Impact of Prosthesis-Patient Mismatch on Long-term Functional Capacity After Mechanical Aortic Valve Replacement

Accepted Manuscript Impact of Prosthesis-Patient Mismatch on Long-Term Functional Capacity After Mechanical Aortic Valve Replacement Hélène Petit-Eisenmann, MD, Eric Epailly, MD, Michel Velten, MD, PhD, Jelena Radojevic, MD, Bernard Eisenmann, MD, Hélène Kremer, MD, PhD, Michel Kindo, MD, PhD PII:

S0828-282X(16)00222-1

DOI:

10.1016/j.cjca.2016.02.076

Reference:

CJCA 2065

To appear in:

Canadian Journal of Cardiology

Received Date: 29 October 2015 Revised Date:

19 February 2016

Accepted Date: 20 February 2016

Please cite this article as: Petit-Eisenmann H, Epailly E, Velten M, Radojevic J, Eisenmann B, Kremer H, Kindo M, Impact of Prosthesis-Patient Mismatch on Long-Term Functional Capacity After Mechanical Aortic Valve Replacement, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.02.076. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Impact of Prosthesis-Patient Mismatch on Long-Term Functional Capacity After Mechanical Aortic Valve Replacement

Hélène Petit-Eisenmann, MD1, Eric Epailly, MD2, Michel Velten, MD, PhD3, Jelena

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Radojevic, MD1, Bernard Eisenmann, MD2, Hélène Kremer, MD, PhD2, Michel Kindo, MD, PhD2

Department of Cardiology, Strasbourg University Hospital, France

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Department of Cardiac Surgery, Strasbourg University Hospital, France

3

Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, France

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Short title: Impact of prosthesis-patient mismatch

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Word count: 4501

Address for correspondence: Dr. Hélène Petit-Eisenmann, Service d’Explorations Fonctionnelles Non Invasives, Nouvel Hôpital Civil, 1 place de la porte de l’Hôpital, 67091 Cedex,

France.

Phone:

+33369550961

Fax:

+33369551873,

E-mail:

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Strasbourg

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[email protected]

Keywords:

Aortic stenosis, aortic valve replacement, prosthesis-patient mismatch, maximal oxygen uptake, cardiopulmonary exercise testing, quality of life.

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ACCEPTED MANUSCRIPT BRIEF SUMMARY Patients with prosthesis-patient mismatch (PPM) after mechanical aortic valve replacement face a moderate decrease in functional capacity in the long term compared with those without PPM, despite normalization of left ventricular mass and systolic and diastolic functions. For

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young patients with symptomatic significant aortic stenosis undergoing mechanical aortic valve replacement, PPM should be prevented as far as possible at the time of the surgery in

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order to confer high post-operative exercise capacity.

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ACCEPTED MANUSCRIPT ABSTRACT

Background The impact of prosthesis-patient mismatch (PPM) following aortic valve replacement (AVR)

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for aortic stenosis (AS) on exercise capacity remains controversial. The aim of this study was to analyze the long-term impact of PPM after mechanical AVR on maximal oxygen uptake

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(VO2max).

Methods

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The study included 75 patients who had undergone isolated mechanical AVR for AS with normal left ventricular (LV) function between 1994 and 2012. Their functional capacity was evaluated on average 4.6 years post-AVR by exercise testing, including measurement of their VO2max, and by determining their NYHA functional class and SF-36 score. Two groups were

echocardiography:

a

Results

PPM

group

(iEOA<0.85cm²/m²)

and

a

no

PPM

group

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(iEOA≥0.85cm²/m²).

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defined by measuring the patients’ indexed effective orifice area (iEOA) by transthoracic

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PPM was present in 37.0% of the patients. The percentage of the predicted VO2max achieved was significantly lower in the PPM group (86.7±19.5% versus 97.5±23.0% in the no PPM group; p=0.04). Compared with the no PPM group, the PPM group contained fewer patients in NYHA functional class I and their mean SF-36 physical component summary score was significantly lower. The mean transvalvular gradient was significantly higher in the PPM group than in the no PPM group (p<0.001). Systolic and diastolic function and LV mass had normalized in both groups. 3

ACCEPTED MANUSCRIPT Conclusions PPM is associated in the long term with moderate but significant impairment of functional capacity, despite optimal LV reverse remodeling and normalization of LV systolic and

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diastolic function.

