Impact of Valve Prosthesis-Patient Mismatch on Left Ventricular Mass Regression Following Aortic Valve Replacement

Impact of Valve Prosthesis-Patient Mismatch on Left Ventricular Mass Regression Following Aortic Valve Replacement Giordano Tasca, MD, Federico Brunelli, MD, Marco Cirillo, MD, Margherita DallaTomba, MD, Zen Mhagna, MD, Giovanni Troise, MD, and Eugenio Quaini, MD Department of Cardiac Surgery, Poliambulanza Hospital, Brescia, Italy Background. Valve prosthesis-patient mismatch is a frequent problem in patients undergoing aortic valve replacement and its main hemodynamic consequence is to generate high transvalvular gradients through normally functioning prosthetic valves. The persistence of high gradients may hinder or delay the regression of left ventricular hypertrophy after aortic valve replacement. Methods. The aim of the study was to determine the impact of prosthesis-patient mismatch on the postoperative regression of left ventricular mass. Left ventricular mass was measured by Doppler echocardiography in 109 patients undergoing aortic valve replacement with a single type of bioprosthesis (Carpentier-Edwards Perimount) for pure aortic stenosis. Prosthesis-patient mismatch was defined as a projected indexed effective orifice area less than 0.90 cm 2 /m 2. On this basis, 58/109 (53.2%) patients had prosthesis-patient mismatch. Results. There was a good correlation (r 0.61, p < 0.001) between the postoperative mean transprosthetic gradient and the projected indexed effective orifice area. The absolute and relative left ventricular mass regression was significantly (p 0.002 and p 0.01, respectively) lower in patients with prosthesis-patient mismatch ( 48 47 g, 17% 16%) compared to those with no prosthesis-patient mismatch ( 77 49 g, 24% 14%). In multivariate analysis, a larger projected indexed effective orifice area, female gender and a higher preoperative left ventricular mass are independent predictors of greater left ventricular mass regression. Conclusions. This study shows that in patients with pure aortic stenosis prosthesis-patient mismatch is associated with lesser regression of left ventricular hypertrophy after aortic valve replacement. These findings may have important clinical implications given that prosthesis-patient mismatch is frequent in these patients. (Ann Thorac Surg 2005;79:505 10) 2005 by The Society of Thoracic Surgeons The presence of left ventricular (LV) hypertrophy is associated with a two- to threefold increase in cardiovascular-related mortality [1, 2]. Increased LV mass is an independent predictor of mortality in patients with systemic arterial hypertension as well as in normotensive patients [3]. LV hypertrophy is a strong independent risk factor for mortality in patients undergoing aortic valve replacement (AVR) [4, 5]. Normalization of LV mass is therefore a crucial goal of AVR. Unfortunately, the extent of LV mass regression may vary extensively from one patient to the other and it is often incomplete. These findings underline the importance of identifying and, whenever possible, avoiding risk factors for persisting LV hypetrophy following valve replacement. Valve prosthesis-patient mismatch (PPM) is present when the effective orifice area (EOA) of the inserted prosthetic valve is too small relative to body surface area (BSA). PPM is defined as a valve effective orifice area Accepted for publication April 12, 2004. Address reprint requests to Dr Tasca, UF di Cardiochirurgia, Poliambulanza Hospital, Via L. Bissolati 57, 25125 Brescia, Italy; e-mail: cchsegreteria.poli@poliambulanza.it. indexed for body surface area (IEOA) equal to or greater than 0.8 to 0.9 cm 2 /m 2 [6 9]. This is a frequent problem in patients undergoing AVR (20% to 70% prevalence), and its main hemodynamic consequence is to generate high transvalvular gradients through normally functioning prosthetic valves [7 10]. Residual transprothetic pressure gradients are important to consider because an increased gradient will evidently result in an increased LV workload, thus potentially jeopardizing the regression of LV mass after AVR. There has been very few studies on the impact of PPM on LV mass regression and there persists some controversy regarding this issue [11, 12]. The objective of this study was to examine if there is a relation between PPM and the extent of LV mass regression after AVR. Patients and Methods The study population includes 109 patients with pure aortic stenosis (AS) who underwent AVR between September 1997 and July 2002. All patients received a Carpentier-Edwards Perimount (CEP) bioprosthesis (Edwards Lifesciences, Irvine, CA). The distribution of 2005 by The Society of Thoracic Surgeons 0003-4975/05/$30.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2004.04.042

