- Email: [email protected]
Usefulness of Preoperative Stroke Volume as Strong Predictor of Left Ventricular Remodeling and Outcomes After Aortic Valve Replacement in Patients With Severe Pure Aortic Regurgitation
Usefulness of Preoperative Stroke Volume as Strong Predictor of Left Ventricular Remodeling and Outcomes After Aortic Valve Replacement in Patients With Severe Pure Aortic Regurgitation Mario Sénéchal, MDa,*, Mathieu Bernier, MDa, François Dagenais, MDb, Michelle Dubois, BScc, Isaïe-Nicolas Dubois-Sénéchal,c and Pierre Voisine, MDb In most patients with aortic regurgitation (AR), aortic valve replacement (AVR) results in favorable left ventricular (LV) remodeling and normalization of the LV ejection fraction (EF). However, some patients with severe AR will not have favorable remodeling and their LVEF will not normalize. The goal of the present study was to determine whether remodeling and clinical outcomes after AVR could be predicted from simple preoperative echocardiographic analysis. A total of 56 consecutive patients with chronic severe pure AR who underwent AVR had preoperative (5 ⴞ 2 days), early postoperative (5 ⴞ 2 days), and late postoperative (328 ⴞ 88 days) echocardiographic data retrospectively analyzed. The LV diameter, The LVEF and stroke volume (SV) were measured. The reduction in LV end-diastolic dimension decreased by 14% (from 65 ⴞ 6 mm to 56 ⴞ 8 mm, p <0.001) early after AVR, with an additional reduction of only 6% late after AVR. More than 2/3 of the overall reduction in end-diastolic dimension was observed the week after AVR. Forty-six patients (82%) had positive early LV remodeling, defined as a 10% reduction in the LV end-diastolic diameter 1 week after AVR. All patients with early LV remodeling had a preoperative SV of >97 ml, which was the best predictor of late postoperative LVEF of >45% (sensitivity 98% and specificity 100%). Patients with a preoperative SV of >97 ml had a markedly greater event-free survival rate (92% vs 13%, p <0.001) at 3 years. In conclusion, in patients undergoing AVR for chronic severe pure AR, preoperative SV is the best predictor of LV remodeling and outcomes. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1008 –1013) Most symptomatic patients undergoing aortic valve replacement (AVR) for aortic regurgitation (AR) have symptom improvement after AVR. Others, however, develop progressive congestive heart failure, the most common cause of late postoperative death. In such patients, irreversible myocardial changes presumably occur before or concomitantly with the development of symptoms that lead to the operation.1–3 Therefore, the reliable prediction of postoperative left ventricular (LV) systolic function is of critical concern in establishing the appropriate timing of AVR. To detect subclinical LV myocardial dysfunction, the parameters of LV systolic function such as LV ejection fraction (EF) have been widely used. However, it is not uncommon that the preoperative LVEF does not correlate with the postoperative LVEF.4 – 8 Therefore, there is a clinical need to identify a new parameter to predict postoperative LV remodeling, systolic function, and outcomes in patients un-
a
Department of Cardiology, bDepartment of Cardiovascular Surgery, and cResearch Center, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada. Manuscript received April 14, 2011; revised manuscript received and accepted May 17, 2011. Dr. Sénéchal is recipient of a grant from the Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada. *Corresponding author: Tel: (418) 656-8711; fax: (418) 656-4581. E-mail address: [email protected] (M. Sénéchal). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.05.035
