoperative left ventricular ejection fraction or PPM.
In conclusion, the clinical relevance and the prevention of PPM seem subordinate and
to improve patient outcome, priority should be given to the design of a durable, nonthrombogenic prosthesis permitting easy handling and reducing surgical complexity.
8
Abbreviations
AS
AVR
AVI
BNP
BSA
CABG
CFR
CPB
COPD
CVI
DHF
EOA
EOAi
GOA
GOAi
IABP
ICU
IVSd
LA
LCOS
LFLG AS
LPWDd
LV
LVEDD
LVESD
LVEF
LVH
LVIDd
LVMI
LVMR
LVOT
MI
PHF
PPM
QoL
ROC
SVD
TPG
TVI
aortic stenosis
aortic valve replacement
aortic valve insufficiency
brain-type natriuretic peptide
body surface area
coronary artery by-pass grafting
coronary flow reserve
cardiopulmonary bypass
chronic obstructive pulmonary disease
cerebrovascular insult
diastolic heart failure
effective orifice area
indexed effective orifice area (EOA/BSA)
geometric orifice area
indexed geometric orifice area (GOA/BSA)
intra-aortic balloon pump
intensive care unit
interventricular septum at end-diastole
left atrium dimension at end-systole in parasternal long axis view
low cardiac output syndrome
low-flow, low-gradient aortic stenosis
left ventricular posterior wall dimension at end-diastole
left ventricle
left ventricular end-diastolic diameter
left ventricular end-systolic diameter
left ventricular ejection fraction
left ventricular hypertrophy
left ventricular internal dimension in diastole
left ventricular mass index
left ventricular mass regression
left ventricular outflow tract
myocardial infarction
postoperative heart failure
prosthesis-patient mismatch
quality of life
receiver operating characteristic
structural valve deterioration
transprosthetic gradient
time-velocity integral
9
Introduction
1.1 Prosthesis-patient mismatch – the concept
Prosthesis-patient mismatch (PPM) was first described by Rahimtoola in 1978 (1) who
stated that “mismatch can be considered present when the effective prosthetic valve
area, after insertion into the patient, is less than that of a normal human valve”.
Rahimtoola suggested that the degree of PPM could be quantified, which would aid in
identifying patients at risk of clinical sequelae caused by this condition. The
pathophysiology of mismatch was subsequently proposed to be related to persistent
valve gradients based on in vitro studies conducted by Dumesnil and Yoganathan (2).
They demonstrated an exponential relationship between the mean transprosthetic
pressure gradient and the indexed effective orifice area (EOAi, i.e. PPM) for aortic
bioprostheses in an in vitro physiologic pulse-duplicator system. Their findings led to
the recommendation that the EOAi should ideally not be less than 0.9 to 1 cm2/m2 for
aortic bioprostheses to minimize residual postoperative transprosthetic pressure
gradients. This subsequently led to the premise that there may be a correlation between
the decrease in transvalvular gradient and the clinical improvement seen after surgery
(3;4). With the development of Doppler echocardiography, in vivo observations
demonstrated that normally functioning valve prostheses could have relatively high
postoperative transvalvular gradients corresponding to the phenomenon previously
referred to as prosthesis–patient mismatch (5-7). PPM was suggested to occur more
often in patients with large body surface area (BSA), in whom a high cardiac output
across a small orifice area may produce high transprosthetic gradients (1;8). Hence, the
calculated effective orifice area (EOA) of a specific prosthesis has frequently been
adjusted for BSA to ensure its hemodynamic performance for an individual patient.
The most widely accepted and validated parameter for identifying PPM is the indexed
EOA, which is the EOA of the prosthesis divided by the patient’s BSA (9;10).
Prosthesis–patient mismatch has been recognized as a functional hemodynamic
abnormality rather than being due to an intrinsic defect of the prosthesis and is
identified as a nonstructural dysfunction by the Society of Thoracic Surgeons (11).
Previous studies have demonstrated that mismatch is a common phenomenon when
using a relatively conservative definition (i.e., EOAi≤0.85 cm2/m2), observed in 20 to
70% whereas the prevalence of severe PPM ranges from 2 to 10% (9;12).
1.2 Classification of PPM
It has previously been demonstrated by Pibarot et al. (9) that the relation between the
transprosthetic gradients and the EOAi is nonlinear and that the gradient increases
exponentially when the EOAi falls below 0.8 to 0.9 cm2/m2 as shown in Figure 1.1.
The value of EOAi≤0.85 cm2/m2 is thus generally regarded as the threshold for PPM
with values between 0.65 and 0.85 cm2/m2 being classified as moderate PPM and
<0.65 cm2/m2 as severe PPM (3;5;7;9;13).
10
Figure 1.1 Correlation between mean transvalvular gradient and indexed effective
orifice area in patients with a stented bioprosthesis (dots), a stentless bioprosthesis
(circles), an aortic homograft (triangles), and a pulmonary autograft (squares).
Reproduced from Pibarot and Dumesnil (9).
1.3 Determinants of prosthesis-patient mismatch
Mismatch has been shown to occur more frequently in patients receiving a small
prosthesis, in those with valvular stenosis as the predominant lesion before the
operation, and in patients with a high BSA, and greater age (1-3;7). Larger patients
may be predisposed to mismatch because they have high cardiac output requirements,
and greater narrowing of their valvular annulus in relation to their body size, compared
to smaller patients (9). The incidence of mismatch has been demonstrated to increase
with decreasing prosthesis size, and patients given valves ≤21 mm tend to show higher
transvalvular gradients (14;15). It must however be emphasized that severe mismatch
may occur in patients receiving a prosthesis >21 mm (3;7). Mismatch occurs more
frequently in patients with stenotic native valves as they generally have smaller
valvular annuli than those with regurgitant valves (16). Furthermore, calcific aortic
stenosis is by far the most prevalent lesion in older patients undergoing aortic valve
replacement (AVR).
1.4 Hemodynamic impact of prosthesis-patient mismatch
The main consequence of prosthesis–patient mismatch is the generation of a high
transvalvular gradient through a normally functioning prosthetic valve. Assuming a
normal cardiac index of 3 l/min/m2, implantation of a prosthesis with an EOA of 1.3
cm2 in a patient with a BSA of 1.5 m2 will theoretically result in a mean
transprosthetic gradient (TPG) of about 13 mmHg. The mean TPG would theoretically
11
be 35 mm Hg if the same prosthesis were to be implanted in a patient with a BSA of
2.5 m2 (10).
The increased transvalvular gradient associated with PPM has been shown to result in
an increased left ventricular (LV) work, which in turn influenced the regression of LV
hypertrophy (LVH) (17-20). LVH is in turn a strong independent risk factor for
mortality as well as a major determinant of systolic and diastolic function and exercise
capacity in patients undergoing valve replacement (21;22). Normalization of LV mass
is therefore a crucial goal of AVR. The persistence of LVH associated with PPM has
been proposed to be one of the factors contributing to adverse outcomes related to
PPM. However, Sharma et al. (23) reviewed the published literature on LV mass
regression (LVMR) after valve replacement for aortic stenosis over the past 23 years.
They found that surgical correction of stenosis by valve replacement led to
unequivocal regression of LV mass regardless of the type of valve inserted with the
bulk of the hypertrophy regressing within the first 6 months of operation. These
findings are supported by more recent publications also demonstrating that the extent
of LVMR is maximal during the first 6 postoperative months and influenced only by
the preoperative degree of hypertrophy and the presence of hypertension (24). In other
studies, neither prosthesis size nor type was correlated with LVMR (25;26). One
explanation of the conflicting resluts related to LVMR and PPM may be that many
studies showing long-term detrimental effects of LVH have been conducted in patients
with hypertensive and ischemic heart disease (27;28). It remains to be seen whether
similar consequences are observed with respect to the hypertrophy due to valvular
disease.
The difference in TPG between patients with PPM and those without may be even
more important during exercise, given that gradients are a square function of flow.
Recently, Bleiziffer et al. (29) were the first to report that the presence of PPM
significantly influenced the peak physical exercise capacity, according to stress test
echocardiography, following AVR. The authors suggested that their findings could be
explained by an increase in hemodynamic burden resulting from higher gradients in
patients with PPM. Another possible explanation is that PPM may limit the increase in
cardiac output during exercise, similar to that observed in native aortic stenosis. This
may in turn limit the capacity of the cardiac function to match the increasing metabolic
demand during intense exercise. Mannacio et al. (30) evaluated the impact of PPM
defined as EOAi<0.75 cm2/m2 on exercise capacity and arrhythmias. The authors
demonstrated that high mean TPG (above 50 mmHg) during exercise had 95%
sensitivity and 72% specificity for predicting arrhythmia. However, PPM failed to
demonstrate any significant correlation to early or late mortality, morbidity, or LVMR.
In contrast, Izzat et al. (31) examined a series of patients with modern, small aortic
valve prostheses examined at rest and during dobutamine-stress testing. They found
that the main predictor of a high transprosthetic gradient was related to the inherent
characteristics of each prosthesis, while variations in BSA had only a relatively
insignificant effect. They concluded that PPM is not a problem of clinical significance
when using certain modern valve prostheses.
12
The development of LVH in aortic stenosis is accompanied by coronary
microcirculatory dysfunction, demonstrated by an impaired coronary flow reserve
(CFR) (32). CFR in turn, is related to the native aortic valve area and the peak
transvalvular gradients rather than the degree of LVH (33). In theory, inadequate valve
opening or residual transprosthetic gradients will cause turbulent aortic root flow, and
may thus also impair physiological backflow during diastole with subsequent
impairment of CFR. Bakhtiary et al. (34) studied the role of PPM on coronary
perfusion and found that patients with PPM demonstrated less improvement in CFR
than those without. However, the CFR improved for all valve types studied with
complete normalization of CFR following implantation of a stentless valve. The
authors stated that they could not prove any clinical relevance of an impaired CFR on
long-term outcome, and concluded that the flow through the valve prostheses analyzed
may be adequate.
Patients with LV dysfunction and low-flow, low-gradient (LFLG) aortic stenosis
represent 5% to 10% of patients with aortic stenosis. They also represent the most
challenging and controversial subset of aortic stenosis patients with regard to
management (35). Dobutamine stress echocardiography has been shown to be useful in
differentiating patients with truly severe aortic stenosis and concomitant LV systolic
dysfunction from those with pseudo-severe aortic stenosis, in which a weakened
ventricle is incapable of opening an aortic valve that is only mildly or moderately
stenotic (35;36). It is essential to make the distinction between these two subgroups
because patients with truly severe aortic stenosis will generally benefit from AVR,
whereas those with pseudo-severe AS may not. This latter group of patients generally
has a poor prognosis with conservative therapy but a high operative mortality when
treated surgically (36;37). However, patients with LFLG aortic stenosis surviving AVR
exhibit a significant improvement in LV ejection fraction (LVEF) and functional status
and have an acceptable long-term survival (37). It has been suggested that the impact
of PPM on postoperative mortality depends on the severity of mismatch and the degree
of preoperative LV dysfunction (38;39). If this is indeed the case, PPM should
theoretically have a major impact on patients with LFLG aortic stenosis following
AVR. The greatest impact should be on mortality during the early postoperative period
when the LV is most vulnerable (12). Monin et al. (40) reported postoperative
outcomes in a large, multi-center study of consecutive series of patients who
underwent AVR for LFLG aortic stenosis. They found that PPM (moderate in most
cases) had no influence on early postoperative mortality, or on long-term postoperative
outcome. The authors stated that the overall postoperative mortality was mainly
influenced by the LV contractile reserve. They concluded that the performance of
more complex interventions in an attempt to avoid moderate PPM may not be justified
in patients with LFLG aortic stenosis. In another study, Kulik et al. (41) reported that
for patients with LFLG aortic stenosis, PPM following AVR resulted in an impaired
LVMR, and that is was an independent predictor of recurrent episodes of heart failure.
However, early mortality, and LV contractile reserve were not assessed in this study,
which constitutes a major limitation.
13
1.5 The clinical influence of prosthesis-patient mismatch
1.5.1 Survival
Bridges et al. (42) have analyzed PPM in the hitherto largest sample (42,310 patients).
Prostheses with small geometric orifice area (GOA) or EOA were reported to be
associated with increased operative mortality. However, a higher BSA for a given
EOA or GOA was found to be associated with lower operative mortality for patients
receiving prostheses of the same model and size. Furthermore, EOAi and the indexed
GOA were not significant predictors of operative mortality in their multivariable
models. Based on these findings the authors concluded that the practice of using
arbitrary cutoff values of EOAi as a decision tool to determine the type or size of valve
to be utilized in a given patient, in an attempt to decrease operative mortality, was not
advisable. The authors also concluded that in isolated AVR, priority should be given to
prosthesis durability, the experience of the surgeon, and the technical ease and speed
of implantation.
Blackstone et al. (43) found a small increase in 30-day mortality (1–2%) for patients
with an indexed GOA<1.2 cm2/m2. They were unable to identify PPM as a risk factor
for late survival. The authors acknowledged that reduced survival following AVR is
related to many factors with the potential to mask the impact of PPM on late mortality.
They concluded that with currently available prostheses, few patients should require
aortic root enlargement with its attendant complexity, prolonged operation time, risks
of bleeding, heart block, and mortality, particularly if a bioprosthesis is used (44).
In a study by Hanayama et al. (45) on 1129 patients who had undergone AVR and
postoperative echocardiographic assessment of the prosthetic valve with in vivo EOA,
severe mismatch (EOAi<0.60 cm2/m2) had no effect on survival up to 7 years after
surgery. Furthermore, severe PPM had no impact on LVMR or deteriorating NYHAclass. The estimated 7-year survival rate of patients with severe mismatch was 95%.
However, the mean age of the patients with PPM was 62 years at the time of surgery
and the study population was heterogeneous, including patients with aortic
insufficiency and patients undergoing double valve replacement and root procedures.
Blais et al.(12) demonstrated that both severe and moderate PPM were independent
predictors of early mortality and that the impact of PPM is dependent on both its
degree of severity and the LV function. However, the authors acknowledge that there
were limitations in their study in terms of differences in baseline patient
characteristics. Co-morbidity factors such as older age, female gender, coronary artery
disease, hypertension, diabetes mellitus, and emergent/salvage operation were more
prevalent in patients with moderate and severe PPM. The authors stated that it could
not be completely excluded that these co-morbidities may have contributed to the
higher mortality in patients with PPM.
Independent detrimental effects of PPM were also observed by Ruel et al. (46)
although only for patients with impaired preoperative LV systolic function, in whom
PPM was associated with decreased overall long-term survival, a higher degree of
14
heart failure, and reduced LVMR at the time of AVR. Furthermore, Ruel and
coworkers (47) have previously studied risk factors for the composite outcome of heart
failure symptoms and death from heart failure following AVR. Risk factors included
smaller prostheses, higher postoperative TPGs, and PPM, defined as either EOAi≤0.75
cm2/m2 or EOAi≤0.80 cm2/m2. These findings suggest that an increased hemodynamic
burden caused by PPM could be less well tolerated by a poorly functioning ventricle
than by a normal ventricle. However, the classic definition of PPM, EOAi≤0.85
cm2/m2, was not associated with an increased incidence of congestive heart failure,
cardiac related death, their combined occurrence, or all-cause death in this study. The
authors explained that despite all-cause mortality being a robust and easily
interpretable end point, it is limited as a specific indicator by the plethora of
confounding and contributing factors and by the availability of medical therapy for the
palliation of mild to moderate heart failure. In an elderly patient population, competing
causes of death such as coronary disease, valve-related complications, cancer, and
others may also have influenced the effect of PPM on all-cause mortality following
AVR.
The impact of PPM on survival has been demonstrated to be more pronounced in
young patients than older patients of average or large size (48;49). These findings may
be related to the higher cardiac output requirements of younger patients. Younger
patients may also be exposed to the risk of PPM for a longer period of time. Also,
PPM has been reported to have a negative impact on late survival for patients 70 years
of age or above (50). These findings may indicate that attention should be devoted to
attempts to improve PPM in younger patients while adopting a less aggressive
approach in small, elderly patients. Elderly patients may be better served with a
simpler, faster procedure, based on the assumption that PPM does not have a
significant impact on late survival (45).