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ACCEPTED MANUSCRIPT INTRODUCTION The standard treatment for symptomatic aortic stenosis (AS) is prosthetic aortic valve replacement (AVR), providing good results in both the short and long term through reversal of left ventricular (LV) remodeling, enabling recovery of normal LV function.1 All prosthetic

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valves are partially obstructive due to their architecture, but sometimes, when the effective orifice area indexed for body surface area (iEOA) is significantly smaller than that of a normal native valve, prosthesis-patient mismatch (PPM) or nonstructural dysfunction occurs.2,

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PPM has been defined as an iEOA of less than 0.85 cm²/m², and severe PPM as an iEOA of

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less than 0.65 cm²/m².2 Since an exponential relationship exists between iEOA and the transvalvular gradient, an iEOA below 0.85 cm²/m² would generate higher transvalvular gradients and therefore residual obstruction to LV ejection.2

PPM, particularly when severe, appears to reduce short-, medium-, and long-term survival in

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isolated AS, LV reverse remodeling, and exercise capacity.2, 4, 5 However, the data on PPM in the literature are inconsistent: the reported prevalence is highly variable, the long-term results are mixed,6 and its impact on exercise capacity is controversial, due to analysis of often

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heterogeneous populations, small patient numbers, and different types of replacement valves.2,

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The aim of this study was to evaluate the long-term effects of PPM on exercise capacity, by measuring maximal oxygen uptake (VO2max), in a homogeneous population of young patients following isolated mechanical AVR for AS with normal left ventricular function.

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ACCEPTED MANUSCRIPT MATERIAL AND METHODS Eligibility criteria The protocol was approved by the institutional review board, and all participating patients provided written informed consent (ClinicalTrials.gov number, NCT00854698).

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We analyzed the preoperative, intraoperative, and postoperative data on consecutive patients under the age of 60 years who had undergone isolated primary mechanical AVR (without other procedure) for AS in our department between 1994 and 2012, to determine their

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eligibility for the study. The flow diagram of the progress through the phases of this study with inclusion and exclusion criteria, is reported in Figure 1.

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99 patients met these eligibility criteria and 75 patients were included (52 men and 23 women). The preoperative transthoracic echocardiography characteristics are reported in the supplementary file (S1). Before AVR, most were symptomatic: 83% of patients were in NYHA class II or III and 69% had angina. The operative technique and mechanical valve

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characteristics are reported in the supplementary file (S2).

The projected iEOA was determined for 72 of the prosthetic valves, based on published data,2, 6, 10-12

although data were missing for the three ATS valves (Table 1). The mean time between

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Study endpoints

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AVR and inclusion in our study was 4.6 years (range: 0.8–14.7 years).

The primary endpoint was the VO2max measured during exercise testing, expressed as a percentage of predicted VO2max. The secondary endpoints were quality of life (SF-36 score and NYHA class), LV reverse remodeling (LV mass index), and diastolic function (filling pressures determined by echocardiography and B-type natriuretic peptide (BNP) concentration).

Study protocol 6

ACCEPTED MANUSCRIPT Figure 1 describes the study protocol. All the examinations were performed the same day in the following order: physical examination, blood testing, transthoracic echocardiography and exercise testing.

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Bicycle ergometer exercise testing (eBike; General Electric, Bitz, Germany) with 12-lead ECG monitoring was performed using a standardized protocol in which the work rate was increased by increments of 5 Watts/15 seconds. During the test, the patient wore a nose-clip

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and breathed through a mouthpiece with a low resistance valve, and gas exchange analysis was performed (V29C; SensorMedics, Würzburg, Germany).

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The predicted VO2max was established for each patient based on sex, age, height, and weight.13 The following parameters were measured: VO2max, measured to predicted VO2max ratio, ventilatory threshold, exercise duration, maximum work rate, respiratory quotient at peak

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exercise, heart rate, blood pressure, and O2 saturation.

Transthoracic Doppler echocardiography was performed according to the guidelines of the American Society of Echocardiography on all patients by the same operator using an iE33

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from 2009 (Philips Medical Systems, Bothell, WA, USA), with a 1–3 MHz bandwidth transthoracic transducer. Standard data were collected at rest as described elsewhere.14, 15

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Two groups were defined based on measured iEOA: a PPM group including patients whose measured iEOA was <0.85 cm²/m² and a no PPM group including patients whose iEOA was ≥0.85 cm²/m².