dergoing AVR for severe AR. The objective of the present study was to determine whether the preoperative stroke volume (SV) could be used to accurately predict early and late LV remodeling and outcomes in patients with chronic severe pure AR. Methods We studied patients with chronic severe pure AR who had undergone AVR from January 2005 to June 2010 in our institution. Patients with acute AR, coronary artery disease (coronary artery stenosis ⬎50%), atrial fibrillation, aortic stenosis, significant mitral disease (more than mild disease), previous aortic valve surgery, and previous or associated mitral valve replacement or repair were excluded. A total of 56 patients were included in the present study. The study was approved by the local hospital ethic and scientific committees. The patients were separated into 2 groups according to the presence or absence of early LV diastolic remodeling.9 Early diastolic remodeling was defined as an early postoperative LV diastolic dimension reduction of ⱖ10%. Postoperative cardiac events were defined as rehospitalization for congestive heart failure or cardiovascular-related death. The median duration of follow-up was 2.6 ⫾ 2.0 years. Two-dimensional and Doppler transthoracic echocardiographic examinations with commercially available echocardiographic systems (Sonos 5500 or 7500, Philips Medical Systems, Amsterdam, The Netherlands) were www.ajconline.org
Valvular Heart Disease/Postoperative Remodeling in Aortic Regurgitation
1009
Table 1 Clinical and echocardiographic characteristics according to early remodeling status Variable Age (years) Men Mean systolic pressure (mm Hg) Mean diastolic pressure (mm Hg) New York Heart Association functional class Body surface area Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Stroke volume (ml) Left ventricular end-diastolic volume (ml) Left ventricular end-systolic volume (ml) Left ventricular diameter/wall thickness Left ventricular systolic/wall thickness Systolic wall stress
Early Remodeling (n ⫽ 46)
No Remodeling (n ⫽ 10)
p Value
53 ⫾ 2 35 (76%) 125 ⫾ 3 66 ⫾ 1 3.0 ⫾ 0.3 2.0 ⫾ 0.2 47 ⫾ 10 65 ⫾ 6 45 ⫾ 7 130 ⫾ 27 134 ⫾ 31 82 ⫾ 28 6⫾1 4⫾1 128 ⫾ 32
61 ⫾ 4 8 (80%) 127 ⫾ 8 68 ⫾ 3 3.0 ⫾ 0.4 2.0 ⫾ 0.3 32 ⫾ 6 69 ⫾ 8 56 ⫾ 10 70 ⫾ 12 211 ⫾ 59 162 ⫾ 53 7⫾1 5⫾1 185 ⫾ 42
0.06 0.9 0.8 0.5 0.8 0.9 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.002 ⬍0.001 0.001 ⬍0.001 ⬍0.001
Figure 1. (A) Preoperative SV according to early remodeling status. (B) Preoperative LVEF according to early remodeling status. (C) Preoperative end-diastolic diameter (mm/m2) according to early remodeling status. (D) Preoperative end-systolic diameter (mm/m2) according to early remodeling status.
performed 5 ⫾ 2 days before AVR and 5 ⫾ 2 days (early) and 328 ⫾ 88 days (late) postoperatively. The degree of AR (grade 3⫹ to 4) was determined by analysis of color
flow Doppler. The heart diameter was measured using 2-dimensional echocardiographically guided M-mode, as previously described.10 The LV end-diastolic and end-
1010
The American Journal of Cardiology (www.ajconline.org)
Figure 3. Preoperative, early postoperative, and late postoperative LVEF changes in patients with and without significant early remodeling. *Significant difference (p ⬍0.01) compared to patients with early remodeling.
Results
Figure 2. (A) Preoperative, early postoperative, and late postoperative LV end-diastolic diameter changes in patients with and without significant early remodeling. *Significant difference (p ⬍0.01) compared to patients without early remodeling. (B) Preoperative, early postoperative, and late postoperative left ventricular end-systolic changes in patients with and without significant early remodeling. *Significant difference (p ⬍0.01) compared to patients without early remodeling.
systolic volumes and LVEF were determined using the modified biplane Simpson method. End-systolic wall stress was also calculated, as previously described.11 The SV was calculated using the outflow tract diameter measured at the base of the aortic leaflet in the parasternal long-axis view and the pulsed Doppler velocity integral obtained at the same level in the 5-chamber view.12 Continuous variables are presented as the mean ⫾ SD; discrete variables are presented as the frequency distribution. The mean values were compared using the 2-sample independent and paired t test, and categorical variables were compared using conventional chi-square testing. The correlations are reported with Pearson’s coefficient. All time-toevent distributions were estimated with the Kaplan-Meier methods. All reported time-to-event comparisons were made using the log-rank test.