1.5.2 Prosthesis-patient mismatch and morbidity
Based on the assumption that the LV is most vulnerable during the early postoperative period (51) it is reasonale to assume that the increased afterload caused by
PPM would be particularly deleterious, leading to excess morbidity during this period.
Studies on the impact of PPM on postoperative complications, including cardiac
complications, are, however, scarce. Yap et al. (52) found no association between
severe PPM and early morbidity events including stroke, prolonged ventilation, new
renal failure, prolonged postoperative stay, prolonged intensive care unit (ICU) stay, or
readmission within 30 days. Despite the absence of a correlation to morbidity, PPM
was found to be an independent predictor for increased 30-day mortality. The authors
stated that their study may have lacked the power to detect differences in the rates of
early morbidity. Further studies with larger patient populations experiencing more
postoperative events are clearly warranted.
Frapier et al. (53) compared long-term results for morbidity following implantation of
bioprostheses in the aortic position, in a small series of patients, with and without
PPM. At 10 years postoperatively, there was no significant inter-group difference in
15
actuarial freedom from thromboembolism, hemorrhage, endocarditis, structural valve
deterioration or reoperation
1.5.3 Prosthesis-patient mismatch and BMI
The use of the BSA to normalize the EOA may overestimate the prevalence and
severity of PPM in obese patients (49). The interaction between PPM and obesity was
evaluated by Mohty et al. (49) demonstrating that PPM has a negative impact on
survival in patients with a BMI <30 kg/m2, but no significant impact in obese patients.
It thus appears that obesity should be taken into account when assessing the risk of
PPM. The investigators of the Strong Heart Study reported that fat-free mass, which
represents the metabolically active tissues, accounts for 20% to 40% of the weight
difference between lean and obese individuals of the same height (54). They also
demonstrated that stroke volume and cardiac output are more strongly related to fatfree mass than to adipose mass. Hence, a potentially interesting design would be to
normalize the EOA to the fat-free mass, since this parameter appears to be the main
determinant of cardiac output in normal-weight, overweight, and obese people. Future
studies will be necessary to determine if the indexation of EOA can be improved or
refined in the case of obese patients.
1.5.4 Prosthesis-patient mismatch and in vivo EOA
Prosthesis-patient mismatch can be predicted at the time of surgery by obtaining the
EOA for the selected valve type from the literature; referred to as the “projected EOA”
(38) (see Figure 1.2). The discriminatory ability of the projected EOA has been
challenged in previous studies on the impact of PPM on mortality not relying on
projected EOA but on values of EOA measured echocardiographically in vivo.
Florath et al. (55) demonstrated that the projected EOA determined at surgery does not
sufficiently predict mismatch. Instead, the indexed EOA was obtained by
echocardiography 10 days postoperatively and severe PPM was found to be an
independent predictor of midterm survival. The main decrease in survival rate started 5
years after AVR. Similarly, Mohty-Echahidi et al. (56) identified severe PPM,
measured by echocardiography within 1 year of AVR, as an independent predictor of
higher late mortality in patients with 19- or 21-mm St Jude Medical prostheses.
In contrast, Flameng et al. (57) studied a population of patients undergoing AVR using
only the CE Perimount valve. The in vivo EOA was measured in a subgroup of
patients and extrapolation to the entire study population was performed. Severe PPM
was rarely seen when this valve was used, and moderate PPM was found to have no
clinical relevance for early or late mortality or morbidity in terms of hospital
readmission for cardiac reasons. Furthermore, LVH diminished in patients with
moderate PPM to the same extent as in patients without PPM.
16
Figure 1.2 View of a bioprosthesis and a bileaflet mechanical valve with the leaflets in
the fully open position. The area shaded in pink is the effective orifice area.
Reproduced from Pibarot and Dumesnil (10).
The variation in the method of defining PPM, either through in vitro or in vivo
measurements of EOA, makes it difficult to interpret the results of different studies.
This inconsistency has probably contributed considerably to the controversy
surrounding the topic. To add to the complexity of interpreting the clinical relevance
of PPM some authors have attempted to characterize mismatch by using the internal
geometric orifice area (43;58). The GOA is a static manufacturing specification based
on the in vitro measurement of the diameter of the prosthesis. Unfortunately, the
criteria used for its measurement differ from one type of prosthesis to another. The
internal GOA overestimates the EOA to a much larger extent in the case of a
bioprosthesis than in that of a mechanical prosthesis (59;60). Florath et al. (55) have
also demonstrated that the internal GOA had less discriminative power than the
projected indexed EOA for the prediction of postoperative outcome following AVR
(see Figure 1.3).
17
Figure 1.3 Definition of effective orifice area (EOA), and the geometric orifice area
(GOA) with: A) rigid sharp-edged aortic stenosis; B) funnel-shaped aortic stenosis.
The angle θ represents the valvular aperture. Reproduced from Garcia et al (61).
1.5.5 Severe prosthesis-patient mismatch
Studies of native aortic valves show that aortic stenosis becomes associated with
higher mortality and morbidity rates when EOAi falls to less than 0.6 cm2/m2 (62;63).
This association might, if applied to prostheses, explain the lack of a clear effect of
PPM on clinical outcome. Indeed, several studies have been able to independently
show that severe PPM, but not moderate PPM, was an independent risk factor for early
(52) and late survival (49;55;56). However, conflicting results have also been
demonstrated concerning the clinical relevance of severe PPM. Walther et al. (64)
evaluated a relatively large but heterogeneous study population and were able to show
that moderate mismatch was a predictor of impaired long-term survival after AVR.
Surprisingly, the authors found that patients with severe mismatch demonstrated
slightly better survival than patients with moderate PPM. According to a study by
Howell et al. (65), severe PPM occurred in 4-10% of patients undergoing AVR using
both the EOAi and GOAi. The presence of severe PPM, however, did not translate into
increased in-hospital mortality, or decreased survival after discharge from hospital.
1.5.6 Homogeneity and propensity scoring
Some authors have attempted to evaluate the impact of PPM in a strictly defined group
of patients or a homogeneous study population. Mascherbauer et al. (66) evaluated the
impact of moderate PPM on survival after AVR in patients referred for surgery for
isolated severe aortic stenosis. No major impact on perioperative and long-term
survival after AVR could be demonstrated. As previously demonstrated (9) patients
with PPM were significantly older, more hypertensive and symptomatic, had a higher
18
incidence of coronary artery disease and triple vessel disease, and a higher
EuroSCORE. In contrast, Tasca et al. (59) analyzed patients with isolated aortic valve
stenosis, and reported higher midterm mortality and more cardiac events for patients
with PPM defined as EOAi≤0.8 cm2/m2.
Although homogeneity may be required for a valid assessment of PPM, such a study
may be limited as it cannot be excluded that PPM could be a clinically important
phenomenon in patients with coronary artery disease, diseases of the ascending aorta,
or in cases where the etiology of the valve disease is something other than stenosis.
For instance, patients undergoing concomitant coronary artery by-pass grafting
(CABG) are exposed to limited oxygen delivery to the LV myocardium, due to both
prolonged global ischemia and residual coronary ischemia after revascularization (67).
Therefore, hypothetically a mismatch in the supply and demand for energy could occur
in patients with PPM due to the higher LV work load. This would in theory translate
into a higher rate of cardiac complications and perhaps mortality. Limiting the study
population to exclusively surgery for aortic stenosis may therefore not reveal the
“true” clinical impact of PPM.
Baseline differences in patient characteristics, as well as confounders that are not
adjusted for, could explain conflicting findings in previous publications. A randomized
controlled trial could eliminate the effect of several confounding variables and allow
analysis with a real control group. This solution is hardly feasible due ethical reasons.
Therefore, a propensity score analysis may be performed to balance the baseline
covariates between the groups being compared. Urso et al. (68) evaluated elderly
patients (age>75 years) undergoing AVR using a propensity score and multivariate
logistic regression analysis, and reported that long-term survival was not significantly
impaired in patients with moderate PPM despite an incidence of more than 40%. In a
study by Kohsaka et al. (69), propensity score adjustment was used to reduce baseline
differences in patient characteristics in order to avoid treatment selection bias. The
study population was homogeneous in that only mechanical AVR was evaluated. The
authors reported a significant association between moderate and severe PPM and longterm survival following multivariate adjustment and modeling with propensity scoring.
The authors acknowledged the limitation that most of the reference EOA values for the
aortic valve prostheses were derived from the results of a single study.
1.5.7 Prosthesis-patient mismatch and left ventricular mass regression
Patients with aortic valve stenosis and/or aortic regurgitation are subjected to increased
pressure and/or volume load of the left ventricle, leading to either concentric or
eccentric LVH (70). LVH is an independent risk factor for cardiovascular events and
mortality and it has been shown that the long term survival after AVR is directly
related to the extent of LVH regression (27). It has been suggested that PPM could
jeopardize the regression of LVH. Fuster et al. (71) reported that PPM was not an
independent predictor of mortality by itself, but a promoter of the left ventricular mass
index (LVMI). Patients with PPM and high preoperative LVMI demonstrated impaired
survival and a lower LVMR rate than patients without PPM and LVH. Once again,
19
conflicting data suggest the contrary. Bové and colleagues (72) evaluated survival and
hemodynamic outcome following AVR with stentless or stented bioprostheses. They
demonstrated that the preexistence of advanced LVH and systemic arterial
hypertension are the major obstacles for LVMR despite otherwise successful AVR.
1.5.8 Prosthesis-patient mismatch quality of life
Koch and co-workers (73) have previously published a study on the relationship
between prosthetic valve size (GOA) and the Duke Activity Status Index following
AVR. Analyzing data from 1014 patients, the authors reported an overall improvement
of functional quality of life (QoL) for all patients undergoing AVR. GOAi did not
influence functional recovery after AVR, even for thresholds that would be considered
as severe mismatch for patient size. These findings are in agreement with those
reported by Vicchio and colleagues (74), using in vivo EOA and small bileaflet
prostheses, showing that QoL improved equally well regardless of PPM in a
population of septuagenarians. In contrast, Ennker et al. (75) identified PPM (EOAi
0.75<cm2/m2) and small projected EOAi as independent risk factors for impaired
midterm survival and QoL. Interestingly, these findings were related to stentless
valves, a design that is purported to offer superior hemodynamic performance (76). In
a recent study by Urso et al. (68) PPM was found to be associated with a lower
physical component score of the SF-12 quality of life test. However, the authors
pointed out that the multifactorial nature of quality of life does not permit the
conclusion that this association depends exclusively on PPM.
1.5.9 Prosthesis-patient mismatch and aortic valve insufficiency
The different etiologies of aortic valve disease leading to AVR may be unaccountedfor confounding variables when evaluating the impact of PPM after AVR. Aortic valve
insufficiency (AVI) has several different etiologies and effects on the left ventricle,
compared to the stenotic valve. It may therefore be hypothesized that the incidence of
PPM, the extent of postoperative remodeling and the clinical effect of PPM differ
between patients with AVI and AS. In a recent study, Price et al. (77) reported that
PPM was encountered less frequently in patients with AVI and is more clinically
indolent. The authors concluded that special technical maneuvers to facilitate the
implantation of a valve with larger EOAi may increase perioperative morbidity and
mortality and therefore do not seem justified in patients with AI on the basis of
improving long-term survival or freedom from symtoms of congestive heart failure
and death
1.6 Postoperative heart failure
As early as in 1967, Kirklin noted that early death after cardiac surgery was often
related to cardiac output (78). Improvements in surgical techniques, prosthetic design,
and myocardial protection as well as earlier patient referral have led to a decrease in
operative risks associated with AVR during recent decades (79). However, although
the majority of patients considered for AVR have normal LV systolic function (80),
20
myocardial performance may deteriorate while awaiting surgery due to the progress of
AS or increasing aortic regurgitation with subsequent LVH and dilatation. Also,
asymptomatic patients may remain undetected for many years, and often present late in
the natural history of the disease due to the development of symptoms secondary to
ventricular, rather than valvular, disease (81). Furthermore, preoperative
echocardiographic assessment may be influenced by physiological and investigatordependent variations and may not always reflect the myocardial status adequately at
the time of surgery. LV function may also deteriorate intraoperatively secondary to
poor myocardial protection or technical problems leading to prolonged aortic crossclamp and cardiopulmonary bypass (CPB) times.
The preoperative deterioration in LV diastolic and systolic function have important
implications for morbidity and mortality before and after AVR (82-87). The
deleterious effects of LV systolic impairment in patients with severe AS have been
demonstrated by several previous studies, which amongst others, have identified
preoperative LV dysfunction and lack of myocardial contractile reserve as prognostic
indicators of surgical outcome (36;81). However, studies evaluating postoperative
heart failure (PHF), its causes and risk factors following AVR are scarce although this
condition remains an important determinant of poor early and late outcome (88-90). In
general, the treatment of PHF appears uniform, regardless of the preceeding procedure
and underlying cause (91). Furthermore, in spite of the grave consequences of PHF
there is no generally accepted definition of the condition. Most of the previously
published results derive from studies on CABG patients. In 1996, Rao et al. (92)
reported a 9% incidence of low cardiac output syndrome (LCOS) following CABG,
with an operative mortality of 17% compared to 1% for those without LCOS. Efforts
to prevent PHF and to tailor causal treatment following AVR require greater
knowledge and insight into these issues.
1.7 Diastolic dysfunction in patients with aortic valve disease
Diastolic heart failure has been demonstrated in 50% of patients in the elderly
population, causing symptomatic congestive heart failure despite a normal LV ejection
fraction (LVEF) (93). The pathophysiological condition of heart failure in aortic
stenosis derives from increased pressure load on the LV, resulting in myocardial
hypertrophy and diastolic dysfunction, in addition to systolic dysfunction. Dineen and
colleagues (94) demonstrated that the LV ejection fraction was preserved in 60% of
patients with aortic stenosis and diastolic heart failure (DHF). Studies on DHF after
AVR and the relation between PPM and diastolic dysfunction are scarce (84;95), and
the effect of AVR on diastolic function in patients with aortic regurgitation has not
been studied. A previous study using LV bi-plane angiography and high-fidelity
pressure measurements has shown that diastolic function in patients with aortic valve
stenosis deteriorates immediately after AVR. At follow-up, diastolic function is seen
to improve gradually and may be completely normalized long after AVR (85).
Furthermore, impaired LVMR following AVR may be detrimental inasmuch as
persistent LVH is one of the known causes of diastolic heart failure (96). Previous
studies have suggested that the extent of LVMR is strongly and independently related
21
to the presence of PPM (19;20). Others have reported that patients with PPM or small
prostheses exhibited significant reductions in LV mass and, on this basis, concluded
that PPM was not an important issue (26;45;97;98). Bové and colleagues (72) found
the preexistence of advanced LVH to be a major obstacle for LVMR, despite
otherwise successful AVR. The inference from these previous findings, although
inconclusive, suggests that the presence of PPM would have a negative impact on the
recovery of diastolic function.
1.8 Brain-type natriuretic peptide
Natriuretic peptides are released by ventricular myocytes in response to pressure and
volume overload that induces wall stress (99). The biologically active peptide braintype natriuretic peptide (BNP) is cleaved from the inactive fragment NT-proBNP and
released into the circulation where it exerts its vasodilative action and opposes the
renin-angiotensin aldosterone system. Natriuretic peptides, especially BNP, have been
established as an aid in recognizing symptoms of congestive heart failure and in
discriminating between cardiac and non-cardiac dyspnea (100). BNP has also been
reported to be an independent predictor of survival after acute coronary syndrome and
ischemic heart failure in adult patients (101-104). In aortic stenosis, plasma levels of
natriuretic peptides are elevated (105;106), and recent studies have established that
BNP is related to the onset of symptoms (107;108), as well as the prognosis and
outcome of severe asymptomatic AS (107;109-111).