506 TASCA ET AL Ann Thorac Surg PROSTHESIS-PATIENT MISMATCH 2005;79:505 10 Abbreviations and Acronyms AS aortic stenosis AVR aortic valve replacement BSA body surface area CABG coronary artery bypass graft CAD coronary artery disease CEP Carpentier-Edwards Perimount COPD chronic obstructive pulmonary disease EF ejection fraction EOA effective orifice area IVS d interventricular septum thickness IEOA indexed effective orifice area IGF-1 insulinelike growth factor 1 LV left ventricle LVDD left ventricle diastolic diameter LVM left ventricular mass LVMI LVM index NYHA New York Heart Association functional class PPM prosthesis-patient mismatch PW d posterior wall thickness SR sinus rhythm patients in regards to prosthesis size was: 19 mm: 38 patients (34.8%), 21 mm: 39 patients (35.8%), 23 mm: 29 patients (26.6%), 25 mm: 3 patients (2.7%). The patients with more than mild aortic regurgitation, previous myocardial infarction, previous cardiac surgery, and concomitant surgical procedure other than coronary artery bypass grafting (CABG) were excluded. After a clinical follow-up examination at 3 months, the patients were interviewed by telephone annually in order to assess their clinical status and collect survival data. The follow-up was 100% complete. The survivors were invited to undergo an echocardiographic control examination at our hospital between 12 and 24 months postoperatively. Mismatch Definition Previous studies have shown that PPM as well as its consequences on morbidity and mortality can be predicted at the time of operation by calculating the projected IEOA [9, 10, 13 15]. In the present study, the projected indexed IEOA was derived from the published normal in vitro EOA values for the type (CEP) and size of implanted prosthesis divided by the patient s BSA [15]. The in vitro EOA values were: 1.3 cm 2 for the 19-mm valve, 1.5 cm 2 for the 21-mm valve, 1.8 cm 2 for the 23-mm valve, and 2.0 cm 2 for the 25-mm valve. For the purpose of this study, PPM was defined as a projected IEOA of less than 0.90 cm 2 /m 2 as suggested by Pibarot and Dumesnil [7, 9]. Doppler Echocardiographic Measurements Patients were evaluated by Doppler echocardiography 0 to 7 days before operation and between 1 and 2 years after operation. The preoperative and postoperative echocardiographic studies were performed by four experienced echocardiographers using an Acuson 128 Computed Sonograph (Acuson, Mountain View, CA) equipped with 2.5- to 3.5-MHz transducers. The dimensions of the LV were assessed using two-dimensional guided M-mode tracings, with the measurements being made according to the recommendations of the American Society of Echocardiography (ASE) [16]. If the M- mode recordings were technically inadequate, twodimensional measurements were used. LVM was calculated with the corrected ASE formula [17]: LVM 0.8 1.04 IVS d LVID d PWT d 3 LVID 3 13.6 where IVS d is the end-diastolic interventricular septum thickness, LVID d is the LV end-diastolic internal diameter, and PWT d is the LV end-diastolic posterior wall thickness. Residual LV hypertrophy was defined as a LV mass index more than 131 g/m 2 in males and more than 100 g/m 2 in females [18]. LV systolic performance was evaluated by means of the ejection fraction (EF) calculated using Simpson s rule. The peak and mean valve gradients were calculated using the modified Bernoulli equation with correction for subvalvular velocities. Valve EOA was calculated using the continuity equation and indexed with BSA. Statistical Analysis The data were statistically analyzed using SPSS 9.0 software (SPSS Inc. Chicago, IL). The continuous variables were expressed as mean values standard deviation (SD) and compared using a two-tailed t test (paired or unpaired as appropriate). The normality of the distributions in the two groups was tested by means of the Shapiro-Wilk test