The etiology of AR was a bicuspid valve in 23 patients (41%), rheumatic/degenerative disease in 16 patients (29%), aortic dilation in 15 (27%), and miscellaneous causes in 2 patients (3%). Thirty-two patients (57%) required concomitant ascending aortic surgery. Of the 56 patients, 46 (82%) had early significant LV remodeling (10% LV diastolic diameter reduction ⱕ2 weeks after AVR) and 10 (18%) had no early significant LV remodeling. No significant difference was found between patients with and without early remodeling in terms of preoperative demographic and clinical data (Table 1). In contrast, the echocardiographic characteristics were all different between the patients with and without early LV remodeling. On simple linear regression analysis, the preoperative SV (r ⫽ 0.44, p ⬍0.001), LVEF (r ⫽ 0.34, p ⬍0.01), and LV end-diastolic dimension (r ⫽ 0.26, p ⫽ 0.06) correlated with early LV diastolic remodeling. The preoperative presence of a SV of ⱖ97 ml had the best performance for the prediction of early LV remodeling compared to the preoperative LVEF and indexed LV diastolic or systolic diameter (Figure 1). The reduction in the LV end-diastolic dimension decreased by 14% (from 65 ⫾ 6 mm to 56 ⫾ 8 mm, p ⬍0.001) early after AVR, with an additional reduction of only 6% (relative to preoperative values) to 52 ⫾ 8 mm late after AVR. Thus, 69% of the overall reduction in end-diastolic dimension observed during the long-term postoperative evaluation occurred within 2 weeks of AVR. A reduction in the LV end-systolic diameter decreased by 9% (from 47 ⫾ 8 mm to 43 ⫾ 9 mm early after AVR, p ⬍0.001) with an additional reduction of 9% to 39 ⫾ 10 mm late after AVR. By definition, patients with significant early remodeling (ⱖ10% LV end-diastolic diameter early after AVR) had more important LV end-diastolic diameter reduction than patients without significant early remodeling (Figure 2). LV endsystolic reduction was also more important in the group of patients with significant early remodeling (Figure 2). In all patients, the LVEF decreased by 22% from 46 ⫾ 11% to 36 ⫾ 11% early after AVR (p ⬍0.001) with an additional
Valvular Heart Disease/Postoperative Remodeling in Aortic Regurgitation
1011
Table 2 Sensitivity and specificity of diagnostic cutoff values for preoperative variables in predicting late postoperative left ventricular ejection fraction ⱖ45% Variable Stroke volume (ml) Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm/m2) Left ventricular end-systolic diameter (mm/m2)
Diagnostic Cutoff Value
Sensitivity (%)
Specificity (%)
AUC
CCOC (%)
97 40 32 21
98% 87% 74% 85%
100% 89% 30% 10%
0.99 0.94 0.47 0.26
98% 88% 66% 71%
AUC ⫽ area under the curve; CCOC ⫽ correctly classified observations using cutoff value.
Figure 4. Kaplan-Meier survival estimation in patients with or without early remodeling.