1.8.1 Preoperative measurement of brain-type natriuretic peptide in aortic valve
stenosis
In patients undergoing open heart surgery for different reasons, preoperative BNP or
NT-proBNP has been shown to predict postoperative outcome with respect to
perioperative and postoperative survival, postoperative hospital stay, necessity of
intra-aortic balloon pump (112;113), and clinical improvement in patients with severe
heart failure undergoing surgical ventricular restoration (114). In patients with LFLG
aortic stenosis referred for valve replacement, those with high BNP levels had a worse
outcome than those with lower BNP (115). In a recent study of 144 patients with
severe aortic stenosis referred for AVR, preoperative BNP was compared with the
logistic EuroSCORE in an attempt to predict postoperative mortality (116). Patients
with logistic EuroSCOREs greater than 10% had a higher mortality risk (hazard ratio
(HR) 2.86), as had patients with a BNP level greater than 312 pg/mL (HR 9.01).
Although many of these studies are limited by heterogeneous populations and a
relatively small number of patients undergoing AVR, data indicate that preoperative
measurement of BNP may be useful in risk stratification of patients, together with
clinical findings and operative risk scores such as the EuroSCORE.
22
1.8.2 Measurement of brain-type natriuretic peptide following aortic valve
replacement
High BNP levels postoperatively may also predict mortality for patients undergoing
open-heart surgery for different reasons (112). A few studies have previously
examined the development of postoperative BNP after AVR due to aortic stenosis
(117;118). In a study of 22 patients undergoing AVR (117), transiently increased
levels of BNP were seen immediately postoperatively and also when measured before
hospital discharge. But after 6 and 12 months postoperatively, a significant decrease in
BNP was observed. Persistently elevated BNP levels postoperatively indicated poor
overall outcome late after AVR.
In theory, BNP may remain elevated in patients with prosthesis-patient mismatch due
to the residual transprosthetic gradient and increased LV myocardial wall pressure,
although few data are available to date. In a previous study by Qi et al. (118), patients
with the largest EOAi (mean 1.27 cm2/m2) showed a considerable reduction in NTproBNP, whereas patients with the smallest EOAi (mean 0.67 cm2/m2) showed no
significant decrease in NT-proBNP following AVR. Furthermore, in a study by Weber
et al. (119), a significant decrease in NT-proBNP was observed postoperatively, and
this was associated with the type and size of the aortic prosthesis. Patients receiving a
bioprosthesis had higher postoperative NT-proBNP levels than those receiving a
mechanical prosthesis. Smaller prosthesis size was related to higher TPGs and a
tendency towards higher NT-proBNP levels.
The validation of postoperative BNP as a reliable biomarker to facilitate the diagnosis
of heart failure following AVR may be useful in initiating and monitoring patienttailored therapy in the ICU. However, the current evidence is not convincing, and
further knowledge is required in this matter.
1.9 Aortic valve stenosis
Aortic stenosis is the most prevalent valvular heart disease in the developed countries.
Primarily a manifestation of ageing, the disorder is becoming more frequent as the
average age of the population increases (120). The prevalence of aortic stenosis is 13% in the population older than 65 years and around 4% in that older than 85 years.
Age-related degenerative calcification is currently the most common cause of aortic
stenosis in adults and the most frequent reason for AVR (121).
1.9.1 Pathophysiology
Aortic stenosis is characterized by a progressive obstruction of the left ventricular
outflow tract. Narrowing of the aortic orifice to half its usual size, 3-4 cm², causes
little obstruction and only a small pressure gradient across the valve. Progression of
the stenosis causes the LV to adapt to the systolic pressure overload through a
hypertrophic process that results in increased LV wall thickness, while a normal
chamber volume is maintained (63;120). The resulting increase in relative wall
23
thickness is usually sufficient to counter the high intracavitary systolic pressure, and as
a result, LV systolic wall stress (afterload) remains within the normal range. As long
as wall stress is normal, the ejection fraction is preserved (122). The compensated
phase of aortic stenosis, with progressive LVH, may cause the patient to be
asymptomatic for decades. However, if the hypertrophic process is inadequate and the
thickness of the wall does not increase in proportion to the pressure, the wall stress
will increase and the high afterload will cause a decrease in ejection fraction (122124). Although hypertrophy helps to preserve LV systolic performance, the increased
wall thickness impairs coronary blood flow reserve thereby impairing diastolic
function. Therefore, the hypertrophied heart may have reduced coronary blood flow
per gram of muscle and also exhibit a limited coronary vasodilator reserve, even in the
absence of epicardial coronary artery disease (125;126). The hemodynamic stress of
exercise or tachycardia can produce a maldistribution of coronary blood flow and
subendocardial ischemia, which can contribute to systolic or diastolic dysfunction of
the left ventricle. The increased wall thickness leads to a diminished compliance of the
chamber, and the LV end-diastolic pressure increases without chamber dilatation (127129). Thus, increased end-diastolic pressure usually reflects diastolic dysfunction
rather than systolic dysfunction or failure (130). This state of impaired LV diastolic
dysfunction in aortic stenosis has been demonstrated to be associated with increased
mortality (33;131;132).
The survival of asymptomatic patients is similar to that of an age- and gender-matched
healthy population; however, the prognosis worsens significantly as soon as symptoms
develop. The onset of severe symptoms of aortic stenosis—angina, syncope, and heart
failure—remains the major demarcation point in the course of the disease at which
most patients are referred for AVR (63;120;133).
1.10 Aortic valve insufficiency
There are a number of common causes of AVI including idiopathic dilatation of the
aorta, congenital abnormalities of the aortic valve (most notably bicuspid valves),
calcific degeneration, rheumatic disease, infective endocarditis, myxomatous
degeneration, dissection of the ascending aorta, and Marfan syndrome. The majority of
these lesions produce chronic aortic insufficiency with slow, insidious LV dilation and
a prolonged asymptomatic phase (63). Other lesions, in particular infective
endocarditis, aortic dissection, and trauma, more often produce acute severe AVI,
which can result in sudden catastrophic elevation of LV filling pressures and reduction
in cardiac output.
1.10.1 Acute aortic valve insufficiency
Acute AVI is by definition a hemodynamically significant aortic incompetence with
sudden onset across a previously competent aortic valve into a left ventricle not
previously subjected to volume overload. The inability to adapt is worse for
concentrically thickened hypertrophic myocardium typically seen in those with chronic
hypertension. Effective cardiac output is less than that of the chronic state because
24
compensatory dilatation has not occurred, and, hence, LV end-diastolic volume
remains larger than normal but small in comparison with effective stroke volume.
Compensatory changes in heart rate occur, higher than those of chronic AR, to
augment cardiac output. Overall, the hemodynamic effects of acute AVI produce a low
effective cardiac output with an elevated LV diastolic pressure and heart rate. Any
changes in diastolic filling or heart rate, which are maintained in a delicate balance,
lead to the onset of congestive heart failure, and patients frequently present with
pulmonary edema or cardiogenic shock (63).
1.10.2 Chronic aortic valve insufficiency
Chronic AVI is a slow and insidious process, which sets in motion numerous
compensatory mechanisms. The left ventricle accommodates increased volume and
pressure caused by the regurgitant flow by eccentric ventricular hypertrophy, with a
consecutive increase in LV end-diastolic volumes. Cardiac output is maintained with
the aid of the autonomic nervous system. AVI also impairs early diastolic function
because eccentric hypertrophy leads to impaired LV relaxation during later stages of
the disease process (134). The greater diastolic volume permits the ventricle to eject a
large total stroke volume to maintain forward stroke volume in the normal range. This
is accomplished through rearrangement of myocardial fibers with the addition of new
sarcomeres and development of eccentric LV hypertrophy. Although the LVEF
remains in the normal range, the enlarged chamber size, with the associated increase in
systolic wall stress, also results in an increase in LV afterload and is a stimulus for
further hypertrophy (135;136). As the disease progresses, compensatory hypertrophy
permit the ventricle to maintain normal ejection performance despite the elevated
afterload (137;138). The majority of patients remain asymptomatic throughout this
compensated phase, which may last for decades. Eventually, the balance between
afterload excess and hypertrophy cannot be maintained and further increases in
afterload result in a reduction in LVEF. Patients often develop dyspnea at this point in
the natural history. In addition, diminished coronary flow reserve in the hypertrophied
myocardium may result in exertional angina (139). However, this transition may be
much more insidious, and it is possible for patients to remain asymptomatic until
severe LV dysfunction has developed. LV systolic dysfunction is initially a reversible
phenomenon related predominantly to afterload excess, and full recovery of LV size
and function is possible with AVR (63;140). With time, during which the ventricle
develops progressive chamber enlargement and a more spherical geometry, depressed
myocardial contractility predominates over excessive loading as the cause of
progressive systolic dysfunction. This can progress to the extent that the full benefit of
surgical correction of the regurgitant lesion, in terms of recovery of LV function and
improved survival, can no longer be achieved (63).
1.11 Aortic valve replacement
The introduction of valve replacement surgery in the early 1960s has dramatically
improved the outcome of patients with valvular heart disease. Approximately 280 000
valve substitutes are now implanted worldwide each year; approximately half of which
are mechanical valves and half are bioprosthetic valves (38). Despite the marked
25
improvements in prosthetic valve design and surgical procedures over the past
decades, valve replacement does not provide a definitive cure to the patient. Instead,
native valve disease is traded for “prosthetic valve disease,” and the outcome of
patients undergoing valve replacement is affected by prosthetic valve hemodynamics,
durability, and thrombogenicity. Nonetheless, many of the prosthesis-related
complications can be prevented or their impact minimized through optimal prosthesis
selection in the individual patient and careful medical management and follow-up after
implantation.
The average surgical mortality for isolated AVR is approximately 3% to 4% (141) and
1% to 2% in high-volume and experienced medical centers (142). Surgical mortality,
however, increases progressively with age and is up to 9% in octogenarians (143;144).
Additional factors can further increase the risk of operative mortality in asymptomatic
severe AS, including emergent surgery, LV dysfunction, pulmonary hypertension,
coexisting coronary artery disease, and previous open-heart surgery (133).
According to the ACC/AHA guidelines, the choice of prosthesis type should depend
on anticoagulation contraindications, risk of thrombosis, concurrent mitral or tricuspid
mechanical valve and patient preferences (142). One should contemplate the prosthesis
models that have a well-established track record with regard to long-term durability
and low thrombogenicity. Mechanical aortic valves have an estimated average rate of
major thromboembolism of 4 to 8 per 100 patient-years in patients not receiving longterm anticoagulation therapy (145). This risk is reduced to 2.2 per 100 patient-years
with anti-platelet therapy, and further reduced to 1 per 100 patient-years with oral
anticoagulation (warfarin). The incidence of bleeding related to anticoagulation
therapy is 4.6 per 100 patient-years (146), increasing significantly when patients are
≥75 years of age (133). Prosthetic valve endocarditis is an uncommon but potentially
lethal complication of heart valve replacement surgery associated with substantial
morbidity and mortality. Prosthetic valve endocarditis has been estimated to occur at a
rate of 0.3% to 1% per patient-year and to account for 1% to 5% of all cases of
infective endocarditis (147). Bioprosthetic aortic valves have the main risk of
structural valve degeneration and therefore reduced valve durability, although in a
recent meta-analysis, Lund and colleagues (148) did not find any differences in
mortality between patients with mechanical aortic valves and those with bioprosthetic
aortic valves. A bioprosthetic aortic valve is currently a reasonable choice in adult
patients (65-70 years of age) who decline, do not require or have contraindications to
anticoagulation therapy (63).
The choice of a prosthesis that may provide superior hemodynamic performance, thus
preventing PPM, is suggested to be the next step in achieving a patient-tailored
prosthesis. This may be achieved by selecting the model that provides the largest valve
EOA in relation to the patient’s annulus size. Stent design for bioprostheses has
evolved during the past years towards lower profiles and thinner sewing rings striving
to match the hemodynamic and functional characteristics of the native aortic valve
(38). However, despite progress in the construction and design of bioprostheses, parts
of the sewing ring and stent construction are positioned within the aortic outflow tract,
26
causing a degree of blood flow obstruction. The hemodynamic performance is
generally superior in newer than in older generations of prostheses, in mechanical than
in stented bioprosthetic valves (149), and in stentless than in stented prostheses. In a
meta-analysis, Kunadian et al. (76) concluded that stentless aortic valves provide an
improved level of LVMR, reduced gradients, and an improved EOAi, but longer crossclamp and cardiopulmonary by-pass times are required. In contrast, stentless valves
did not show any hemodynamic benefit in terms of LVMR or postoperative mean
gradients in a different meta-analysis by Payne and colleagues (150). Superior
hemodynamic performance has also previously been demonstrated previously for
bioprostheses in complete supra-annular position compared to those placed intraannullary (151), although these differences were not significant in patients with an
aortic annulus of 18 to 20 mm in diameter.
1.12 The small aortic root and alternative surgical strategies
Aortic valve replacement in patients with a small aortic annulus is often challenging
for the surgeon in terms of prosthesis selection. Patients with a small annular size may
be small individuals, and the small valve size will then be matched to their cardiac
output needs. On the other hand, the use of small-sized prostheses in a larger patient
may be the cause of PPM. One should also keep in mind that the measured internal or
external diameter of a “19-mm” valve may vary by up to 4 mm depending on the valve
manufacturer (152). No randomized studies have been performed to investigate
whether a patient with a small aortic annulus is better treated by insertion of a 19-mm
prosthetic valve or by root enlargement and the insertion of a larger valve. There are,
however, several retrospective studies reporting conflicting results. Milano et al. (14)
analyzed two groups of patients receiving 19 or 21 mm mechanical prostheses.
According to their study, EOAi was not an independent predictor of early or late
mortality, but a predictor of cardiac events for patients receiving 19 mm valves. The
authors also reported incomplete regression of LVH in both groups of patients.
Medalion et al. (58) investigated the relation of prosthesis size to survival after AVR.
The statistical analyses in the study included multivariable propensity scores to adjust
for valve selection factors, multivariable hazard function analyses to identify risk
factors for all-cause mortality, and bootstrap resampling to quantify the reliability of
the results. The risk of death was highest immediately after valve replacement but fell
rapidly to its lowest level and gradually rose after about three months. No valve type
or expression of valve size was identified as a risk factor. Adams et al. (153) evaluated
366 patients over 70 years of age undergoing AVR using propensity scoring and
multivariate analysis After combining male sex and small prosthesis size, the authors
could demonstrate that the implantation of a standard 19-mm aortic valve in elderly
men with aortic stenosis may be associated with an increased risk of operative
mortality.
On the other hand, larger aortic bioprostheses have previously been found to be
associated with a lower incidence of re-operation (154). This may be due to patients
with larger prostheses tolerating stenosis or regurgitation secondary to SVD better, or
27
it may reflect a true beneficial effect of larger prosthesis size on SVD, resulting from
lower flow velocities and lower transprosthetic gradients.
In cases of anticipated PPM, alternative procedures such as aortic root enlargement to
accommodate a larger prosthesis of the same mode have been suggested (38). Previous
studies have reported that this procedure can be performed safely for this purpose
(155;156), although the long-term clinical outcome is not improved (157). Earlier
studies showed that aortic annulus enlargement increased the operative mortality, but
patients who underwent enlargement of a small aortic annulus had comparable longterm survival and freedom from cardiac- and valve-related death to those patients who
received larger aortic prostheses (44). In a recent study by Sakamoto et al. (158) the
incidence of PPM in small-built patients with small aortic roots in a Japanese
population with or without annular enlargement was investigated. Their findings
indicated that few patients developed PPM, especially those aged over 65 with a
relatively small BSA, who were able to receive bioprosthetic valves. In patients with a
small aortic annulus younger than 65, the method of first choice for avoidance of PPM
was aortic annular enlargement, or the use of a high-performance bileaflet mechanical
prosthesis as an alternative, with good results. Based on the current evidence, Pibarot
et al. (38) suggested that aortic root enlargement should be considered only in patients
in whom the risk of severe PPM cannot be avoided with the use of a better-performing
prosthesis, and in whom the risk-to-benefit ratio of performing such a procedure is
considered advantageous.
28
Aims of this Research
The general aim of the work presented in this thesis was to bring research on the
concept of prosthesis-patient mismatch a step further in order to achieve a higher
quality of treatment and to improve the outcome for patients undergoing aortic valve
replacement.