The SF-36 questionnaire was used to evaluate the patients’ physical (physical component summary) and mental quality of life (mental component summary).16

Statistical methods. 7

ACCEPTED MANUSCRIPT Normally distributed continuous variables were described by their mean and standard deviation, and compared using Student’s t-test. Binary variables were expressed in terms of numbers and percentages, and analyzed using Pearson’s χ² test. Variables besides PPM that were likely to influence LV mass (e.g. hypertension) were taken

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into account using multivariate analysis. For correlation studies, we used Pearson’s correlation coefficient or, where necessary, Spearman’s rank correlation coefficient.

Statistical analyses were conducted using SAS software V9.3 (SAS Institute, Cary, NC,

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USA). The results obtained in the PPM group were compared with those of the no PPM

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group. Only results with a p-value of less than 0.05 were considered statistically significant.

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ACCEPTED MANUSCRIPT RESULTS: The mean time to follow-up was identical in the PPM and no PPM groups: 4.79 years (range: 0.83–14.72 years) versus 4.45 years (range: 1.02–12.81 years), respectively. Table 1 shows the clinical and biological characteristics at inclusion of the patients in the

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PPM and no PPM groups. PPM was present in 28 patients (37.0%); this group contained equal numbers of men and women. The no PPM group had a significant lower proportion of women (Table 1, p=0.005).

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Besides gender, the only factor for which a statistically significant difference was found between the two groups was body mass index (p=0.001), although there was no significant

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difference between the groups in the amount of weight gained since AVR (+3.15 kg in the PPM group versus +2.23 kg in the no PPM group; p=0.41).

Impact of PPM on VO2max. The results of the cardiopulmonary exercise test are shown in

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Table 2. The measured to predicted VO2max ratio (primary endpoint) was significantly lower (−11.1%) in the PPM group than in the no PPM group (p=0.04). No significant correlation was found between the measured to predicted VO2max ratio and the time since AVR or SVI.

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The maximum work rate, percentage of the predicted maximum heart rate, and maximum heart rate achieved at peak exercise were significantly lower in the PPM group than in the no

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PPM group (Table 2). The ratio of oxygen uptake at the ventilatory threshold to peak oxygen uptake was also significantly lower in the PPM group (p=0.03), although the respiratory quotient did not differ between the two groups. Impact of PPM NYHA class and quality of life. Regarding the functional status, nearly all patients of the no-PPM group were in NYHA class I whereas 39.5% of the patients of the PPM group were in NYHA class II (p=0.001; Table 1). None of the patients in either group had angina at follow-up. The SF-36 questionnaire demonstrated a significantly lower physical quality of life (physical component summary) in the PPM group than in the no PPM group 9

ACCEPTED MANUSCRIPT (p=0.009), whereas no difference was found in mental quality of life (mental component summary) (Table 3). Impact of PPM on echocardiographic parameters and B type natriuretic peptide (BNP). The gain in iEOA (iEOA before AVR compared with iEOA measured at the follow-up visit)

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was significantly smaller in the PPM group than in the no PPM group (+0.30±0.11 cm²/m² versus +0.74±0.27 cm²/m², respectively; p<0.0001). This difference was associated with a significant increase in transvalvular gradients and a significant decrease in the velocity ratio in

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the PPM group compared with the no PPM group (Table 3). Although the LV ejection fractions and LV diameters were identical in the two groups, the SVI was significantly lower

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in the PPM group (p<0.0001, Table 3), due to a significant reduction in LV outflow tract diameter (p<0.0001). The variations between the preoperative and last follow-up SVI were +0.0 ml/m² and + 7.0 ml/m² in the PPM and no PPM groups respectively, with no statistical difference between the 2 groups (p=0.21).

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LV hypertrophy had regressed in both groups (−23 g/m² in the PPM group versus −34 g/m² in the no PPM group). Multivariate analysis found no significant association between the decrease in LV mass and gender or the presence of PPM (p=0.22). The ratio of mitral E

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velocity to early diastolic mitral annular velocity was significantly higher in the PPM group than in the no PPM group (p<0.01; Table 3). However, the diastolic function parameters and

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tissue Doppler imaging did not suggest impaired filling pressures or LV relaxation, and LV mass and ejection fraction values were normal (Table 3). No difference in right ventricular function or estimated systolic pulmonary artery pressure was observed between the groups. Despite a significantly higher BNP in the PPM group (p=0.003), the levels remained systematically within normal range (Table 1). Finally, no correlation was identified in our study between the size of the implanted mechanical aortic valve and the presence of PPM (p=0.26).