increase of 11% (relative to the preoperative values) to 51 ⫾ 13% late after AVR. The patients with significant early remodeling also had a decrease in LVEF early after AVR; however, the LVEF increased significantly late after AVR (Figure 3). In patients without significant early remodeling, the LVEF decreased significantly late after AVR compared to the preoperative values (32% vs 26%, p ⫽ 0.03). The preoperative presence of a SV of ⱖ97 ml had the best performance for the prediction of a LVEF of ⱖ45% late after AVR (Table 2). The patients with a preoperative SV ⬍97 ml had a markedly lower cardiac event-free survival at 3 years compared to those with a preoperative SV of ⱖ97 ml (Figure 4). The outcomes for patients with a SV of ⬍97 ml are presented in Table 3. Discussion In the present study, we have shown that the preoperative SV accurately predicts LV remodeling and the outcomes in patients with chronic severe pure AR. An elevated preoperative SV (i.e., ⱖ97 ml) was present in all patients with significant early remodeling after AVR and was a better predictor of LVEF normalization (ⱖ45%) at the long-term follow-up examination compare to the preoperative LVEF or indexed ventricular dimensions. This is the first study to investigate the utility of preoperative SV in this patient population. Our results suggest that improvement in LVEF during long-term follow-up represents the combined result of an early predominant and late remodeling process occurring
after AVR. Patients with normal preoperative LVEF manifested an impressive early decrease in the LV end-diastolic dimension early postoperatively and significant, but less important, late remodeling. In the same line, Bonow et al9 have also suggested that early remodeling after AVR is important because only a few patients with persistent LV end-diastolic dilation 6 to 12 months after AVR will present a subsequent reduction in the ventricular cavity size to normal.9 Our study has demonstrated that data relevant to long-term prognosis can be obtained in all patients by the simple measurement of preoperative SV and early postoperative LV diameter diastolic reduction. Patients with AR and depressed ventricular function are often considered at very high risk of AVR, and some of them are even denied an intervention because they are believed to be at an irreversible stage of deterioration. Our data underline the importance of considering the SV in assessing the potential for recuperation in these patients, both in terms of ventricular function and survival. In our series, the patients manifesting the greatest reduction in LV end-diastolic dimension after AVR were either those with a normal preoperative LVEF or those with a depressed LVEF but an elevated SV. In contrast, among the patients with preoperative LV dysfunction and reduced SV, the magnitude of decrease in LV end-diastolic dimension was less pronounced, and there was also a significant decrease of LVEF late after AVR. Previous studies have shown that patients with severe AR and markedly low LVEF have greater operative and postoperative mortality rates and greater heart failure risks than patients with mild or no decrease in preoperative LVEF.13 Our study included 35 patients (63%) with systolic dysfunction (LVEF of ⱕ50%); 14 (40%) had severe systolic dysfunction (LVEF of ⱕ35%). Eight patients with severe systolic dysfunction had a preoperative SV of ⬍97 ml (70 ⫾ 12 ml), and 7 (88%) with severe systolic dysfunction and SV ⬍97 ml died or were rehospitalized for heart failure during follow-up. In the group of patients with severe systolic dysfunction but elevated SV (i.e., ⱖ97 ml), the LVEF on last follow-up was 52 ⫾ 6% and no mortality or hospitalization was recorded. Chronic AR is both a volume and a pressure overload condition. Initially, hypertrophy and dilation compensate for the overload, and, thus, the LV systolic function remains normal. However, progressive LV dilation is followed by LV systolic dysfunction, presumably without irreversible myocardial dysfunction at first. Eventually, severe and chronic LV volume overload increases the wall stress, leading to deposition of collagen and subendocardial fibrosis,
1012
The American Journal of Cardiology (www.ajconline.org)
Table 3 Postoperative outcomes of patients with preoperative stroke volume (SV) ⬍97 ml Age (years)
SV (ml)
Clinical Outcomes NYHA
37 52 64 69 81 57 63 54 69 68
52 53 63 63 68 73 73 83 83 84
Follow-Up (d) Events
Preoperative
Postoperative
III III III III III III III III III III
III III III III Death II II III III III
HF hospitalization — HF hospitalization HF hospitalization Death from cardiac cause — — HF hospitalization HF hospitalization HF hospitalization
580 128 427 650 12 1670 214 252 164 565
HF ⫽ heart failure; NYHA ⫽ New York Heart Association.