The specific aims were:
To evaluate the impact of prosthesis-patient mismatch on in-hospital complications,
and early and late mortality, following aortic valve replacement. (Paper I)
To determine the impact of postoperative heart failure on early mortality following
aortic vavle replacement and to determine whether B-type natriuretic peptide is
predictive of postoperative heart failure. (Paper II)
To investigate the influence of prosthesis-patient mismatch when using
bioprostheses with respect to recovery of left ventricular diastolic function and left
ventricular mass regression, and to evaluate the impact of prosthesis-patient
mismatch on midterm outcome following the implantation of bioprostheses. (Paper
III)
To study the influence of prosthesis-patient mismatch on left ventricular remodeling
and the recovery of left ventricular ejection fraction following aortic valve
replacement for severe aortic valve insufficiency, and to evaluate the impact of
prosthesis-patient mismatch on long-term survival. (Paper IV)
29
Material and Methods
3.1 Patients
Patients recruited for the four studies all underwent aortic valve replacement at the
Department of Cardiothoracic Surgery, Lund University Hospital, Sweden. Risk
factors for all adult patients were prospectively collected when the patient was
admitted to the department. The data base contained a total of 248 variables (pre-,
intra- and postoperative) based on the Higgins (159), Parsonnet (160), and STS (161)
patient record forms. Survival data and cause of death were obtained from the Swedish
National Board of Health and Welfare (Socialstyrelsen) or, if necessary, from patient
records.
The study described in Paper I was conducted on a series of 2016 consecutive patients
undergoing a total of 2031 AVR procedures between January 1996 and July 2006.
Paper II describes a study in which 161 patients undergoing AVR between September
2006 and October 2007 were included. The selection was based on consecutive AVR
procedures during a period of time when all cardiac surgery patients were routinely
screened in the ICU for BNP using a point-of-care device (Triage®, Biosite
Diagnostics, San Diego, CA, USA).
Paper III presents a study of 372 patients undergoing AVR with the Sorin Soprano
bovine pericardial bioprosthesis (Sorin Biomedica Cardio SpA, Saluggia, Italy; n=235)
and the Medtronic Mosaic porcine bioprosthesis (Medtronic Inc, MN, USA; n=137)
between July 2004 and February 2007.
The study described in Paper IV included a series of 230 consecutive patients
undergoing AVR between January 1998 and October 2008 based on the inclusion
criterion of severe aortic insufficiency.
3.2 Study design
3.2.1 Paper I
The EOAi was calculated in 1797/2016 patients. Data were missing for the other
patients. Patients with moderate or severe PPM were compared to patients without
PPM to evaluate the impact of PPM on postoperative complications. Stepwise logistic
regression was performed to determine whether PPM was an independent predictor of
the different outcomes. If any of the outcomes were independently predicted by PPM,
separate uni- and multivariate analyses were performed for that specific outcome to
assess its multivariate risk factors, adjusting for any confounding factors. Furthermore,
the influence of PPM on 30-day mortality and long-term survival was addressed.
30
3.2.2 Paper II
B-type natriuretic peptide was measured in 161 patients undergoing AVR with or
without CABG. We sought to validate BNP as a biomarker for postoperative heart
failure following AVR in order to facilitate the diagnosis of low cardiac output
syndrome (LCOS) in this patient category. Receiver operating characteristic (ROC)
analysis was performed to assess the discriminatory ability of BNP to predict LCOS,
30-day mortality and several other postoperative complications The incidence of
LCOS was evaluated, as was the relationship between PPM and BNP.
3.2.3 Paper III
In this paper, two novel approaches were employed to evaluate PPM. The first was to
assess the influence of PPM with respect to the recovery of LV diastolic function. It
was postulated that if PPM caused an increased afterload on the LV, thereby inhibiting
LVMR following AVR, than any preexisting LV diastolic dysfunction would increase
as LVH is a known cause of DHF. Second, despite progress in the design and
construction of bioprostheses, their hemodynamic performance is not yet comparable
to that of the native aortic valve. Third-generation bioprostheses designed for complete
supra-annular implantation offer an alternative for improved hemodynamics, as the
stent is positioned so as to cause less disturbance of aortic blood flow (162),
potentially leading to a decrease in the incidence of PPM and having less impact on
clinical outcome. The Sorin Soprano bovine pericardial bioprosthesis (Sorin
Biomedica Cardio SpA, Saluggia, Italy) is a third-generation bioprosthesis designed
for complete supra-annular implantation, and was chosen for evaluation and
comparison with the performance of the more established Medtronic Mosaic porcine
bioprosthesis (Medtronic Inc, MN, USA).
3.2.4 Paper IV
As previously demonstrated by Rahimtoola (1), for some patients (i.e., those with
severe aortic insufficiency), abnormality in one valve leads to abnormality in another
following surgery, with mild to moderate LV outflow obstruction as a result of PPM.
However, previous studies have demonstrated that PPM is most likely to occur in
patients in whom the predominant lesion is aortic stenosis, as the calcified aortic valve
and aortic root present a surgical challenge for the implantation of a prosthetic valve
with an adequate EOA (9). Because aortic insufficiency often presents with annular
dilatation and an absence of valve calcification, this condition would intuitively be
thought to be unrelated to PPM. Nevertheless, aortic insufficiency has been included in
the analyses of earlier reports investigating the clinical relevance of PPM. Based on
the findings of Rahimtoola (1) it was postulated that if PPM were present following
AVR for severe aortic insufficiency, the residual gradients and increased afterload may
influence LV remodeling. As such, these patients constitute an in vivo model to
evaluate PPM and its impact on LV volumes, mass, and systolic performance.
Patients with acute endocarditis (defined as ongoing antibiotic treatment at the time of
surgery) were included in the study for the purpose of overall survival analysis.
31
However, these patients were excluded when evaluating postoperative LV remodeling
since the pathophysiology of chronic aortic insufficiency with respect to LV
dimensions differs from that of acute aortic insufficiency caused by endocarditis.
3.3 Anesthetic management
Standard premedication with a benzodiazepine was used for all patients. Beta-blocking
agents were given until the day of surgery. Standardized anesthesia was used in all
patients, including induction by propofol infusion, fentanyl, and succinylcholine and
maintenance of anesthesia by continuous infusion of propofol, intermittent doses of
fentanyl, and vecuronium bromide. Propofol was then administered continuously
during cardiopulmonary bypass (CPB), until the end of surgery, and for the first hours
in the intensive care unit. Standard monitoring techniques (5-lead electrocardiogram,
central venous pressure, and invasive arterial blood pressure) were used in all patients
and complied with routine practice at the department.
3.4 Surgical management
After median sternotomy, all patients underwent AVR with CPB performed under
mild hypothermia (34°C). Myocardial protection was achieved by intermittent
anterograde or combined (anterograde plus retrograde) cold blood cardioplegia. The
prostheses were implanted and oriented in accordance with the manufacturer’s
recommendations. With regard to sizing of the prosthesis, the surgeon determined the
largest size hosted by the annulus using the specific sizers provided by the
manufacturer. The final choice of the prosthesis size was based on the sizing of the
patient’s annulus and the best fitting sizer at time of surgery and complied with routine
practice at the department. Prostheses were implanted by means of multiple interrupted
sutures reinforced with Teflon pledgets placed below the aortic annulus. Postoperative
care was provided in the ICU by anesthesiologists and by cardiothoracic surgeons in
the ward.
3.5 Triage® BNP test
Whole blood samples (5 mL) were collected in tubes containing potassium EDTA, and
the BNP level was analyzed immediately using a point-of-care device (Triage, Biosite
Diagnostics, San Diego, CA), as described in Paper II. The samples were obtained
immediately on admittance to the ICU (D0) and on the first postoperative day (D1).
This postoperative time point was chosen in accordance with previous reports showing
that the maximum BNP value remains unchanged up to 6 hours after cardiac surgery
(163), and that a single 24-hour BNP value is a significant predictor of cardiac
dysfunction (113) and is associated with short- and long-term adverse outcomes in
cardiac surgical patients (112). Samples were obtained daily from patients showing
increasing BNP levels until the peak concentration of BNP was reached (Dmax). No
further samples were taken from patients showing a decline in BNP level on the first
postoperative day (D1<D0).
32
3.6 Echocardiography
Complete two-dimensional, pulsed Doppler echocardiographic examinations were
performed using a Philips I33 echocardiograph (Andover, MA, USA) with a 2.5-MHz
broadband transducer, as described in Paper III and IV. Measurements were made as
recommended by the European Society of Cardiology (164) and averaged over three
cycles in sinus rhythm and six cycles in the presence of atrial fibrillation. Long- and
short-axis views were obtained from the parasternal window, and LV inner dimensions
were measured at end-diastole, and at end-systole using M-mode echocardiography.
The left ventricular end-diastolic diameter (LVEDD) was defined as the beginning of
the Q-wave on the electrocardiogram (ECG). The left ventricular end-systolic diameter
(LVESD) was measured as the smallest LV dimension during the period between peak
septal motion and peak anterior movement of the LV posterior wall. If possible, the
LV mass was calculated using the formula LV mass = 1.04 [(LVIDd + IVSd +
LPWDd) 3 - (LVIDd) 3] - 13.6, and was normalized to the patient’s BSA. In cases
where the acoustic window was poor, wall thickness was assessed visually, and LVH
categorized as normal, mild, moderate, or severe. Regional and global LV systolic
function was assessed from the apical two- and four-chamber view. LV systolic
function was defined as impaired if there was evidence of global or regional
hypokinesia in more than one segment of the left ventricle. The LVEF was determined
using the area-length method described in Paper III and, if applicable, calculated using
the modified Simpson’s method, as described in Paper IV. The pressure gradients
(peak and mean) of the prostheses were calculated from continuous-wave Doppler
measurements using the modified Bernoulli equation. Regurgitant jets were localized,
and then graded using a combination of the diameter of the base of the jet, the
extension of the jet into the left ventricle, and the density and slope of the aortic
regurgitant signal recorded during continuous-wave Doppler measurements.
The EOA of the prosthesis was estimated by multiplying the time-velocity integral
ratio between LV outflow tract and the prosthesis by the area of the LV outflow tract,
using the continuity equation.
In the study presented in Paper III, the diastolic function was determined and defined
accordingly: LV inflow was measured in pulsed-wave Doppler mode at the tip of the
mitral valve leaflets, and the following variables were recorded: peak velocity of early
(E) and late (A) filling, and the deceleration time of the E wave velocity. Diastolic
function was graded as normal, impaired relaxation, pseudonormal, or restrictive
filling. Normal was defined as an E wave velocity greater than the A wave velocity
and normal-sized left atrium. Impaired relaxation was defined as E wave velocity
lower than A wave velocity and deceleration time greater than 250 ms.
Pseudonormalization was defined as E wave velocity higher than A wave velocity,
enlarged left atrium, and an E/A ratio greater than 1. The E wave was correlated to the
e′ from the tissue Doppler velocity of the medial atrioventricular plane and the ratio
was calculated. In patients with E greater than A, an E/e′ = ratio greater than 15 was
considered pathologic, indicating that the patient had a moderate diastolic dysfunction
with a pseudonormal inflow of the LV. Restrictive filling was defined as an E/A ratio
greater than 2 and deceleration time less than 150 ms.
33
3.7 Definitions
In the first study (Paper I), the indexed EOA for each prosthesis was derived from
previously published reference values of EOA divided by the patient’s body surface
area. The application of this method is referred to as the projected EOAi and has
previously been described and validated by Pibarot et al. (9;10).
In the second study (Paper II), patients were defined as suffering from postoperative
heart failure (i.e., LCOS) if inotropic support was required for >24 hours (dobutamine
or levosimendan with or without additional norepinephrine infusion) or if treatment
with an intra-aortic balloon pump (IABP) was required for more than 24 hours in the
ICU. The institution of inotropic support was left to the discretion of the individual
physician, and was guided by hemodynamic data (mean arterial pressure <60 mmHg,
SvO2 <55%, CVP >15 cmH2O, lactate >3 mmol/L, oliguria, and if a pulmonary artery
catheter was present: cardiac index <2.2 L/min/m2, pulmonary artery pressure >30
mmHg, systemic vascular resistance <800-1000 dynes · s · cm5) and
echocardiographic evidence of LV or right ventricular dysfunction. The use of an
IABP was indicated by deteriorating circulation and increasing filling pressure after
weaning from CPB.
In the third study (Paper III), the EOA was determined using echocardiographic (in
vivo) measurements. There are several pitfalls associated with in vivo EOA
measurements inherent to the method of echocardiography. However, this method has
been described and validated by Mohty-Echahidi et al.(56) and we hypothesized that
the in vivo measurement might reflect a more clinically relevant scenario than in vitro
measurements of EOA.
In the final study (Paper IV), the projected EOAi was applied for the determination of
PPM. Due to insufficient published data for the St Jude Epic Supra (size 27) and
Mitroflow Pericardial (size 27) bioprostheses, echocardiographic measurements were
used to derive the EOA for two patients.
In all studies, the PPM was defined as not clinically significant if the EOAi was >0.85
cm2/m2, as moderate if it was between ≤0.85 cm2/m2 and 0.65 cm2/m2, and as severe if
it was ≤0.65 cm2/m2.
Early mortality was defined as all-cause mortality within 30 days of surgery.
3.8 Statistical analyses
All statistical analyses were performed and graphs plotted using the SPSS statistical
software package (SPSS 15.0, Chicago, IL, USA), except in the first study (Paper I),
where the Intercooled Stata statistical package version 9.2 (Stata Corporation, College
Station, TX, USA) was employed.
Statistical significance was defined as p≤0.05. Results were provided in standard
fashion, with categorical data as proportions, and continuous variables expressed as
34
mean ± SD. Student’s t-test was used to evaluate continuous variables. For categorical
variables, the chi-squared test was used, except when the expected frequencies were
lower than five, in which case Fisher’s exact test was used. For continous variables not
following a normal distribution, a non-parametric analysis (Mann-Whitney U test) was
used.
Multivariate analyses were performed in all studies using stepwise logistic regression
analysis to determine independent predictors for the different outcomes (in-hospital
complications and 30-day mortality). The inclusion criterion for the full model for
each outcome was p<0.2, and the limit for stepwise backward and forward elimination
was p<0.1. In Paper I, patients for whom any risk factor used in the model was missing
were excluded from the analysis. In Papers II-IV missing values were replaced using
the probability imputation technique (165).
Receiver operating characteristic analysis and the Hosmer-Lemeshow goodness-of-fit
test were used in the first two studies (Paper I & II) to describe discriminatory
performance and the predictive accuracy of the model.
The Kaplan-Meier estimate of the survivor function was used in all studies to plot
long-term survival for the groups compared. The log-rank test was used to compare
statistical differences between the groups. The stepwise Cox proportional hazards
analysis model was used for risk adjustment to identify independent risk factors for
overall mortality after AVR.
In the second study (Paper II), the correlation coefficients were calculated using
Pearson’s linear model. The threshold for BNP was determined by the ROC
coordinates for maximal sensitivity and minimal loss of specificity. The best cutoff
point for clinical use was chosen based on the approach of minimizing errors
equivalent to maximizing the sum of sensitivity and specificity. The discriminatory
power (i.e., the c-index) was evaluated by calculating the areas under the ROC curves.
To compare the areas under the resulting ROC curves, the nonparametric approach
described by DeLong et al. (166) was used.
In the third study (Paper III), the Wilcoxon signed-rank test and the McNemar test
were used to assess differences between two related continous variables.
In the final study (Paper IV), the paired-sample t-test was used to compare changes in
preoperative and postoperative echocardiographic data (intra-group comparison).
3.9 Ethical aspects
The studies were performed according to the principles of the Helsinki Declaration of
Human Rights and were approved by the Ethics Committee for Medical Research at
the Medical Faculty of Lund University, Sweden. Written informed consent was
obtained ftom the patients in study III.
35
Results
4.1 Impact of patient-prosthesis mismatch on in-hospital complications
According to univariate analysis, postoperative atrial fibrillation, postoperative
neurological events and prolonged ICU stay were significantly more common in
patients with PPM. However, following multivariate analysis only an increased risk of
postoperative neurological events (OR 2.26, 95%CI 1.05-4.83, p=0.037) was
independently associated with PPM (EOAi ≤0.85 cm2/m2) (Table 3.1).