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ACCEPTED MANUSCRIPT Impact of severe PPM. Eleven patients (15% of the total population) had severe PPM (measured iEOA< 0.65 cm²/m²). A significant increase in mean aortic transvalvular gradient was observed with increasing PPM severity: 18.6 mmHg, 16.1 mmHg, and 12.8 mmHg in severe PPM, moderate PPM, and no PPM, respectively (p=0.002). The measured to predicted

(86.2±22.7% versus 87.1±17.5% respectively; p=0.90).

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DISCUSSION

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VO2max ratio did not significantly differ between the severe and moderate PPM groups

Our study demonstrates that in the long term, after mechanical AVR for AS, PPM is

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associated with moderate but significant impairment of objective functional capacity during exercise, with a decrease in VO2max. The NYHA class and physical quality of life, were also significantly reduced in the presence of PPM. This reduction in functional capacity was present despite the fact that the patients’ LV systolic and diastolic functions were within

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normal limits, their LV mass and filling pressures had normalized, and their BNP levels were within normal range. The SVI measured by preoperative echocardiography was significantly lower in the PPM group compared to the no PPM group but without attaining the level

change.

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defining low-flow output. After mechanical AVR, the SVI in both groups did not significantly

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It is noteworthy however that all of the patients had benefited from AVR: at the follow-up assessment, none of them had angina, their NYHA class had decreased, and they achieved good results in the exercise test. The degree of impairment of exercise capacity in patients with heart disease correlates with disease severity, with VO2max, measured to predicted VO2max ratio, and ventilatory threshold all declining with increasing NYHA class.17 While normal subjects without heart disease achieve 100.2±15.9% of their predicted VO2max, NYHA class I patients achieve only 87.9±15.8% and NYHA class II patients achieve only 73.4±14.9%.17 In our study, the functional results of the patients in the no PPM group were 11

ACCEPTED MANUSCRIPT comparable with those of subjects with no heart disease, while the results in the PPM group resembled those of patients with NYHA class I heart disease. In our study, the percentage of the predicted maximum heart rate and their respiratory quotient confirmed that maximal effort had been achieved and that we were assessing the VO2

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plateau. The ventilatory threshold was consistent with an exercising population, which was confirmed by the patients’ responses in interview and in the SF-36 questionnaire. The blood pressure were within normal range in both groups, reflecting satisfactory management of

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hypertension. The resting heart rate indicated good chronotropic competence. The significantly lower peak heart rate achieved during exercise in the PPM group may be related

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to the higher proportion of patients taking beta-blockers, although the difference in betablocker use was not statistically significant.

To our knowledge, long-term functional capacity has never been evaluated in an objective standardized way, using the measured to predicted VO2max ratio in young patients with

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mechanical prosthetic aortic valves with PPM. Tatineni et al. found that exercise duration correlated with the size of the mechanical prosthesis six months post-AVR.18 Others found that a smaller iEOA was associated with reductions in VO2max, maximum tolerated workload

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and ventilatory threshold 10 months after mechanical AVR.19 There have been some discrepancies in the published reports. These discrepancies may be explained, at least in part,

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by the fact that one study did not have patients with severe PPM20 and others reports used the prosthesis size rather that the iEOA for their analysis.21, 22 It is well established that PPM must be defined by the valve’s effective functional area on echocardiography, rather than its geometric area.12 Finally, in our study, we observed that reduced exercise capacity was associated with a reduction in physical quality of life, evaluated using the SF-36 questionnaire. Another study revealed similar results using the SF-12 health survey.23 Transvalvular gradients have been demonstrated to increase in PPM.2, 24 None of our patients had a mean gradient higher than 20 mmHg, even in the presence of severe PPM. LV 12

ACCEPTED MANUSCRIPT hypertrophy regress rapidly after surgery25, 26 and can continue for up to a decade.27 It may be more pronounced with mechanical prostheses than with bioprostheses.28 The long follow-up in our series made it possible to observe normalization of the LV mass index. As previously reported in the literature, the two groups had statistically different E/e’ ratios and BNP

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concentrations.29 However, all of the echocardiographic parameters and the BNP levels were within normal limits in both groups in our study since LV mass and systolic and diastolic function had normalized, these factors do not explain the reduction in the objective measure

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of functional capacity, VO2max, in our PPM group. A similar picture was seen for SVI, which although reduced in the PPM group was not below the threshold of 35 mL/m² that is usually

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recognized as indicative of paradoxical low flow.15 Despite AVR, no significant increase of the SVI was observed in either groups during the follow-up. This finding highlights that others conditions might interfere regarding the SVI variations.