and, when abnormal, the data were log transformed. The discrete variables were compared using the 2 test. The relationship between the postoperative mean transprosthetic gradient and the projected IEOA was evaluated by means of simple linear regression analysis, after logarithmic transformation, in order to calculate r (Pearson s correlation coefficient). Multiple linear regression analysis was used to identify the independent predictors of LVM regression; p values of less than 0.05 were considered significant. Results Preoperative and Operative Data The patients preoperative and operative characteristics are shown in Table 1. Patients with PPM and those with no PPM were similar in respect to these data except for gender distribution, body mass index, and aortic valve pressure gradients. The prevalence of LV hypertrophy before operation was more than 90% in both groups. Patients with PPM had a higher proportion of smaller prostheses as shown in Figure 1. However, it should be noted that a significant proportion of patients with a small ( 21 mm) prosthesis had no PPM and, inversely, several patients with a larger prosthesis had PPM. Prosthetic Valve Hemodynamics The interval between preoperative and postoperative Doppler echocardiography control was 1.5 0.34 yrs in

Ann Thorac Surg TASCA ET AL 2005;79:505 10 PROSTHESIS-PATIENT MISMATCH 507 Table 1. Preoperative and Operative Data Parameters PPM No PPM p Value Number of patients 58 51 - Age (years) mean SD 76.1 5.8 75.8 6.3 NS Gender (male %) 34 68 0.001 BSA (m 2 ) (mean SD) 1.79 0.18 1.73 0.17 NS BMI (kg/m 2 ) 26.7 3.2 24.6 4.4 0.005 Mean aortic gradient (mm Hg) (mean SD) 51.7 11.9 46.6 13.4 0.04 Peak aortic gradient (mm Hg) (mean SD) 87.8 19.2 77.8 20.5 0.01 Aortic area indexed (cm 2 /m 2 ) (mean SD) 0.46 0.1 0.49 0.1 NS LV hypertrophy (%) 99 95 NS Hypertension (%) 72 59 NS Diabetes (%) 15 13 NS COPD (%) 9 16 NS Arteriopathy (%) 28 19 NS SR (%) 91 84 NS CAD (%) 43 41 NS NYHA class (mean SD) 2.3 0.7 2.2 0.7 NS Concomitant CABG (%) 66 55 NS BMI body mass index; BSA body surface area; CABG coronary artery bypass grafting; CAD coronary artery disease; COPD chronic obstructive pulmonary disease; LV left ventricle; NYHA New York Heart Association; PPM prosthesis-patient mismatch; SR sinus rhythm. No PPM group and 1.6 0.32 in PPM group (p NS). No structural or functional abnormalities of the prostheses were found during the postoperative control examination. The prosthetic valve hemodynamic data are shown in Table 2. As expected, patients with PPM had significantly lower projected and postoperative IEOAs and higher postoperative peak and mean transprosthetic pressure gradients. The average postoperative IEOA tended to be slightly lower than the projected IEOA, although this was not statistically significant. There was a good correlation (r 0.61, p 0.0001) between the projected IEOA and the postoperative mean transprosthetic gradient (Fig 2). Impact of PPM on Left Ventricular Mass and Function The preoperative and postoperative values as well as the absolute and relative changes in LV mass and function are shown in Table 3. Overall, interventricular septum thickness, LV posterior wall thickness, LV internal dimension, LV mass, and LV mass index all decreased significantly after AVR. However, the pattern of LV remodeling was different in the two groups with lesser decrease in LV internal dimension in patients with PPM. Preoperative and postoperative LV mass and LV mass index were significantly higher in patients with PPM compared with those with no PPM. Nonetheless, absolute and relative LV mass regression was significantly lower in patients with PPM. In multivariate analysis, larger projected IEOA (ie, lesser degree of PPM), female gender and higher preoperative LV mass were independent predictors of greater LVM regression after AVR (Table 4). The improvement of LV ejection fraction was similar in both groups. Fig 1. Distribution of prosthesis sizes in patients with mismatch and those with no mismatch. Number of patients in each CEP size groups: CEP 19 38 pts, CEP 21 39 pts, CEP 23 29 pts, CEP 25 3 pts. mismatch; no mismatch. (CEP Carpentier- Edwards Perimount.) Comment As in previous studies [11, 12, 19 21], gender and preoperative LV mass have also been identified as independent predictors of LV mass regression in the present study. It is well known that there is a gender-related difference in the behavior of pressure overload-induced LV hypertrophy, with males developing a greater mass, less concentric hypertrophy, more systolic stress and a lower LV ejection fraction [22]. As reported in other studies [23 25], regression of LV hypertrophy was not complete in more