Table 3.1.Results of univariate and multivariate analysis of in-hospital complications
for patients with and without PPM after AVR
AF
PPM
EOAi≤0.85
(cm2/m2)
n
%
335
40.4
Non-PPM
EOAi>0.85
(cm2/m2)
n
%
237
31.0
Univariate
Multivariat
e
p-value
<0.001
p-value
ns
IABP
4
0.5
7
0.9
0.306
…
LCOS
35
4.3
44
5.8
0.176
ns
AMI
25
3.1
26
3.4
0.695
…
Renal failurea
49
6.0
36
4.8
0.274
…
MOF
4
0.5
3
0.4
0.774
…
Reoperation for
bleeding
50
5.2
50
5.8
0.603
Neurological
eventb
81
10.0
30
4.0
<0.001
0.002
Hours on
ventilatorc
17.6
53.2
16.7
42.5
0.755
…
LOS ICU (days)c
2.0
3.1
1.7
2.2
0.018
ns
LOS total (days)c
10.5
7.6
10.1
6.8
0.241
…
30-day mortality
22
2.3
24
2.8
0.518
…
AF = atrial fibrillation; IABP = intra-aortic balloon pump; LCOS = low cardiac output
syndrome; AMI = acute myocardial infarction; aSerum creatinine >200 µmol/L; MOF
= multi-organ failure; bincluding TIA/RIND/CVI; cmean ± SD; LOS = length of stay.
4.2 Risk factors for postoperative neurological events
Due to the multifactorial nature of postoperative neurological complications, separate
uni- and multivariate analyses were performed for risk factors for postoperative
36
neurological events. The multivariate analysis highlighted several independent risk
factors for postoperative neurological events, including PPM (Table 3.2). The
discriminatory ability of the logistic model was assessed by ROC analysis with an
AUC of 0.80 (95% CI 0.75-0.85). The p-value for the Hosmer-Lemeshow goodnessof-fit test was 0.84, indicating adequate calibration.
Table 3.2 Multivariate risk factors for postoperative neurological events
(CVI;RIND;TIA)
Risk factor
OR
95% CI
p-value
PPM (EOAi ≤ 0.85
2.26
1.10-4.83
0.037
2
2
cm /m )
BMI
1.10
1.03-1.17
0.004
DM
2.53
1.33-4.80
0.005
CPB (min)
1.03
1.01-1.04
<0.001
Age
1.05
1.01-1.10
0.014
Cross-clamping time
0.97
0.95-0.99
0.006
PPM = patient-prosthesis mismatch; BMI = body mass index; DM = diabetes
mellitus; CPB = cardiopulmonary bypass
4.3 Left ventricular mass regression and diastolic dysfunction
The reduction of both peak and mean transvalvular gradients after AVR resulted in a
significant reduction of LV mass index, 144 ± 43 g/m2 (preoperatively) versus 126 ±
40 g/m2 (postoperatively; p<0.001; n = 127). There was no significant difference in
LV mass regression between patients with moderate PPM (p = 0.535) or severe PPM
(p = 0.653) and patients without PPM.
The implantation of a Sorin Soprano or Medtronic Mosaic prosthesis was not a
predictor of postoperative improvement of diastolic (p=0.714) or systolic LV function
(p=0.276). Neither moderate (p=0.726) nor severe PPM (p=0.353) was a predictor of
impaired diastolic or systolic LV function (p=0.519 and p=0.083, respectively)
postoperatively.
Patients with moderate PPM had significantly higher mean (16.5 ± 5.5 mm Hg versus
14.0 ± 5.8 mm Hg; p=0.004) and peak (29.9 ± 9.6 mm Hg versus 25.7 ± 9.5 mm Hg;
p=0.005) transprosthetic gradients than patients without PPM. Similarly, patients with
severe PPM had significantly higher mean (17.7 ± 5.3 mm Hg versus 14.9 ± 5.6 mm
Hg; p<0.001) and peak (32.8 ± 9.3 mm Hg versus 26.6 ± 9.3 mm Hg; p<0.001)
transprosthetic gradients than patients with moderate PPM or without PPM. The
hemodynamic performance of the prostheses presented in Paper III is summarized in
Table 3.3.
37
Table 3.3 Preoperative and postoperative Doppler echocardiographic parameters
Sorin
Soprano
Mean
gradient
(mmHg)
Peak
gradient
(mmHg)
EOA (cm2)
LVMI
(g/m2)
EOAi
(cm2/m2)
PPM (%)
EOAi (≤
0.85 cm2/m2)
EOAi (≤
0.65 cm2/m2)
Medtronic
Mosaic
Mean
gradient
(mmHg)
Peak
gradient
(mmHg)
EOA (cm2)
LVMI
(g/m2)
EOAi
(cm2/m2)
PPM (%)
EOAi (≤
0.85 cm2/m2)
EOAi (≤
0.65 cm2/m2)
Size 18 (18.00 mm)
20 (19.96 mm)
22 (21.89 mm)
24 (23.91 mm)
(n=63)
(n=92)
(n=62)
(n=18)
Preop.
Postop.
Preop.
Postop.
Preop.
Postop.
Preop.
Postop.
50±17
19±6†
(n=48)
44±16
15±5† ‡
(n=71)
43±15
14±5† ‡
(n=49)
34±13
12±4†
(n=14)
82±28
33±10†
(n=48)
76±25
27±8† ‡
(n=70)
73±23
25±8†
(n=49)
58±17
23±7†
(n=14)
0.65±0.2
134±33
-
1.19±0.3†
(n=45)
123±44
(n=14)
0.70±0.2
(n=45)
0.7±0.2
135±44
-
1.3±0.2†
‡
(n=68)
127±40
(n=33)
0.71±0.1
(n=68)
0.7±0.2
145±39
-
1.4±0.4†
‡
(n=47)
133±38
(n=23)
0.73±0.2
(n=47)
0.7±0.2
239±6
-
1.7±0.6†
(n=13)
144±64‡
(n=7)
0.89±0.3
(n=13)
-
89
-
88*
-
81*
-
62*
-
40
-
38*
-
36*
-
15*
Size 19 (16.58 mm)
21 (18.51 mm)
23 (20.56 mm)
25&27 (22.55&
24.06 mm)
(n=8)
(n=47)
(n=52)
(n=28+2)
Preop
Postop
Preop
Postop
Preop
Postop
Preop
Postop
66±5
21±8†
(n=5)
54±19
18±7† ‡
(n=34)
41±20
16±6† ‡
(n=42)
39±11
16±5†
(n=21)
84±33
39±12†
(n=5)
90±28
33±13† ‡
(n=34)
75±26
30±10†
(n=42)
70±17
30±9†
(n=21)
0.5±0.1
NA
-
1.3±0.4†
(n=5)
146±44
(n=2)
0.8±0.2
(n=5)
0.6±0.2
150±47
-
1.3±0.5†
(n=31)
112±29†
(n=17)
0.8±0.3
(n=31)
0.7±0.2
150±40
-
1.3±0.3†
(n=39)
112±29†
(n=20)
0.7±0.2
(n=39)
0.9±0.3
156±47
-
1.6±0.4†
‡
(n=21)
147±43 ‡
(n=11)
0.8±0.2
(n=21)
-
60
-
68*
-
82*
-
71*
-
40
-
42*
-
59*
-
29
(p=0.03)
Values are means ± SD. † p<0.05 preop. vs. postop.; ‡ p<0.05 between valve sizes
postoperatively; * p=ns between valve sizes; EOA= effective orifice area; EOAi=
indexed effective orifice area; LVMI= left ventricular mass index; NA = data not
available
38
4.4 Left ventricular remodeling following AVR for severe aortic valve
insufficiency
The overall incidence of PPM (EOAi ≤0.85 cm2/m2) was 22.2% (51/230). The
incidence of severe PPM (EOAi ≤ 0.65 cm2/m2) was 2.2% (6/230). There was no
significant difference in the reduction of mean LVEDD (p=0.31) or mean LVESD
(p=0.79) between the non-PPM and the PPM groups. The LVEDD was reduced in the
non-PPM group from 66±9 mm to 55±9 mm postoperatively (p<0.001) while the
LVEDD in the PPM group was reduced from 65±9 mm to 56±10 mm (p<0.001). The
LVESD was reduced in the non-PPM group from 49±10 mm to 40±10 mm
postoperatively (p<0.001) while the LVESD in the PPM group was reduced from
50±11 mm to 39±10 mm (p<0.001). Patients with preoperative LV dysfunction
(ejection fraction <50%) demonstrated a significant improvement in postoperative
LVEF in both the non-PPM (36±8% to 44±12%, p<0.001) and PPM groups (33±7% to
46±11%, p=0.001) but no significant difference could be demonstrated in the rate of
improvement between the two groups (p=0.23). The influence of PPM on LV
dimensions, LVEF and transprosthetic gradients during follow-up are summarized in
Table 3.4.
39
Table 3.4 Pre- and postoperative Doppler echocardiographic data for patients
undergoing AVR for severe aortic valve insufficiency
Non-PPM
PPM
p-value (95% CI)
Preoperative
variables
LVEDD (mm)
66±9
65±9
0.49 (-2.4-5.0)
LVESD (mm)
49±10
50±11
0.63 (-7.0-4.2)
LVEF (%)
47±10
45±12
0.36 (-2.3-6.2)
LVH
moderate/severe (%)
40 (36)
5 (25)
0.35
55±9
56±10
0.67 (-5.3-3.4)
11±9 (<0.001†)
9±10 (<0.001†)
0.31 (-2.1-6.8)
40±10
39±11
0.64 (-4.0-6.5)
9±10 (<0.001†)
8±17 (<0.001†)
0.79 (-5.9-7.7)
48±11
48±11
0.94 (-5.0-5.4)
1±11(0.169†)
2±13 (0.443†)
0.74 (-4.4-6.3)
39 (42)
2 (18)
0.20
LVM, (g) mean
reduction ‡
37±117 (0.068)
48±59 (0.141)
0.72
Mean gradient
(mmHg)
14±6
17±5
0.14 (-6.9-0.9)
Max gradient
(mmHg)
24±9
33±10
<0.001 (4.0-13.1)
Postoperative
variables
LVEDD (mm)
LVEDD reduction
(mm)
LVESD (mm)
LVESD, reduction
(mm) ‡
LVEF (%)
LVEF, absolute
improvement (%)
LVH
moderate/severe (%)
Values given are mean ± SD, or percentage of patients. LVEDD = left ventricular enddiastolic diameter, LVESD = left ventricular end-systolic diameter; LVEF = left
ventricular ejection fraction; LVH = left ventricular hypertrophy. Cases with
endocarditis were not excluded from the evaluation of LVH. † intra-group
comparison; ‡ Wilcoxon signed ranks test
40
4.5 Predictors of postoperative heart failure
Patients with postoperative heart failure (n=37) demonstrated a more than 10-fold
increase in 30-day mortality (8.1%, 3/37) than patients without postoperative heart
failure (0.8%, 1/124), p=0.038. Two levels of BNP were evaluated, the median (BNP
>133 pg/mL) and a cutoff (BNP >82 pg/mL) based on ROC analysis (Figure 3.1). The
inclusion of the cutoff level 82 pg/mL in multivariate analysis rendered the following
independent predictors of PHF: BNP (D0) >82 pg/mL (OR 5.9, p=0.004; 95%CI, 1.720), chronic obstructive pulmonary disease (COPD) (OR 17.8; p<0.001; 95% CI, 3.980), operative fluid balance (mL) (OR 1.0004; p=0.002; 95% CI, 1.0001-1.001), and
CPB time (min) (OR 1.02; p=0.005; 95% CI, 1.005-1.03). The independent predictors
of PHF when the cutoff for BNP (D0) was 133 pg/mL in multivariate analysis are
presented in Table 3.5. The area under the ROC curve for BNP as a predictor of
postoperative heart failure was 0.69. The evaluated BNP levels were not found to be
independent predictors of prolonged ICU stay (>48 hours) or prolonged ventilator
support (>48 hours) in multivariate analysis.
Figure 3.1 ROC curve:
BNP level on arrival at
the ICU vs.
postoperative heart
failure. AUC = 0.69.
1,0
Sensitivity
0,8
0,6
0,4
0,2
0,0
0,0
0,2
0,4
0,6
0,8
1,0
1 - Specificity
Table 3.5. Independent predictors of postoperative heart failure following AVR
Variable
OR
p-value
95%CI
Chronic obstructive pulmonary
15.3
<0.001
3.7-64
disease
BNP >133 pg/mL
3.4
0.013
1.3-8.7
Operative fluid balance (mL)
1.0004
0.002
1.0001-1.001
Cardiopulmonary bypass time (min)
1.020
0.002
1.007-1.033
4.6 Impact of PPM on early mortality
In the first study (Paper I), the overall 30-day mortality was 2.6% (46/1797). Severe
PPM was present in 3.8% of the study population (n=68), and moderate PPM in 49.5%
41
(n=890). There were no significant differences in 30-day mortality between the severe,
moderate and non-PPM groups. Causes of early mortality were cardiac-related in 67%
of patients (30/45) and non-cardiac in 33% (15/45), and were distributed evenly
between the PPM and non-PPM groups (p=ns).
The same risk variables that were used to analyze risk factors for postoperative
neurology in Paper I were also used in uni- and multivariate analyses to identify risk
factors for 30-day mortality. Independent risk factors for 30-day mortality in
multivariate analysis were: age >80 years (OR 3.0, p<0.001), preoperative NYHA
class IV (OR 2.9, p=0.004), preoperative atrial fibrillation (OR 3.2, p=0.001) and
cross-clamp time (min) (OR 1.02, p<0.001).
The 30-day mortality was significantly higher in the second study in patients with
heart failure (group II, 8.1%, 3/37) than in patients without postoperative heart failure
(group I, 0.8%, 1/124; p=0.038) following AVR with or without concomitant CABG.
The cause of death was cardiac-related in all patients (circulatory collapse, 4/4). There
was no significant relation between the BNP levels and 30-day mortality (BNP>82
pg/mL, p=0.298 and BNP>133 pg/mL, p=1.0). ROC analysis of BNP (D0) and 30-day
mortality produced a non-significant AUC (p=0.27).
The overall 30-day mortality in the third study was 1.7% (4 of 235 patients) in the
Sorin Soprano group and 2.9% (4 of 137 patients) in the Medtronic Mosaic group
(p=0.473). None of the early deaths occurred during the operation. Causes of 30-day
mortality were cardiac-related in 3 of 8 patients and noncardiac in 5 of 8 of the patients
(gastrointestinal hemorrhage in 1 patient, cerebrovascular insult in 2 patients, ischemic
bowel disease in 1 patient, renal failure in 1 patient). Multivariate analysis identified
advanced age (p=0.030), preoperative myocardial infarction (p=0.049), diabetes
mellitus (p=0.026), female sex (p=0.025), moderate aortic annular calcification
(p=0.042), perioperative myocardial infarction (p=0.036), and postoperative
cerebrovascular insult (p=0.031) as independent risk factors for 30-day mortality.
Early mortality was not affected by moderate (p=1.000) or severe PPM (p=0.565). No
significant differences were found when comparing the two valve groups regarding
postoperative complications (re-operation for bleeding, p=0.662; postoperative atrial
fibrillation, p=0.465; LCOS, p=0.239; renal failure, p=0.121; and length of stay in the
ICU, p=0.270).
In the final study, the 30-day mortality rate was 2.2% (5/230). Two of the early deaths
were mors in tabula. The causes of 30-day mortality were cardiac failure in four
patients and renal failure in one patient. Early mortality was not affected by moderate
(p = 0.31) or severe PPM (p = 1.0). Postoperative renal dysfunction (serum creatinine
>200 mmol/L) occurred in 14% (7/50) of the patients with PPM and in 4% (6/178) of
the patients without PPM (p = 0.01). Three of these patients required hemodialysis
postoperatively. There was a significant association between PPM and a prolonged
need for inotropic support (>24 h) (n=10 (20%) vs. n=17 (10%), p=0.043).
42
4.7 Impact of PPM on late mortality
The log-rank test showed a significant difference in long-term survival for patients
with PPM compared to those without, p=0.006 (Paper I) (Figure 3.2). However,
following adjustment for potential confounders in multivariate analysis, PPM was not
identified as an independent risk factor for overall mortality (p=ns). Independent risk
factors for overall mortality after AVR were age >80 years (HR 1.6, p<0.001), NYHA
class IV (HR 1.4, p=0.006), preoperative AF (HR 1.71, p<0.0001), diabetes mellitus
(HR 1.35, p=0.023), preoperative renal failure (HR 4.2, p<0.001), peripheral vascular
disease (HR 1.68, p=0.001) and concomitant CABG (HR 1.39, p=0.006).