and resulting in progressive LV dysfunction in patients with AR. Invasive and noninvasive techniques have suggested that dP/dt might be the reference standard in the evaluation of LV contractility.14 –17 The prediction of postoperative LV systolic function with Doppler-derived dP/dt in patients with chronic AR has been proposed by Kang et al.4 Doppler-derived dP/dt showed a significant independent correlation with late postoperative LVEF.4 Using a micromanometer catheter for the measurement of LV dP/dt in patients with advanced heart failure, Gold et al18 demonstrated an excellent correlation between SV and LV dP/dt maximum (r ⬎0.98). Many studies have demonstrated the correlation between the SV and other parameters of LV performance. In cardiac resynchronization therapy, the correlation between changes in the wall motion stress index and SV has been validated.19 Furthermore, investigators have demonstrated that the variation in the SV with dobutamine infusion correlated with the contractile reserve and LV remodeling.19 –22 In patients with low-gradient aortic stenosis, the assessment of an increase in SV by dobutamine stress echocardiography has the potential to stratify operative risks.20 Those studies are clearly suggesting a link between the SV and the presence and extent of viable myocardium in patients with heart failure from systolic dysfunction. In a population of 61 patients with chronic severe pure AR, Wahi et al23 have performed exercise echocardiography to evaluate contractile reserve (increment of LVEF after exercise). Their findings indicate that contractile reserve identified by exercise echocardiography was useful in the prediction of progressive deterioration of LV function after AVR. In the same line, Bonow et al1 have demonstrated that patients with severe pure AR who manifested the greatest reduction in LV end-diastolic dimension after AVR were either those with normal preoperative LVEF or those with depressed LVEF but preserved exercise tolerance, presuming the presence of contractile reserve in both populations. Accordingly, the clinical response to treatment such as  blockade or revascularization in patients with LV systolic dysfunction has been shown to be dependent on the presence and extent of viable myocardium.24 In the presence of severe pure AR, the SV depends on the regurgitant volume and also on the capacity of the left
ventricle of “pumping” this volume overload. In these conditions, preservation of an elevated SV despite a severe systolic dysfunction (LVEF ⱕ35%) suggests that sufficient viable myocardium is present to allow eventual favorable remodeling after AVR. In patients with chronic severe pure AR, the left ventricle adapts to a slowly increasing load by undergoing so-called eccentric hypertrophy. The LV chamber size increases in proportion to the regurgitant volume, the LV wall thickness increases proportionally to maintain the wall stress within physiologic limits, and LV function is maintained at normal or near-normal levels. Eventually, however, hypertrophy cannot keep pace with the increasing regurgitant volume, and, with time, dilation of the LV chamber will be out of proportion to its degree of hypertrophy and LV function fails. We suggest that when LVEF decreases, there is a subgroup of patients whose myocardial dysfunction remains reversible, characterized by a “preserved SV.” In these patients, systolic function responds favorably to surgical removal of valvular regurgitation and to the reversal of ventricular dilation. In contrast, when compensatory mechanisms become exhausted, irreversible myocardial dysfunction supervenes in the subgroup of patients “without preserved SV.” The present study had several limitations. The number of patients in the present cohort was relatively small. Also, the duration of follow-up was relatively short, and the additional alteration in LV function (and especially the clinical condition) might have been seen if the cohort had been followed up for a longer period. The retrospective analysis of the data was another shortcoming. Finally, we did not perform any viability study to allow us to confirm our hypothesis on the possible relation between preoperative SV and contractile reserve. 1. Bonow RO, Borer JS, Rosing DR, Henry WL, Pearlman AS, McIntosh CL, Morrow AG, Epstein SE. Preoperative exercise capacity in symptomatic patients with aortic regurgitation as a predictor of postoperative left ventricular function and long-term prognosis. Circulation 1980;62:1280 –1290. 2. Hirshfeld JW, Epstein SE, Roberts AJ, Glancy DL, Morrow AG. Indices predicting long-term survival after valve replacement in pa-