PPM demonstrated by echocardiography does not appear to coincide with projected PPM

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determined in the operating room using tables designed to prevent PPM.10, 11 In our study, 17% of patients had projected PPM at the time of AVR (1.3% for severe PPM) whereas the prevalence of PPM measured by echocardiography was 37% (11% with severe PPM). The

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sensitivity and specificity of projected PPM as a predictor of echocardiographicallyconfirmed PPM remains moderate in the literature, with a sensitivity of 71%–73% and a

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specificity of 67%–80%.12, 30 The same is true for measured PPM, for which the sensitivity is 53% and the specificity 83%.30 STUDY LIMITATIONS

We recruited patients over a long period due to the strict eligibility criteria adopted. Severe symptomatic AS, requiring surgery, occurs more frequently in the elderly. In addition, many patients who underwent AVR before the 2000s could not be included because they had since developed neoplasia or atrial fibrillation or had been fitted with a pacemaker; finally, several patients were excluded because they concomitantly underwent enlargement of the aortic 13

ACCEPTED MANUSCRIPT annulus. So although our decision to study a highly specific, homogeneous, active population made it possible to demonstrate the impact of PPM on exercise capacity, it also introduced bias by selecting healthy patients who had received postoperative rehabilitation and continued

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to lead an active professional life and take part in recreational sporting activities.

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ACCEPTED MANUSCRIPT CONCLUSION Our study demonstrates that PPM following AVR using a mechanical prosthesis for isolated AS leads in the long term to a moderate but significant reduction in exercise capacity, despite optimum reversal of LV remodeling and normalization of systolic and diastolic function.

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However, in heterogeneous populations, the impact of PPM remains modest, with minimal functional, echocardiographic and biological consequences. PPM is nevertheless worth avoiding in young patients who practice sport, in order to preserve their subsequent quality of

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life.

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ACCEPTED MANUSCRIPT Funding Sources: This study was supported by a grant from the French Ministry of Health (PHRC I 2008 n° API 03-10) and Strasbourg University Hospital.

Aknowledgements: to the Clinical Investigation Center-INSERM 1434, Strasbourg

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University Hospital, France

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Disclosures: None.

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ACCEPTED MANUSCRIPT REFERENCES

1. Cormier B, Luxereau P, Bloch C et al. Prognosis and long-term results of surgically

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treated aortic stenosis. Eur Heart J 1988;9 Suppl E:113-20. 2. Pibarot P, Dumesnil JG. Hemodynamic and clinical impact of prosthesis-patient mismatch in the aortic valve position and its prevention. J Am Coll Cardiol

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2000;36:1131-41.

3. Rahimtoola SH. The problem of valve prosthesis-patient mismatch. Circulation

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1978;58:20-4.

4. Bleiziffer S, Eichinger WB, Hettich I et al. Impact of patient-prosthesis mismatch on exercise capacity in patients after bioprosthetic aortic valve replacement. Heart

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2008;94:637-41.

5. Tasca G, Mhagna Z, Perotti S et al. Impact of prosthesis-patient mismatch on cardiac events and midterm mortality after aortic valve replacement in patients with pure

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aortic stenosis. Circulation 2006;113:570-6.

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6. Mohty D, Dumesnil JG, Echahidi N et al. Impact of prosthesis-patient mismatch on long-term survival after aortic valve replacement: influence of age, obesity, and left

ventricular dysfunction. J Am Coll Cardiol 2009;53:39-47.

7. Blais C, Dumesnil JG, Baillot R, Simard S, Doyle D, Pibarot P. Impact of valve prosthesis-patient mismatch on short-term mortality after aortic valve replacement. Circulation 2003;108:983-8.