Figure 3.2 KaplanMeier plots
representing overall
survival of patients with
and without PPM.
No patient required repeated surgery during follow-up owing to prosthetic structural
valve deterioration (SVD) (Paper III). One patient with a Medtronic Mosaic
bioprosthesis underwent prosthetic explant during the follow-up period because of
prosthetic valve endocarditis with a subvalvular abscess, but no sign of SVD was seen
perioperatively. Independent risk factors for late mortality after AVR in this study
were preoperative diastolic dysfunction (pseudonormalization; HR 3.6), severe
postoperative LVH (HR 8.8), preoperative cerebrovascular insult (HR 5.9),
preoperative myocardial infarction (HR 3.2), preoperative LVEF 0.30 to 0.50 (HR
4.7), preoperative NYHA class IV (HR 4.0), postoperative dialysis (HR 28.0), and reoperation for bleeding (HR 5.2). The actuarial survival at 2 years was 91.4% ± 2.7 for
patients receiving the Sorin Soprano prosthesis and 90.5% ± 2.9 for patients receiving
the Medtronic Mosaic prosthesis (p=0.476). Multivariable proportional hazard
regression analysis for risk factors affecting overall survival after AVR demonstrated
no significant difference in survival between the patients receiving the two different
prostheses (p=0.480).
The survival rates at 1, 2 and 5 years in the final study (Paper IV) were 90.2% ± 4.2,
79.7% ± 5.8 and 71.3% ± 6.9 for the PPM group and 97.2% ± 1.3, 95.8% ± 1.5 and
89.3% ± 3.0 for the non-PPM group, respectively, p=0.001 (Figure 3.3). Following
43
adjustment for confounding factors using Cox multivariate analysis, no significant
difference in survival could be demonstrated between patients with PPM and those
without PPM, p=0.23. Implantation of a stented bioprosthesis (HR 4.1), greater age
(HR 1.07) and CPB time (HR 1.01) were found to be independent predictors of
mortality. The overall survival rates for the whole study population at 1, 2 and 5 years
were 95.6%±1.4, 92.1%±1.8 and 85.1%±2.9, respectively. Four patients demonstrated
signs of SVD with prosthetic calcification during follow-up. Two of the patients
required repeat surgery and explantation during follow-up due to prosthetic
endocarditis.
Figure 3.3 Unadjusted
overall survival of
patients with severe
aortic insufficiency
following AVR (nonPPM and PPM)
4.8 Postoperative appearance of BNP and the relation between BNP and PPM
Patients with PHF had a mean BNP value on arrival at the ICU (D0) of 379 ± 417
pg/mL (median 270 pg/mL ranging from 22-1940), whereas the mean BNP value for
patients without PHF was 207 ± 274 (median 100 pg/mL, ranging from 8-1800;
p<0.001). Patients with PHF showed a significantly higher increase in BNP level on
the first postoperative day (D1) than those without PHF (mean increase of 362 ± 552
pg/mL vs. 78 ± 169 pg/mL, p<0.001). Patients with preoperative NYHA classes III/IV
had significantly higher mean BNP levels on arrival at the ICU (D0 = 335 ± 375
pg/mL) than patients in NYHA classes I/II (D0 = 136 ± 184 pg/mL; p<0.001). The
BNP level on arrival at the ICU showed a weak but significant linear relationship to
the preoperative LV ejection fraction (r = 0.471, p<0.001).There was no significant
correlation between PPM and BNP on arrival at the ICU (r = -0.053, p=0.511).
44
Discussion
The term valve prosthesis–patient mismatch was introduced by Rahimtoola in 1978 to
describe a condition in which the in vivo prosthetic valve EOA is smaller than that of
the native valve (1). According to this broad definition, every patient with a prosthetic
heart valve has PPM because the leaflets of both mechanical and bioprosthetic valves
are mounted on frames that occupy space in the periphery of the valve where the loss
of effective orifice is greater than in its central portion. This loss of EOA may or may
not be clinically significant, depending on the size and type of prosthetic valve
implanted. However, as with native heart valve disease, the thresholds between normal
valve orifice and pathophysiologically important stenosis are quite broad, and the
clinical and hemodynamic consequences are variable. Generally, patients with a native
aortic valve area of less than 1.0 cm2 (0.5-0.6 cm2/m2 based on BSA 1.6-1.9 m2) who
have a mean transvalvular gradient greater than 40 mmHg are judged to have severe
aortic stenosis in the presence of normal cardiac output (63). Most patients with this
degree of AS remain asymptomatic for many years and their likelihood of survival is
good as long as they remain symptom free (62;167). However, the valve area at which
individuals become symptomatic is quite variable (168), and there is no agreement on
what constitutes a severe aortic valve area index. A valve area index of 0.45 cm²/m²
has been suggested to be helpful in defining severity in some cases (120), although this
threshold has to date not been evaluated. Prosthetic valve stenosis (i.e., PPM) should
intuitively not behave differently if similar degrees of LV obstruction are present.
Because all prosthetic heart valves are inherently stenotic, a certain degree of
obstruction should be harmful to the patient. Therefore, we asked the question: do
obstructive prosthetic valves increase operative mortality and morbidity, impair LV
remodeling, or affect survival after AVR?
5.1 Postoperative morbidity
In Paper I, PPM was identified as an independent risk factor for postoperative
neurological events, including stroke, RIND and TIA. A considerable number of
elderly patients develop perioperative neurological complications following AVR
(169). These complications range from subtle cognitive dysfunction to more evident
postoperative confusion, delirium, and less commonly, clinically apparent stroke. One
explanation of our finding may be the more cumbersome surgical procedure in a small
aortic root with extensive calcification, which is commonly observed in patients with
native valvular stenosis (170). A more hypothetical explanation may be that postprosthetic turbulence caused by PPM leads to shear stress in a surgically manipulated
and vulnerable ascending aorta, and that these shear forces may cause rupture of
calcified plaques adjacent to cannulation sites and the aortotomy, causing embolic
debris (171). Furthermore, it has previously been postulated that shear stress induces
platelet activation, causing adherence to atheromatous plaques on vessel walls, with
subsequent embolization (172). Weinstein postulated that end-hole aortic cannulas
direct a high-velocity jet at the left carotid orifice, and may be responsible for a
proportion of perioperative strokes and postoperative neurological dysfunction (173).
Similarly, an increased transvalvular velocity and higher gradients secondary to PPM
45
may induce shear stress on the atheromatous aorta. Although postoperative
neurological complications following AVR have multiple etiologies, the present
findings suggest that PPM may be of relevance for this particular outcome. The
adequacy of the multivariate analysis was supported by an AUC of 0.8 (CI 0.75-0.85)
and a p-value in the Hosmer-Lemeshow test of 0.84, indicating an accurate and wellcalibrated statistical model. Furthermore, PPM had the second highest odds ratio, as
verified by both backward and forward stepwise logistical regression analysis.
Previous studies addressing the influence of PPM on postoperative morbidity are
scare. Adams et al.(153), reported a trend towards prolonged ICU stay in relation to
PPM (OR 1.8, 95% CI 0.99-3.5, p=0.05). A small valve did not appear to increase the
risk of any other of the investigated morbidities although a number of them occurred
infrequently. Because AVR is conducted in an increasingly aged population, with
several co-morbidities, these patients may be at increased risk of developing LCOS
during the postoperative period. Pharmacological support for LCOS is often required
during and after weaning from cardiopulmonary bypass, and this acute deterioration in
LV function may continue into the intensive care unit (51). Mismatch results in an
elevated residual LV afterload inducing increased myocardial metabolism in an
already unfavorable postoperative metabolic state following CPB. Hence, PPM would
in theory cause a prolonged need for inotropic support as well as prolonged ICU stay.
However, following adjustment for confounding postoperative variables, surprisingly,
neither of these two complications were found to be significant in Paper I. Vanky et al.
(174) have previously demonstrated that in patients with aortic stenosis the high
preoperative myocardial oxygen extraction ratio of 64% decreased to 52% following
AVR. Accordingly, myocardial oxygen consumption decreased by almost 20%
(although the latter did not reach statistical significance). The authors speculated that
the decrease in myocardial oxygen extraction was mainly explained by the unloading
impact of AVR on myocardial workload. These findings support the statement that
PPM may not be important in the immediate postoperative clinical setting following
AVR with respect to cardiac-related complications.
5.2 Impact of PPM on early mortality
Previous studies have identified several independent predictors of early mortality in
relation to AVR (12;45;57;158). Similar risk factors, such as high age and preoperative
AF, were identified in Paper I. Neither severe nor moderate PPM was found to be an
independent risk factor for increased 30-day mortality. The reported effects of PPM on
early mortality following AVR vary; some studies have found impaired survival
(12;175), while others were not able to demonstrate any negative influence (45;58;65).
AVR offers an immediate reduction in afterload on the LV, as well as reduced
myocardial workload and a dramatic improvement of the LV ejection fraction (176).
On this basis, the logical implications would be that small residual transprosthetic
gradients should not have a significant impact on early mortality.
46
5.3 Postoperative heart failure
Despite improvements in surgical techniques and myocardial protection in the field of
cardiac surgery, pharmacological support for low cardiac output syndrome is often
required during and after weaning from cardiopulmonary bypass, and the acute
deterioration in ventricular function may continue into the intensive care unit (51). In
spite of the serious and critical consequences of postoperative heart failure, there is no
consensus regarding what constitutes LCOS with the existential data mainly derived
from studies on CABG patients. Definitions include low cardiac output (cardiac index
<2.4 L/min/m2) with evidence of organ dysfunction (51), use of more than four
inotropic drugs, left ventricular assist device or IABP (177), and the requirement for
postoperative IABP or inotropic support for >30 min to maintain arterial blood
pressure above 90 mmHg or CO >2.2 L/min (88). Causes of LCOS are multifactorial,
but include myocardial ischemia during cross-clamping, reperfusion injury,
cardioplegia-induced myocardial dysfunction, activation of inflammatory and
coagulation cascades, and unreversed preexisting cardiac disease. Organ dysfunction
and multiple organ failure are among the main causes of prolonged hospital stay after
cardiac surgery, with subsequent increases in the use of resources and health care
costs, as well as increasing morbidity and mortality (51). Therefore, optimization of
cardiac output and oxygen delivery through early recognition of LCOS may improve
clinical outcome as well as decrease health care costs.
Studies addressing causes and risk factors for LCOS following AVR are sparse,
although postoperative heart failure remains an important predictor of poor outcome
(88-90). The results presented in Paper II showed that the 30-day mortality was more
than 10-fold higher (8.1% vs. 0.8%) in patients with postoperative heart failure. The
association between PHF and 30-day mortality emphasizes the importance of early
diagnosis and the initiation of adequate therapy in the ICU.
In Paper II, we found that an elevated BNP level on arrival at the ICU is an
independent predictor of postoperative heart failure after AVR. Because the secretion
of BNP is rapid and the half-life short (T1/2 = 20 minutes) (99), BNP levels reflect
acute changes in LV wall stress. Furthermore, Morimoto et al. (163) have shown that
BNP levels do not change during CPB and remain unchanged 6 hours after weaning
from bypass. Therefore, the analysis of postoperative BNP levels measured
immediately on arrival in the ICU could theoretically provide valuable information
regarding the current myocardial status. However, it must be emphasized that as a
single variable, the predictive value of an increased BNP level was relatively weak
(AUC = 0.69). These results are similar to the findings of Provenchere et al. (113),
who found an elevated BNP level on the first postoperative day to be a predictor of
postoperative cardiac dysfunction within 5 days of cardiac surgery.
At present, a wide range of threshold values of BNP and its precursor Nt-proBNP is
used to predict symptoms and LCOS onset in various studies, preventing any cutoff
from being sufficiently able to aid clinical management (107;112;113;178;179).
Furthermore, the presence of renal disease (180), pulmonary hypertension (181), and
obesity (182) may all interfere with the predictive value of BNP measurements. Using
47
ROC analysis, we found that a BNP level of >82 pg/mL on admittance to the ICU may
be an important threshold for diagnosing postoperative heart failure after AVR (Paper
II). A similar level of BNP (80 pg/mL) has previously been evaluated and reported as a
relevant cutoff level for the diagnosis of preoperative heart failure (104;183;184).
However, a low cutoff may lead to an unnecessarily aggressive therapeutic approach
and would therefore be of limited clinical value. Berendes et al. (184) found that the
baseline BNP levels in patients with valve disease were increased, and, therefore, we
also chose to evaluate the hypothetically more useful median BNP level of 133 pg/mL.
This cutoff level was also predictive of PHF, leading to a higher specificity in terms of
identifying patients with LCOS. Hutfless et al. (112) have previously shown that
elevated peak BNP levels postoperatively and increased maximum change in BNP
levels were associated with prolonged hospital stay and increased 1-year mortality
after cardiac surgery. However, the reliability of their conclusions was limited by the
small number of patients undergoing AVR (n = 19) and the fact that no multivariate
analysis was performed. In another study, Skidmore et al (185) suggested that failure
of BNP to improve postoperatively indicates ongoing heart failure. The findings
presented in Paper II revealed similar results, with a significantly higher change in the
mean BNP level from arrival in the ICU to postoperative day 1 in patients with PHF,
than in patients without heart failure.
In the present work (Paper II), prolonged CPB time and positive operative fluid
balance were also found to be independent predictors of postoperative heart failure.
Both variables may reflect higher surgical complexity and a technically more
demanding procedure. COPD was also identified as an independent predictor of
postoperative heart failure. BNP has been reported to play an important role in the
development of COPD, particularly in the presence of right heart overloading. COPD
may result in pulmonary hypertension (186) causing right ventricle dysfunction and
secondary secretion of BNP (181;187). However, pulmonary hypertension was not
identified as an independent predictor of PHF in the present work, although this may
reflect the relatively low number of patients with pulmonary hypertension and requires
further evaluation. Neither a preoperative LVEF >50% nor LVEF > 30% predicted
PHF independently. This finding may reflect the immediate beneficial effect of AVR,
i.e. afterload reduction, but also underlines the importance of additional diagnostic
tools for predicting PHF.
Based on the findings reported in Paper II, BNP should not be considered a
replacement for a postoperative echocardiographic examination of the patient, but as
an additional diagnostic tool and prognostic marker.
5.4 Impact of PPM on diastolic heart failure
Diastolic heart failure (defined as pseudonormalization or restrictive filling), in the
absence of impaired LV ejection fraction, was present in nearly half of the patients
(Paper III). Preoperative LV mass index was significantly higher in this group than in
the patients with normal diastolic dysfunction and those with impaired relaxation
(p=0.008). Persistent LVH is one of the known causes of DHF (96) and the pre48
existence of advanced LVH has been demonstrated to be a major obstacle for LVMR
despite otherwise successful AVR (72). Therefore, the presence of PPM would
intuitively have a negative impact on the recovery of diastolic function. However, no
significant relation could be demonstrated between impaired recovery of DHF and
PPM. Previous studies have demonstrated that the regression of LV mass after AVR
peaks after 1 year (84), and that the degree of DHF may deteriorate up to 10 years
postoperatively, despite significant LVMR (95). The findings reported in Paper III are
limited by the exclusive use of echocardiographic techniques for the diagnosis of
diastolic abnormalities and the fact that the follow-up period was relatively short.
Therefore, we cannot rule out that a longer follow-up period might provide further
information regarding diastolic remodeling for patients undergoing aortic valve
replacement.
In a recent study, Brown et al. (188) evaluated a small series of patients undergoing
AVR for various reasons using projected EOA, despite having echocardiographic data
available. PPM was not predictive of death or total cardiac events over an intermediate
follow-up period of 3 years. However, persisting diastolic dysfunction was associated
with PPM, and cardiac events were significantly associated with the presence of
diastolic dysfunction, independent of PPM. Survival was particularly decreased in
patients with more severe classes of diastolic heart failure. These findings stand in
contrast to our results, but underline the clinical relevance of DHF as an important
variable before and following AVR.