508 TASCA ET AL Ann Thorac Surg PROSTHESIS-PATIENT MISMATCH 2005;79:505 10 Table 2. Prosthetic Valve Hemodynamic Data Parameters PPM No PPM p Value Number of patients 58 51 Mean transprosthetic gradient (mm Hg) mean SD 19.8 5.9 13.5 4.4 0.0001 Peak transprosthetic gradient (mm Hg) mean SD 33.2 9.7 23.8 7.5 0.0001 Projected EOA (cm 2 ) mean SD 1.44 0.17 1.69 0.15 0.0001 Projected indexed EOA (cm 2 /m 2 ) mean SD 0.79 0.06 0.98 0.07 0.0001 Postoperative EOA (cm 2 ) mean SD 1.38 0.24 1.53 0.3 0.0001 Postoperative indexed EOA (cm 2 /m 2 ) mean SD 0.76 0.14 0.89 0.18 0.0001 BSA body surface area; EOA effective orifice area; indexed EOA EOA/BSA; PPM prosthesis-patient mismatch. than 50% of studied patients 1 to 2 years after operation. The normalization of LV mass is a complex phenomenon that is determined by several patient- and prosthesisrelated factors. In this context, the incomplete regression of hypertrophy after the removal of the hypertrophic trigger may be explained by potentially irreversible changes in the hypertrophied myocytes and interstitium that may occur as a consequence of long-standing disease [26 28]. Furthermore, nonhemodynamic genetic [29], IGF-1 [30], and environmental factors may also be involved in the process of LV mass regression [31]. However, it should be emphasized that the influence of PPM was not analyzed in most of previous studies and it would appear evident that most previously identified risk factors for residual LV hypertrophy after AVR were hardly preventable or modifiable. A large amount of literature is available on the effect of AVR on LV hypertrophy regression. However, there are very few studies that directly address this issue in relation to PPM. In a study including 1103 patients with a porcine bioprosthetic valve, Del Rizzo and coworkers [11] found a strong and independent relationship between the indexed EOA and the extent of LV mass regression following AVR. There was a mean decrease in LV mass of 23% in patients with an indexed EOA of more than 0.8 Fig 2. Correlation (r 0.61, p 0.0001) between the projected IEOA and the postoperative mean transprosthetic gradient. Value obtained by means of logarithmic transformation. j observed; linear. (IEOA indexed effective orifice area.) cm 2 /m 2 compared with only 4.5% in those with an indexed EOA of equal to or less than 0.8 cm 2 /m 2 (p 0.0001). In contrast to these results, Hanayama and associates [12] found no significant relationship between PPM and regression of LV hypertrophy. However, the majority of patients included in this retrospective study did not undergo a complete echocardiographic follow-up of LV mass (preoperative base line and/or postoperative measurements not available). Furthermore, 50% of the patients with severe PPM included in this study still had significant LV hypertrophy more than 5 years after AVR. The major finding of our study is that PPM is associated with lesser regression of LV mass after AVR. More- Table 3. Preoperative and Postoperative LV Mass and Function Parameters PPM 58 No PPM 51 p Value Echocardiography followup 1.6 0.32 1.5 0.34 NS (yrs) IVS d (mm) mean SD Pre 13.7 1.6 14.3 1.9 NS Post 12.4 1.6 a 12.8 1.6 a NS PWT d (mm) mean SD Pre 13 1.4 13.1 1.8 NS Post 11.5 1.6 a 11.3 1.6 a NS LVID d (mm) mean SD Pre 48.4 5.7 54.3 7.4 0.01 Post 47.3 5.4 47.8 6.4 a NS LVM (g) mean SD Pre 266 58 303 75 0.005 Post 218 56 a 226 63 a NS LVM absolute regression 48 47 77 49 0.002 (g) mean SD LVM relative regression 17 16 24 14 0.01 % mean SD LVMI (g) mean SD Pre 149 31 176 44 0.0001 Post 121 27 a 129 34 a NS Residual hypertrophy 64 54 NS (% of patients) EF (%) mean SD Pre 62 10 56 13 0.007 Post 66 8 a 60 11 a 0.0001 a Postoperative vs preoperative p value 0.05. EF ejection fraction; IVS d interventricular septum thickness; LVID d left ventricular diastolic diameter; LVM left ventricular mass; LVMI left ventricular mass index; PPM prosthesispatient mismatch; PWT d posterior wall thickness.