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ACCEPTED MANUSCRIPT 8. Hong S, Yi G, Youn YN, Lee S, Yoo KJ, Chang BC. Effect of the prosthesis-patient mismatch on long-term clinical outcomes after isolated aortic valve replacement for aortic stenosis: a prospective observational study. J Thorac Cardiovasc Surg

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2013;146:1098-104. 9. Howell NJ, Keogh BE, Barnet V et al. Patient-prosthesis mismatch does not affect survival following aortic valve replacement. Eur J Cardiothorac Surg 2006;30:10-4.

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10. Pibarot P, Dumesnil JG. Patient-prosthesis mismatch is not negligible. Ann Thorac Surg 2000;69:1983-4.

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11. Walther T, Rastan A, Falk V et al. Patient prosthesis mismatch affects short- and longterm outcomes after aortic valve replacement. Eur J Cardiothorac Surg 2006;30:15-9. 12. Pibarot P, Dumesnil JG, Cartier PC, Metras J, Lemieux MD. Patient-prosthesis

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mismatch can be predicted at the time of operation. Ann Thorac Surg 2001;71:S265S268.

13. Wasserman K , Hansen JE, Sue DY, Whipp BJ. Normal Values. In: Wasserman K,

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editor. Principles of Exercise Testing and Interpretation. Philadelphia, Lea & Febiger,

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1987:72-84.

14. Baumgartner H, Hung J, Bermejo J et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr

2009;22:1-23.

15. Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low-gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 2007;115:2856-64.

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ACCEPTED MANUSCRIPT 16. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473-83. 17. Itoh H, Taniguchi K, Koike A, Doi M. Evaluation of severity of heart failure using

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ventilatory gas analysis. Circulation 1990;81:II31-II37. 18. Tatineni S, Barner HB, Pearson AC, Halbe D, Woodruff R, Labovitz AJ. Rest and exercise evaluation of St. Jude Medical and Medtronic Hall prostheses. Influence of

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primary lesion, valvular type, valvular size, and left ventricular function. Circulation 1989;80:I16-I23.

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19. De CM, Milano A, Musumeci G et al. Cardiopulmonary exercise testing in patients with 21mm St. Jude Medical aortic prosthesis. J Heart Valve Dis 1999;8:522-8. 20. Fernandez J, Chen C, Laub GW et al. Predictive value of prosthetic valve area index

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for early and late clinical results after valve replacement with the St Jude Medical valve prosthesis. Circulation 1996;94:II109-II112. 21. Becassis P, Hayot M, Frapier JM et al. Postoperative exercise tolerance after aortic

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valve replacement by small-size prosthesis: functional consequence of small-size

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aortic prosthesis. J Am Coll Cardiol 2000;36:871-7. 22. Hirooka K, Kawazoe K, Kosakai Y et al. Prediction of postoperative exercise tolerance after aortic valve replacement. Ann Thorac Surg 1994;58:1626-30.

23. Urso S, Sadaba R, Vives M et al. Patient-prosthesis mismatch in elderly patients undergoing aortic valve replacement: impact on quality of life and survival. J Heart Valve Dis 2009;18:248-55.

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ACCEPTED MANUSCRIPT 24. Pibarot P, Dumesnil JG, Lemieux M, Cartier P, Metras J, Durand LG. Impact of prosthesis-patient mismatch on hemodynamic and symptomatic status, morbidity and mortality after aortic valve replacement with a bioprosthetic heart valve. J Heart Valve

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Dis 1998;7:211-8. 25. Fuster RG, Montero Argudo JA, Albarova OG et al. Patient-prosthesis mismatch in aortic valve replacement: really tolerable? Eur J Cardiothorac Surg 2005;27:441-9.

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26. Tasca G, Brunelli F, Cirillo M et al. Impact of valve prosthesis-patient mismatch on left ventricular mass regression following aortic valve replacement. Ann Thorac Surg

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2005;79:505-10.

27. Scott SM, Luchi RJ, Deupree RH. Veterans Administration Cooperative Study for treatment of patients with unstable angina. Results in patients with abnormal left

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ventricular function. Circulation 1988;78:I113-I121.

28. Weber A, Noureddine H, Englberger L et al. Ten-year comparison of pericardial tissue valves versus mechanical prostheses for aortic valve replacement in patients younger

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than 60 years of age. J Thorac Cardiovasc Surg 2012;144:1075-83.