5.5 Stented bioprostheses for supra-annular implantation
Third-generation bioprostheses designed for complete supra-annular implantation offer
a means of avoiding PPM, as the stent is positioned such that the disturbance of aortic
blood flow will potentially be less. Garcia and associates (71) demonstrated that PPM
after AVR is a predictor of late cardiac death and poor early survival for patients with
increased LV mass index, but concluded that the incidence of PPM was reduced with
the use of the latest generation of supraannular prostheses. In Paper III, we assessed
the Sorin Soprano prosthesis, a third-generation pericardial bioprosthesis available for
commercial use in Europe since 2003. This bioprosthesis is implanted in the supraannular position and may therefore be of advantage in patients with small aortic annuli
(162;189). We found a high incidence of severe PPM (39.8%) and no similar
incidence figures have been reported previously. In contrast, previous studies have
demonstrated lower transvalvular gradients and a low incidence of PPM when using
the Sorin Soprano valve (71;162). However, despite the high incidence of PPM in our
study, similar results have been found regarding postoperative transprosthetic
gradients, EOAs, and degree of LVMR in other previously published reports
(151;190). Furthermore, despite a high incidence, PPM was not found to be a
significant predictor of impaired LVMR, regardless of severity. Improvements in
hemodynamic outcome reached statistical significance only at the larger prosthetic
sizes, and this finding is in accord with a previous study by Botzenhardt and associates
(151). Overall, our study demonstrated favorable LVMR and excellent clinical
outcome for the Sorin Soprano bioprostheses.
49
The choice of in vivo EOA in Paper III was based on an editorial by Rahimtoola (191)
following the publication of two studies reporting conflicting results concerning the
influence of PPM on early and late mortality (64;65). Rahimtoola suggested the
following measures in order to be able to address the issue of mortality in patients with
PPM correctly:
 1. Prosthetic EOA should be calculated from echocardiographic/Doppler studies,
at 6 and/or 12 months after AVR (192);
 2. severe PPM should be defined as EOAi ≤ 0.6 cm2/m2 as it is not possible to
measure with any degree of precision to a hundredth of a centimeter (192); and
 3. the cause of death should be determined by a ‘blinded’ committee, or in an
adjudicative manner, regardless of whether death is due to cardiac causes related
to a prosthetic heart valve, cardiac causes not related to a prosthetic heart valve,
or non-cardiac causes.
5.6 Impact of PPM on LV remodeling in aortic valve insufficiency
Measures suggested to prevent PPM and to tailor surgical strategies appear to be same,
regardless of the procedure and underlying etiology causing valve replacement (38).
Previous studies have demonstrated that PPM is most likely to occur in patients in
whom the predominant lesion was aortic stenosis, as the calcified aortic valve and
aortic root present a surgical challenge for the implantation of a prosthetic valve with
an adequate EOA (9). Because aortic insufficiency often presents with annular
dilatation and an absence of valve calcification, this condition could intuitively be
believed to be unrelated to PPM. However, the results in Paper IV suggest that PPM
may occur in up to 22% of the patient population undergoing surgery for severe aortic
insufficiency. Although this lesion has been included in the analysis in earlier reports
(42), until recently, no previous studies had focused on the possible influence of PPM
on LV remodeling in severe AVI.
Aortic valve insufficiency with preoperative impairment of LVEF and increased
LVESD has a predicted annual mortality of 10-20% in the absence of surgical
intervention (140). It has also been demonstrated that preoperatively impaired LVEF
and increased LVEDD are two of the most important determinants of survival and
recovery of LV function following valve surgery (193-195). The volume overload on
the left ventricle in AVI is resolved following AVR, but in the presence of PPM it has
been suggested that it is replaced by an increase in the transprosthetic gradient (1).
Theoretically, PPM could lead to impaired restoration of LV dimensions as the
afterload on the left ventricle and pressure gradient are increased. However, the
present findings suggest that the transprosthetic gradients do not influence the
postoperative LV remodeling negatively, as the recovery rates of LV dimensions were
comparable in both groups. On the contrary, the present findings, suggest that the
50
residual gradient resulting from the prosthesis is more than compensated for by the
relief of the excessive work load on the left ventricle through AVR.
The presence of PPM was associated with a significantly higher transprosthetic
gradient in two of the present studies (Paper III and IV). In Paper IV, no significant
impact of PPM is reported regarding the recovery of LVEF or LVH regression. In
patients with poor preoperative LV function (LVEF less than 50%), the LVEF
improved to a great extent in both groups, regardless of PPM. This finding is
supported by a previous study by Chaliki et al. (196), who demonstrated a significant
postoperative improvement in LVEF in patients with aortic insufficiency and poor
preoperative LV function. Furthermore, Carroll et al. (197) and Lamb et al. (70) found
that the LVEDD and LV volumes in patients with aortic insufficiency returned to
almost normal values within 2 weeks of AVR, whereas a significant regression of
LVH took at least 6 months. They concluded that complete regression of LVH may
take many years. Other studies have shown that patients with severely reduced LVEF
and preoperatively dilated LV do not exhibit complete regression of LV dimensions
following AVR for aortic insufficiency (194;196). Current evidence indicates that
regression of LVH is a time-consuming process and, therefore, a longer follow-up time
may be required to further elucidate the influence of PPM on LVH regression
following AVR due to aortic valve insufficiency.
5.7 Impact of PPM on mortality
In Paper I, it is reported that crude long-term survival in patients with PPM was
impaired compared to those without PPM. The difference, however, was not
significant after adjusting for risk factors for overall mortality. Similar findings have
been reported in previous studies addressing the effect of PPM on long-term survival
(7;53;58;175). Blackstone and colleagues (43) studied more than 13,000 patients
following AVR with a mean follow-up time of 5.3 years, and found no reduction in
survival after adjusting for preoperative risk factors. In contrast, both Rao et al. (175)
and Mohty-Echahidi and coworkers (56) reported that severe PPM had a significant
negative impact on long-term survival. These disparate findings may indicate the need
to identify a subgroup in a population undergoing AVR in which PPM might have a
significant impact on clinical outcome.
Several risk factors for early and late mortality after AVR with bioprostheses are
presented in Paper III, confirming the findings of previous studies (198). However,
neither moderate nor severe PPM was found to be an independent risk factor for
increased early or late mortality. Furthermore, no significant differences in clinical
outcome could be related to type of prosthesis. Lund and coworkers (84) have
previously reported impaired systolic and diastolic LV function to be independent
preoperative predictors of early as well as late mortality after AVR, and suggested the
underlying mechanism to be mainly concentric LVH. In contrast, Nakagawa and
colleagues (199) found that the occurrence of DHF did not affect postoperative early
mortality. In the present study, diastolic dysfunction (pseudonormalization) and
preoperative advanced LVH were predictors of late mortality. The divergence in the
51
results of previous studies may reflect differences in the duration of follow-up and thus
the dynamic remodeling process, which is initiated by the reduction of LV afterload
resulting from AVR (72;200).
The overall survival rates for patients undergoing AVR for severe acute and chronic
AVI were 96% at 1 year and 85% at 5 years. The survival in the present work is
favorable compared to those reported in previous studies where, depending on the
degree of LV dysfunction, 1- and 5-year survival rates vary between 81 and 92%, and
68 and 82%, respectively (194;201). The improved survival demonstrated in Paper IV
could in part be explained by the relatively recent inclusion period. Bhudia et al.(194)
demonstrated that survival following AVR improved dramatically across their study
time frame for patients with aortic insufficiency and LV dysfunction. The survival rate
reported in Paper IV was significantly reduced in the presence of PPM, according to
univariate analysis. However, in multivariate Cox proportional hazard analysis, only
age at surgery (HR 1.07), duration of CPB (HR 1.01) and implantation of a
bioprosthesis (HR 4.1) had a significant influence on survival. The age limit for
implanting a bioprostheses at our department is around 70 years and therefore these
patients naturally have a shorter life expectancy. Inferior hemodynamics and PPM is
more likely to occur following implantation of a bioprosthesis than a mechanical
prosthesis (38). Sequential multivariate analysis was performed to test the statistical
model in which bioprosthesis as a variable was excluded. Furthermore, we created a
conjugate variable for patients with PPM receiving a stented bioprosthesis. In neither
of these sequential steps was PPM found to be a significant predictor of survival.
There were differences in baseline patient characteristics between the two groups in
Paper IV that may have influenced the results. However, by excluding possible
confounders and performing sequential multivariate analysis, the ability of the model
to test for the influence of PPM was improved.
Prolonged CPB has been demonstrated to be strongly associated with impaired
survival in previous studies (202), and this was supported by the present results. CPB
is an intra-operative variable and may be a dominant predictor influencing the ability
of multivariate test models to assess the impact of PPM. However, following the
exclusion of CPB, PPM was still not found to be a significant predictor of survival.
Mohty et al. (49) reported that severe PPM following surgery for aortic stenosis had a
negative effect on late survival in patients younger than 70 years, but not in the elderly
population. These results are consistent with those of Moon et al. (48), suggesting that
the impact of PPM on postoperative outcome is more pronounced in young patients
than in older ones. Younger patients have higher cardiac output requirements and are
generally more physically active and, due to their longer life expectancy, they are
exposed to the risk of PPM for a longer period of time. In several studies, including
that presented on Paper IV, the mean age of the patients with aortic insufficiency was
lower than that for patients with aortic stenosis (201;203). Therefore, patients with
aortic insufficiency would theoretically constitute a suitable population for evaluating
the impact of PPM on survival. However, in our study, patients with PPM did not
52
show impaired survival compared to non-PPM patients when adjusted for potential
confounding variables.
5.8 General discussion
How can the results of the present work be explained when logic suggests that
sustained elevated transprosthetic energy loss should translate into impaired LV
remodeling and decreased long-term survival? The answer is not straightforward, but
the following hypotheses may offer some explanation.
The natural history of mild, native aortic valve stenosis is unknown. At least moderate
PPM mimics the hemodynamic properties of mild native aortic stenosis. Furthermore,
progressive aortic disease tends to become apparent in elderly persons, a patient
category where mild non-progressive stenosis may be well tolerated due to less cardiac
output demanding physical activity (43).
Patients who undergo AVR have slightly lower long-term survival than an age-, sex-,
and race-matched controls (43;176;204). Mortality is affected by complications
resulting from warfarin anticoagulation treatment, particularly its variability (205),
among patients with mechanical devices, and by re-operation for SVD among those
with biological prostheses. Paper IV reports a difference in survival according to type
of prosthesis. The implantation of a bioprosthesis was an independent predictor of
increased late mortality (HR 4.1; 95% CI 1.8-9.7). Type of prostheses was, however,
not found to be a significant predictor of impaired survival in our earlier studies (Paper
I & III), which is consistent with previously published findings (206). Once again, the
multifactorial nature of reduced survival after AVR may mask subtle individual
components of its leading causes, such as the implantation of a small prosthesis in
relation to patient size, or the type of prosthesis chosen. Degenerative aortic valve
stenosis is a disease of elderly patients with already limited life spans. Although we
tested for interactions between age and PPM (Paper IV) we found none: Elderly
patients may simply not live long enough to manifest impaired survival related to
PPM.
The incidence of severe PPM (0.65 cm2/m2) is low in many reports (64;65), although
this was not supported by the results presented in Paper III. In order to unanimously
find a significant impact on clinical outcome, perhaps the threshold for severe PPM
should be lowered to 0.45-0.50 cm2/m2 corresponding to severe native aortic valve
stenosis (207). This strategy would, for natural reasons, limit the number patients
available for analysis, as almost no prostheses would reach this level of PPM unless
SVD occurs postoperatively.
The relatively small increase in early mortality previously found among patients with
PPM (12) may serve as a biological selection process. However, Blackstone and
colleagues evaluated 1109 patients with small prostheses (with a labeled size of 19
mm or smaller) and reported that early mortality was sufficiently low, and survival
sufficiently long to suggest that this is not an important explanation.
53
The way in which manufacturers label valves sizes varies and may lead to
inappropriate hemodynamic comparisons between valves with the same nominal size
(152). Prosthesis size may be based on physical dimensions or functional performance.
Physical dimensions include labeled size and internal orifice size. Since
manufacturers’ conventions for labeling prosthesis size differ among devices, some
authors have chosen the geometric internal orifice diameter to characterize PPM
because the internal geometric area is suggested to be more reproducible (152).
Functional size includes in vitro and in vivo effective orifice areas. The former may be
static at a variety of steady flow rates or dynamic with a variety of pulsatile waveforms
and flow rates (208); the latter is estimated clinically under a range of incompletely
controlled conditions in patients by echocardiography according to various formulas.
In vivo EOA varies from moment to moment with patient activity (5), cardiac output
and blood pressure, and dynamics of the LV tract, as well as intrinsic prosthesis
properties, although it is strongly correlated with the geometric internal orifice area.
(5). However, in vivo EOA is unavailable at the time of selecting prosthesis for AVR.
Pibarot and colleagues (209) and Dumesnil and coworkers (5) have suggested that
rather than using geometric prosthesis dimensions as a reference for prosthesis size, a
reference value of in vivo EOA should be used, termed the projected EOA. However,
this strategy has several drawbacks. It suffers from flow dependency, a large scatter in
the data, rest versus exercise differences, and limited availability of data for each
prosthesis size and model.
Identifying a high transvalvular pressure gradient in a patient with a prosthetic valve is
often a difficult diagnostic challenge and may not always indicate a prosthesis-patient
mismatch. High transprosthetic pressure gradients may be present after AVR due to
intrinsic stenosis or a state of high cardiac output. The most logical approach to
assessing intrinsic prosthesis performance is to compare the EOA measured by
Doppler echocardiography to the reference values measured either in vitro or in vivo
for the same model and size of prosthesis. A value substantially lower than the
reference values may suggest an intrinsic stenotic process (e.g., tissue ingrowth,
thrombus, calcification), and even more so if there had been a progressive reduction in
the EOA over time (9).
If the finding of a high transvalvular gradient is mainly due to PPM, as indicated by an
EOA consistent with normal reference values but an indexed EOA ≤0.85 cm2/m2, there
are no precise management guidelines at present. If the patient develops the usual
symptoms associated with aortic stenosis and has an indexed EOA compatible with
severe stenosis (EOAi ≤0.60 cm2/m2), re-operation should be considered, as is the case
for native valves (207). However, according to Hanayama et al.(45), one should not
use one set of assumptions and logic for PPM and a completely different set for
treating patients with native aortic valve disease. It is rare to operate on patients with
moderate gradients (mean TPG 20-35 mmHg) and no symptoms (except for other
concomitant cardiac surgery) as long-term survival is not improved in these patients. If
there were clear scientific evidence that PPM with mild to moderate gradients and
54
EOAi <0.85 cm2/m2 decreased long-term survival, all patients with mild to moderate
aortic stenosis would have been referred for redo AVR. Similarly, evidence from
exercise gradients is often used to support the PPM theory. The commonly adopted
theory is that patients with mild to moderate gradients at rest have much higher
gradients during exercise. If one were to use consistent logic, the inference from this
theory would be that we should exercise all patients with mild to moderate native
aortic stenosis, and operate on patients with high exercise gradients to improve longterm survival. This regimen is currently not applied due to lack of supportive evidence
(63).
Finally, it was mainly the use of small-sized aortic valve prostheses in the era of
caged-ball prostheses that had raised concerns about the presence of significant
residual gradients, with the potential detrimental sequelae in the left ventricle (1).
Thus, the concept of PPM was based on reports evaluating first -generation biological
and mechanical prostheses.
5.9 Limitations
The patients in these studies were those treated at a single department and may not be
representative of those at other centers. None of the studies was randomized but
instead retrospective, introducing the possibility that selection bias might cause
differences in patient groups, which might influence survival but are not accounted for,
even with the extensive multivariable analyses conducted. Furthermore, all outcomes
were not investigated, and PPM might have an impact on functional recovery, heart
failure symptoms, rehospitalization, and impaired quality of life. Survival is not the
only outcome of AVR, although it is the most important. The Kaplan-Meier and Cox
proportional hazard methods require the implicit assumption that censoring is
independent of clinical outcome, which cannot be verified. It is possible that patients
lost to follow-up may have had outcomes that were important but not accounted for in
the analyses or that resulted in their being lost to follow-up. Survival data obtained
from studies with large patient numbers decrease the risk of type II errors. On the other
hand, great difficulties arise when one has to examine indices of LV hemodynamics
and function over time for a large number of patients over a long period of time. There
are situations in which the use of complex forms of aortic valve replacement, such as
aortic valve homografts, pulmonary valve autotransplantation, aortic root enlargement
procedures, and stentless xenograft valves, are indicated. Single-center studies are
limited particularly regarding the number of patients receiving small prostheses, and
multi-center studies are therefore required. Finally, low operative mortality
necessitates a large study with a sufficient number of deaths to achieve adequate
statistical power.