Ann Thorac Surg TASCA ET AL 2005;79:505 10 PROSTHESIS-PATIENT MISMATCH 509 Table 4. Independent Predictors of Absolute LVM Regression in Multiple Regression Analysis Standardized Coefficients ( ) p Value Model: r 0.61, R 2 37%, p 0.0001 Female gender 0.257 0.005 Arteriopathy 0.107 0.251 Hypertension 0.071 0.390 Coronary artery disease 0.056 0.541 Sinus rhythm 0.037 0.699 Preoperative LVM 0.492 <0.0001 Projected effective orifice area 0.263 0.001 Dependent variable: absolute LVM regression. LVM left ventricular mass. over, this association remained significant after adjustment for other relevant factors including gender and preoperative LV mass. This finding is consistent with the pressure gradient indexed EOA relation, whereby the pressure gradient and thus the LV workload increase markedly when the IEOA becomes lower than 0.8 to 0.9 cm 2 /m 2 [7, 8, 13, 32]. Previous studies have reported that PPM is associated with inferior hemodynamics, more cardiac events, and higher mortality rates after AVR [10, 14, 15, 33, 34]. The results of the present study suggest that the persistence of LV hypertrophy associated with PPM may be one of the factors contributing to the PPM-related adverse outcomes. In our previous study of the CEP valve [23], we did not find any significant difference between 19-, 21-, and 23-mm CEP valve sizes in regards to LV mass regression. The results of the present study do not necessarily contradict our previous findings given that prosthesis size is not a good predictor of postoperative transprosthetic gradients and thus of PPM [13]. Accordingly, other studies have reported that IEOA (ie, the degree of PPM) but not prosthesis size are independent predictors of postoperative mortality [14, 15]. In the present study, we elected to use the projected IEOA rather than the postoperative IEAO to predict PPM for the several reasons. The IEOA measured by Doppler echocardiography after operation may be influenced by several factors (including subvalvular geometry, the orientation of the prosthesis, the nonuniformity of the subvalvular velocity profile, and measurement errors) [35]. In contrast, the projected IEOA is not affected by these factors and is not operator dependent. And more importantly, it can be calculated at the time of operation to predict PPM and can thus be used to prevent PPM as shown in previous studies [13, 36]. In this context, Pibarot coworkers [32] have demonstrated that the projected IEOA correlates well with postoperative resting and exercise transprosthetic gradients and that it can thus be used to identify the patients who have a high gradient on the basis of PPM. The good correlation found between the postoperative resting gradient and the projected IEOA, in the present study, further corroborate the results of Pibarot and colleagues [9]. It should be considered that the vast majority of the studies that have analyzed the impact of PPM on postoperative outcomes have used the projected IEOA to define PPM. Clinical Implications The clinical implication of this study may be important given that PPM is a frequent occurrence after AVR and that, as opposed to other risk factors, it can be prevented by implementing a preventive strategy at the time of operation [9, 13, 36]. Hence, if the projected IEOA of the prosthesis initially considered for implantation is less than 0.9 cm 2 /m 2, the surgeon could either perform a supraannular implantation or an aortic root enlargement in order to implant a larger prosthesis of the same type or, alternatively, he could also attempt to implant another type of prosthesis with a larger EOA (eg, stentless bioprostheses or bileaflet mechanical valve of new generation). Study Limitations In the present study, we used in vitro EOAs to calculate the projected IEOA. Indeed, there has been relatively few data published in the literature regarding the in vivo EOAs of the CEP valve at 1 to 2 years after operation and these data are based on a small number of patients [37]. Nonetheless, previous studies reported that, for stented bioprostheses as well as for mechanical valves, there is a strong correlation between in vitro and in vivo EOAs, although in vitro EOAs tend to overestimate in vivo EOAs by 10 to 15% [7, 38]. Preoperative LV mass had a significant influence on the extent of LV mass regression after operation. The fact that patients with PPM had a lower preoperative LV mass may thus have contributed to the lower LV mass regression observed in these patients after AVR. Nonethless, it should be emphasized that the projected IEAO remained an independent predictor of LV mass regression even after adjusting for preoperative LV mass in mutlivariate analysis and the percentage of patients meeting the criteria for LV hypertrophy was higher in the mismatch group. Regression of LV hypertrophy occurs in large part during the first 2 years after operation but it continues at a slower rate for several years thereafter [39, 40]. Longer follow-up of the patients included in this study is therefore necessary to determine if the difference between groups will increase over time. Conclusion This study shows that in patients with pure AS, PPM may hamper the regression of LV mass after AVR. 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