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29. Melina G, Angeloni E, Benedetto U et al. Relationship between prosthesis-patient mismatch and pro-brain natriuretic peptides after aortic valve replacement. J Heart Valve Dis 2010;19:171-6.

30. Bleiziffer S, Eichinger WB, Hettich I et al. Prediction of valve prosthesis-patient mismatch prior to aortic valve replacement: which is the best method? Heart 2007;93:615-20.

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ACCEPTED MANUSCRIPT TABLES Table 1 - Patient characteristics at enrollment PPM

no PPM

Variable

p-value (n= 47)

Age, years

56.8±6.6

56.9±6.7

Women, %

50.0

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Demographic data

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(n=28)

NS

19.2

0.005

1.94±0.17

NS

29.9±9.1

27.2±3.8

0.01

60.5

91.5

0.001

39.5

8.5

0.001

50

31.9

NS

60.7

40.4

NS

Hematocrit, %

41.5±3.6

41.8±2.8

NS

Creatinine, µmol/L

75.3±16.1

72.9±18.2

NS

B-type natriuretic peptide, ng/L

53.7±40.1

29.6±27.0

0.003

0.98±0.19

1.16±0.28

0.006

1.94±0.22

Body mass index, kg/m² NYHA functional class I, %

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NYHA functional class II, % β-blocker, %

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Antihypertensive treatment, % Biological data

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Body surface area, m²

Projected iEOA, cm²/m²

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ACCEPTED MANUSCRIPT Data are mean ± SD or percentage of patients. Prosthesis-patient mismatch (PPM) was defined as a measured indexed effective orifice area (iEOA) <0.85 cm²/m² and no PPM was defined as iEOA≥0.85 cm²/m² NYHA = New York Heart Association; Projected iEOA = iEOA reference values for the

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prostheses at the time of the surgery.

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ACCEPTED MANUSCRIPT Table 2 – Cardiopulmonary exercise testing for the functional evaluation of patients with or without prosthesis-patient mismatch

no PPM

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PPM Variable

p-value

(n=28)

(n=47)

VO2max, mL/kg/min

22.3±7.0

Measured to predicted VO2max ratio, %

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Primary endpoints

0.004

86.7±19.5

97.5±23.0

0.04

143.6±44.8

180.8±47.5

0.001

VO2 at VT/peak VO2, %

60.3±10.2

54.9±9.7

0.03

Respiratory quotient

1.18±0.10

1.22±0.09

NS

72.3±9.9

76.9±12.7

NS

139.6±25.7

152.6±17.2

0.01

% of predicted maximum heart rate,%

85.4±14.9

93.8±10.7

0.006

Basal O2 saturation, %

97.9±1.0

98.0±1.0

NS

Peak O2 saturation, %

96.7±1.8

97.3±1.2

NS

Basal SBP, mmHg

140.7±20.1

137.1±14.0

NS

Peak SBP, mmHg

194.0±28.1

201.6±18.7

NS

Secondary endpoints

EP

Basal heart rate, bpm

TE D

Maximum work rate, watt

M AN U

27.7±7.8

AC C

Peak heart rate, bpm

23

ACCEPTED MANUSCRIPT 81.9±9.8

85.2±9.5

NS

Peak DBP, mmHg

97.3±19.2

95.4±11.9

NS

Data are mean ± SD. NS, not significant

RI PT

Basal DBP, mmHg

Prosthesis-patient mismatch (PPM) was defined as a measured indexed effective orifice area (iEOA) <0.85 cm²/m² and no PPM was defined as iEOA≥0.85 cm²/m²

SC

VO2max = maximal oxygen uptake; measured to predicted VO2max ratio = ratio of measured VO2max to predicted VO2max using the Wasserman equation; VO2 at VT/peak VO2 = ratio of

M AN U

oxygen uptake at the ventilatory threshold to peak oxygen uptake; Respiratory quotient = ratio of oxygen uptake to carbon dioxide output (VO2/VCO2), HR = heart rate; SBP = systolic

AC C

EP

TE D

blood pressure; DBP = diastolic blood pressure.