55
Future perspectives
For symptomatic patients with severe aortic valve stenosis, open-heart surgery with
aortic valve replacement using cardioplegia under cardiopulmonary bypass remains
the gold standard. Cumulative surgical experience and technical improvement over
more than five decades have led to excellent perioperative results with low mortality
and morbidity. Long-term results are convincing as long-term survival is close to that
in the average population, and the durability of biological prostheses is favorable in the
elderly. Even in octogenarians, aortic valve replacement is feasible with acceptable
results. The importance of patient-prosthesis mismatch has been the subject of a
substantial number of publications during the past decade. However, the majority of
these studies are small and retrospective including different definitions of mismatch as
well as heterogeneous populations. In the author’s opinion, there is no convincing
evidence that patient-prosthesis mismatch should be considered a matter of priority
when performing aortic valve replacement. Despite excellent peri- and postoperative
clinical results a large randomized trial is warranted to gain insight and deeper
knowledge in this matter. As this is not possible, due to ethical reasons, the following
strategies may assist in elucidating the concept of patient-prosthesis mismatch:
To facilitate comparisons of hemodynamic measurements and clinical endpoints
standardized criteria and definitions of the term prosthesis-patient mismatch is
required.
A potentially interesting design would be to normalize the EOA to the fat-free mass,
since this parameter appears to be the main determinant of cardiac output in normalweight, overweight, and obese people (previously elaborated in Introduction).
A multi-institutional study would allow a gathering of a substantial number of
patients with maximized homogeneity of baseline characteristics and with a
sufficient number of deaths to achieve adequate statistical power.
56
Conclusions
Based on the findings of the studies presented in this thesis the following major
conclusions can be drawn:
Paper I
 Prosthesis-patient mismatch is an independent risk factor for postoperative
neurological events following aortic valve replacement. However, this probably
reflects a more complex surgical procedure in a small aortic root with extensive
calcification.
 Prosthesis-patient mismatch was present in nearly half of the patients
undergoing aortic valve replacement, although severe PPM was rare, but no
impact ws found on early or late survival.
 Postoperative high transprosthetic gradients were not correlated with low cardiac
output syndrome.
Paper II
 Postoperative heart failure following aortic valve replacement was associated
with high early mortality.
 A postoperatively elevated BNP level was a predictor of heart failure after aortic
valve replacement, although its discriminatory ability was relatively poor.
Paper III
 Prosthesis-patient mismatch did not impair the recovery of diastolic function or
left ventricular mass regression.
 Prosthesis-patient mismatch was not a predictor of poor survival following
implantation of the Sorin Soprano or the Medtronic Mosaic bioprostheses during
aortic valve replacement.
Paper IV
 The presence of prosthesis-patient mismatch did not influence postoperative LV
remodeling in terms of regression of the LV dimensions.
 There was no difference in postoperative recovery of LV systolic function in
patients with and without prosthesis-patient mismatch, and the LV remodeling
process was initiated regardless of preoperative LVEF.
 Prosthesis-patient mismatch was common in patients with severe aortic
insufficiency undergoing aortic valve replacement, although severe prosthesispatient mismatch was rare.
 Prosthesis-patient mismatch was not a predictor of increased early or late
mortality following aortic valve replacement for severe aortic insufficiency.
57
Populärvetenskaplig sammanfattning (Summary in Swedish)
Aortastenos, dvs. en förträngning och förkalkning av hjärtats aortaklaff
(vänsterkammarens utflödesklaff), är näst efter kranskärlssjukdom den vanligaste
orsaken till att patienter genomgår hjärtkirurgi i den industrialiserade delen av världen.
Kombinationen av en åldrande befolkning i västvärlden och en förbättrad
hjärtdiagnostik har lett till en kontinuerlig ökning av antalet patienter som remitteras
för aortaklaffkirurgi. Vid operation för aortastenos avlägsnas den förkalkade klaffen
och ersätts med en konstgjord klaffprotes. Operation för aortainsufficiens (läckage i
aortaklaffen) är mindre vanligt. När aortaklaffen inte är förkalkad, kan den hos vissa
patienter repareras, men den vanligaste åtgärden är fortfarande att byta den sjuka
klaffen mot en klaffprotes. I stora drag kan man dela upp moderna klaffproteser i två
grupper: mekaniska och biologiska. Mekaniska klaffproteser är vanligen tillverkade av
olika kolfibermaterial. Fördelen med denna typ av klaffprotes är att den har en
väsentligen obegränsad livslängd, men nackdelen är att den kräver livslång
antikoagulationsbehandling (behandling som motverkar blodproppar). Biologiska
klaffproteser är vanligen tillverkade av aortaklaffar tagna från grisar, alternativt är
klaffbladen tillverkade av perikard (hjärtsäck) från kalv. Fördelen med biologiska
klaffproteser är att de inte behöver antikoagulationsbehandling, men nackdelen är att
bioproteserna har en begränsad hållbarhet.
Valet av klaffprotes har varit föremål för en omfattande debatt de senaste decennierna.
Utvecklingen av klaffproteser har successivt förbättrat protesernas hemodynamiska
egenskaper, men grundkonstruktion är dock av sådan art att en förträngning över
protesen alltid kvarstår jämfört med en normal aortaklaff. Det är dock otvetydigt så att
en hjärtoperation med insättandet av en klaffprotes i aortaposition, oavsett etiologi,
förbättrar patientens överlevnad, symptom och hemodynamik. Efter operationen
genomgår hjärtat en ombyggnadsprocess som leder till att vänsterkammarens
pumpfunktion förbättras och hjärtmuskelförtjockningen successivt går tillbaka. Det är
dock ännu oklart vilken betydelse implantation av en liten klaffprotes med liten
öppningsarea (EOA; effective orifice area) har för samma utfallsvariabler. Under sin
operation får patienten en klaffprotes som storleksanpassas efter aortaannulus – oftast
21-27 mm. En klaffoperation på små patienter kan bli mycket komplicerad pga. en
trång aortaannulus med uttalad förkalkning varför dessa patienter oftare får en relativt
liten klaffprotes inopererad. Små klaffproteser har en mindre EOA, vilket leder till
högre transvalvulära gradienter. Eftersom människor med större kroppsyta har en
större hjärt-minutvolym så har de också teoretiskt sett behov av en större klaffprotes
med större EOA. För att få ett jämförbart mått på patienternas, teoretiskt sett, ”minsta
acceptabla klaffprotesstorlek” har man i tidigare studier indexerat EOA mot kroppsyta
och benämnt detta indexerad klaffarea (EOAi).
Baserat på experimentella flödesmodeller har man tidigare påvisat en exponentiell
relation mellan EOAi och transvalvulära gradienter och ur detta samband har man
sedan härlett tröskelvärden vid vilka negativa kliniska konsekvenser skulle kunna
uppstå. Denna teori är tidigare beskriven i litteraturen som prosthesis-patient mismatch
(PPM). Förklaringen till eventuella negativa kliniska konsekvenser av PPM är
58
följande: en kvarstående utflödesobstruktion, dvs. förhöjd afterload, vilket tvingar
vänsterkammaren att arbeta hårdare med ökat syrgasbehov till följd. Detta merarbete
leder till en kvarvarande förtjockning av vänsterkammarmuskeln, som i kombination
med det ökade arbetet, föreslås leda till en försämrad överlevnad och minskande
arbetskapacitet. Det finns fler kirurgiska åtgärder som man kan ta till för att undvika
PPM i samband med aortaklaffkirurgi, men de har alla ett gemensamt och det är att de
ökar operationens komplexitet. En ökad kirurgisk svårighetsgrad leder generellt till
ökad mortalitet och morbiditet varför det är viktigt att utröna huruvida PPM har några
kliniska konsekvenser av dignitet. Trots att en klaff med liten EOA teoretiskt skulle
kunna hindra en effektiv postoperativ ombyggnadsprocess och därmed intuitivt borde
leda till försämrade resultat så råder det i dagsläget ingen konsensus med avseende på
kirurgisk handläggning. Evidensgraden är låg och tidigare publikationer visar på långt
ifrån entydiga resultat. Detta kan delvis förklaras av att många studier är små och
heterogena med avseende på studiepopulation, men också pga. Att man använt många
olika definitioner för PPM. Detta har sammantaget lett till att man med säkerhet
varken kunnat påvisa eller avskriva en klinisk relevans för PPM.
Avhandlingen syftar till att studera prosthesis-patient mismatch och dess kliniska
betydelse ur nya infallsvinklar. I de arbeten som presenteras evalueras PPM och dess
relevans för postoperativ morbiditet, vänsterkammarens återhämtningsförmåga
avseende systolisk- och diastolisk funktion samt regressionsgraden av
vänsterkammarhypertrofi. Vidare undersöks incidensen av postoperativ hjärtsvikt efter
aortaklaffkirurgi och en specifik hjärtsviktsmarkör (BNP; brain natriuretic peptide)
utvärderas kliniskt. Patienter som genomgår aortaklaffoperation på basen av
aortainsufficiens har ofta en annulär dilatation och frånvaro av kalcifiering i aortaroten
– två faktorer som borde motverka uppkomsten av PPM. Om prosthesis-patient
mismatch förekommer hos denna patientkategori så föreligger en hypotetisk in vivo
modell som kan användas för att studera effekten av PPM på vänsterkammarens
återhämtningsförmåga med avseende på dimensioner och funktion.
Resultaten från denna avhandling talar för att PPM leder ej till försämrad överlevnad
på kort eller lång sikt. Dock löpte patienter med prosthesis-patient mismatch en större
risk att drabbas av neurologisk påverkan, inklusive stroke (slaganfall), i det
postoperativa förloppet. Detta fynd förklaras sannolikt av att patienter med prosthesispatient mismatch oftare har en trång aortarot med uttalad förkalkning vilket leder till
att det kirurgiska ingreppet ökar i komplexitet med ökar risken för stroke som följd.
Förekomsten av prosthesis-patient mismatch samvarierar sannolikt med dessa faktorer
så att även avancerade statistiska metoder kan ha svårt att justera för effekter av
kovariater. Våra resultat visar också att PPM ej påverkar den postoperativa
återhämtningen av vänsterkammarens systoliska eller diastoliska funktion. Våra fynd
talar också för att vänsterkammarhypertrofi och vänsterkammarmassa gick i regress
oavsett förekomst av PPM eller ej. Vidare kunde vi visa att postoperativ hjärtsvikt
efter aortaklaffkirurgi predikterar sämre överlevnad, men ingen association mellan
PPM och postoperativ hjärtsvikt kunde påvisas. Dessutom kunde vi visa att
vänsterkammarens dimensioner och systoliska funktion återhämtar sig oavsett
59
förekomst av PPM hos patienter som genomgår aortaklaffkirurgi pga.
aortainsufficiens.
I denna avhandling studeras effekten av PPM på selekterade utfallsvariabler, dvs.
överlevnad, komplikationer efter kirurgi samt hjärtats funktion, storlek och tjocklek.
Huruvida PPM kan ha en klinisk relevans avseende fysisk ansträngningsförmåga har
dock ej studerats.
Sammanfattningsvis förefaller prosthesis-patient mismatch som variabel ej utgöra en
riskfaktor för försämrad överlevnad eller kardiella postoperativa komplikationer.
Förekomsten av PPM verkar ej heller utgöra ett hinder för vänsterkammarens
postoperativa remodellering med avseende på massa, funktion och dimensioner. Vår
sammanvägda slutsats för denna avhandling är att PPM inte verkar ha någon större
klinisk relevans och därför bör man enligt vår mening undvika att komplicera det
kirurgiska ingreppet i syfte att implantera en hemodynamiskt överlägsen klaffprotes.
Vår åsikt är att man istället bör man premiera en för kirurgen lättanvänd klaffprotes,
som i kombination med ett standardiserat tillvägagångssätt, leder till kortast möjliga
operationstid med bibehållen säkerhet.
60
Acknowledgements
Welcome to the certainly most-read and probably most enjoyable part of this thesis.
Although the appearance of one author’s name on the cover may suggest that this is
the product of a single individual, the help of many others has been more than
essential. The faults of this thesis are all mine, but a number of people guided and
supported me and made this work possible. Sometimes I was ungrateful, and
occasionally regretted having to disregard their advice, but I still owe my heartfelt
gratitude to:
Associate Professor Johan Sjögren, my friend, supervisor and mentor, whom I
admire both professionally and personally. Your vast knowledge, unstoppable
enthusiasm and working spirit has guided and assisted me to scientific maturity. Your
love of cardiothoracic surgery has inspired me to pursue perfection in my clinical
skills. Together, we have trodden the numerous paths of research, sometimes ending
up in dead-end, sometimes in dark alleys. No matter where we ended up, you managed
to lead us through and to eventually find our way, driven by a never-ending source of
positivism and passion for learning. Thank you for believing in me, praising my merits
and overlooking my shortcomings.
Johan Nilsson, MD, PhD, my co-supervisor and friend, for sharing his knowledge in
research methodology, statistical skills and cardiac surgery. Your surgical skills and
clinical knowledge have been of great inspiration to me and I am privileged to be able
to address you as my surgical mentor. Other people think scientifically, you think
science.
Anders Roijer, MD, PhD, my co-supervisor, for instructing me in the great art of
echocardiography, for being a supportive mentor, for inspirational talks and a great
sense of humor leading to happy moments in our sessions at the “echo lab”.
Carsten Lührs, MD, my co-author and clinical mentor, for believing in me and
trusting me, and not allowing me to give up after my first year in cardiothoracic
surgery. Thank you for sharing your unique clinical knowledge and your highly
trained surgical skills. Not being able to share the operating room with you anymore is
a great personal loss, and your absence from the operating floor is a loss to the
discipline of cardiothoracic surgery. Finally, without your database, this thesis would
not have been possible.
My co-author, Lars Algotsson, MD, PhD, for sharing his knowledge and experience
in anesthesia and intensive care, and for providing a research-friendly atmosphere in
the intensive care unit, affording great learning opportunities, and for taking care of
“my patients”.
61
I would also like to thank:
Professor Stig Steen, Director of the Cardiothoracic Surgery Research in Lund, for
providing an excellent scientific environment and for sharing his vast knowledge in
cardiopulmonary research.
Our secretary, Mrs. Birgitta Sjögren, for great professionalism and effective handling
of patient records, for never saying no, and for always being glad to help.
During this work I have collaborated with many colleagues for whom I have great
regard, and I wish to extend my warmest thanks to all those who have helped me with
my work at the Department of Cardiothoracic Surgery, Lund University Hospital.
The staff of cardiothoracic wards 17 and 18, the OR and the ICU at Lund University
Hospital, for taking care of the patients with great competence.
To all my friends, especially Daniel, Servet and Johan P, who stuck with me through
thick and thin, and who shared my joys and my sorrows.
To my parents, Amir and Shahnaz: the proverb goes “good parents give two things to
their children: roots and wings”…thank you for, despite the discouraging odds, giving
me both.
To my brother Shahin for being an inspiration and always leading me along the right
path during times of mischief. Malin, Alice and Lily: thinking of you brings joy to my
heart. Near or far, you are always with me.
To my parents-in-law, for taking me into their arms and their family. Your passion and
quest for natural experiences add a much-needed and appreciated dimension to my
life. I am so grateful for your indomitable support of my family.
To my beautiful daughter, Saga, you are the best thing that ever happened to me. I love
you from the bottom of my heart.
And above all, my wife Ann, you are the sea upon which I float. Without you, this
would not have been possible. You mean the world to me.
The research presented in this thesis was supported by grants from:
Region Skåne Health Care
Lund University Hospital
62
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