24

ACCEPTED MANUSCRIPT Table 3 – Echography data at rest and SF-36 score for patients with or without prosthesis-patient mismatch

no PPM

RI PT

PPM Variable

p-value

(n=28)

(n=47)

65.6±6.2

LV mass/BSA, g/m²

63.8±6.2

NS

M AN U

LVEF, %

SC

LV function and dimensions

93.2±25.7

105.4±30.7

NS

48.4±6.7

49.8±7.0

NS

30.3±4.6

31.6±5.1

NS

39.0±10.1

50.3±9.9

<0.0001

2.1±0.2

2.3±0.2

<0.0001

21.9±4.0

22.9±5.6

NS

iEOA, cm²/m²

0.68±0.08

1.16±0.28

<0.0001

AV mean gradient, mmHg

17.2±5.7

12.8±5.0

<0.001

Velocity ratio, %

39.3±6.6

52.6±10.4

0.001

1.1±0.4

1.0±0.3

NS

LVEDD, mm

SVI, mL/m²

LVOT, cm

AC C

TVILVOT , cm

EP

Aortic valve parameters

TE D

LVESD, mm

Conventional diastolic parameter E/A ratio

25

ACCEPTED MANUSCRIPT Tissue Doppler imaging 8.3±2.6

6.9±1.9

<0.01

RVFAC, %

45.3±10.0

43.8±10.4

NS

RV S’, cm/s

10.7±2.5

10.9±2.4

NS

sPAP, mmHg

26.4±7.7

25.7±4.0

NS

E/e’ (lateral)

SC

RI PT

Right ventricular function

Physical component summary

50.8±7.5

55.1±6.3

<0.01

47.5±7.9

49.3±9.8

NS

TE D

Mental component summary

M AN U

SF-36 score

Data are mean ± SD. NS = not significant.

Prosthesis-patient mismatch (PPM) was defined as a measured indexed effective orifice area

EP

(iEOA) <0.85 cm²/m² and no PPM was defined as iEOA ≥0.85 cm²/m² LV = left ventricular; LVEF = LV ejection fraction; BSA = body surface area; LVEDD = LV

AC C

end diastolic diameter; LVESD = LV end systolic diameter; SVI = stroke volume index; LVOT = LV outflow tract diameter; TVILVOT = time-velocity integral of the LV outflow tract; E/A ratio = ratio of mitral E velocity to mitral A velocity; e’ = early diastolic mitral annular velocity; RVFAC = right ventricular fractional area change; sPAP = systolic pulmonary artery pressure; SF-36 = Short Form-36 quality of life questionnaire.

26

ACCEPTED MANUSCRIPT Figure legends Figure 1: Flow diagram of the study protocol AVR=aortic valve replacement; LV=left ventricular; NYHA=New York Heart Association; SF-36=Short Form-36 quality of life questionnaire; BNP=B type natriuretic peptide .

RI PT

Prosthesis-patient mismatch (PPM) was defined as a measured indexed effective orifice area

AC C

EP

TE D

M AN U

SC

(iEOA)<0.85 cm²/m² and no PPM was defined as iEOA≥0.85 cm²/m²

27

ACCEPTED MANUSCRIPT Patient screening

Assessed for eligibility AVR (n=4960)

Isolated primary mechanical AVR (n=1272)

Alive at last follow-up (n=980)

Inclusion criteria • Age 18 – 60 years (n=481) • Aortic stenosis (n=323)

M AN U

SC

Met inclusion criteria (n=323)

RI PT

Mechanical AVR (n=2322)

Enrollment

99 Eligible

24 Excluded • 21 No reply • 3 Not interested

TE D

Inclusion

EP

75 Included

Study protocol Clinical examination, NYHA functional class + SF36 Blood test: hematocrit, creatinine and BNP Transthoracic echocardiography Bicycle ergometer exercise testing

AC C

1. 2. 3. 4.

Allocation Transthoracic Echocardiography

Statistical analysis

Exclusion criteria • LV dysfunction at the time of AVR and before inclusion (n=40) • Moderate or sever aortic insufficiency before AVR (>2/4) (n=32) • Coronary artery disease (n=14) • Renal dysfunction (n=8) • Chronic respiratory failure (n=15) • Heart failure in the month prior to inclusion (n=2) • Pacemaker (n=24) • No sinus rhythm (n=34) • Previous or current cancer (n=13) • Disorders of higher cortical function (n=29) • Other cardiopathy (n=6) • Contraindications to exercise testing on a bicycle ergometer (n=7)

28 Patients (37.0%) PPM group

47 Patients (63.0%) No PPM group