Valvular Heart Disease/Postoperative Remodeling in Aortic Regurgitation
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
tients with aortic regurgitation and patients with aortic stenosis. Circulation 1974;50:1190 –1199. Henry WL, Bonow RO, Borer JS, Ware JH, Kent KM, Redwood DR, McIntosh CL, Morrow AG, Epstein SE. Observations on the optimum time for operative intervention for aortic regurgitation. I. Evaluation of the results of aortic valve replacement in symptomatic patients. Circulation 1980;61:471– 483. Kang HJ, Kim YJ, Sohn DW, Oh BH, Lee MM, Park YB, Choi YS. Prediction of postoperative left ventricular systolic function with Doppler-derived dP/dt in patients with chronic aortic regurgitation. J Am Soc Echocardiogr 2003;16:1111–1115. Hwang MH, Hammermeister KE, Oprian C, Henderson W, Bousvaros G, Wong MJ, Miller DC, Folland E, Sethy G. Preoperative identification of patients likely to have left ventricular dysfunction after aortic valve replacement: participants in the Veterans Administration cooperative study on valvular heart disease. Circulation 1989;80:165–176. Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bayley KR, Seward JB. Aortic regurgitation complicated by extreme left ventricular dilation: long-term outcome after surgical correction. J Am Coll Cardiol 1996;27:670 – 677. Onishi T, Kawai H, Tatsumi K, Kataoka T, Sugiyama D, Tanaka H, Okita Y, Hirata KI. Preoperative systolic strain rate predicts postoperative left ventricular dysfunction in patients with chronic aortic regurgitation. Circ Cardiovasc Img 2010;3:134 –141. Paraskevaidis IA, Kyrzopoulos S, Farmakis D, Parissis J, Tsiapras D, Iliodromitis K, Kremastinos DT. Ventricular long-axis contraction as an earlier predictor of outcome in asymptomatic aortic regurgitation. Am J Cardiol 2007;100:1677–1682. Bonow RO, Dodd JT, Maron BJ, O’Gara PT, White GG, McIntosh CL, Clark RE, Epstein SE. Long-term serial changes in left ventricular function and reversal of ventricular dilatation after valve replacement for chronic aortic regurgitation. Circulation 1988;78:1108 –1120. Tajik AJ, Seward JB, Hagler DJ, Mair DD, Lie JT. Two-dimensional real-time ultrasonic imaging of the heart and great vessels: technique, image orientation, structure identification, and validation. Mayo Clin Proc 1978;53:271–303. Reichek N, Wilson J, St John Sutton M, Plappert TA, Goldberg S, Hirshfeld JW. Noninvasive determination of left ventricular end-systolic stress: validation of the method and initial application. Circulation 1982;65:99 –108. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984;79:425– 431. Chaliki HP, Mohty D, Avierinos JF, Scott CG, Schaff HV, Tajik AJ, Enriquez-Sarano M. Outcomes after aortic valve replacement in patients with severe aortic regurgitation and markedly reduced left ventricular function. Circulation 2002;106:2687–2693. Daniel WG, Hood WP, Siart A, Hausmann D, Nellessen U, Oelert H, Lichtien PR. Chronic aortic regurgitation: reassessment of the prog-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
1013
nostic value of preoperative left ventricular end-systolic dimension and fractional shortening. Circulation 1985;71:669 – 680. Greves J, Rahimtoola SH, McAnultry JH, DeMots H, Clark DG, Greenberg B, Starr A. Preoperative criteria predictive of late survival following valve replacement for severe aortic regurgitation. Am Heart J 1981;101:300 –308. Siemienczuk D, Greenberg B, Morris C, Massie B, Wilson RA, Topic N, Bristow JD, Cheitlin M. Chronic aortic insufficiency: factors associated with progression to aortic valve replacement. Ann Intern Med 1989;110:587–592. Rahimtoola SH. Valve replacement should not be performed in all asymptomatic patients with severe aortic incompetence. J Thorac Cardiovasc Surg 1980;79:163–172. Gold MR, Niazi I, Giudici M, Leman RB, Sturdivant JL, Kim MH, Waggoner AD, Ding J, Arcot-Krishnamurthy S, Daum D, Yu Y. Acute hemodynamic effects of atrial pacing with cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2009;20:894 –900. Sénéchal M, Lancellotti P, Garceau P, Champagne J, Dubois M, Blier L, Molin F, Philippon F, Dumesnil JG, Pierard L, O’Hara G. Usefulness and limitation of dobutamine stress echocardiography to predict acute response to cardiac resynchronization therapy. Echocardiography 2010;27:50 –57. Tribouilloy C, Lévy F, Rusinaru D, Guéret P, Petit-Eisenmann H, Baleynaud S, Jobic Y, Adams C, Lelong B, Pasquet A, Chauvel C, Metz D, Quéré JP, Monin JL. Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. J Am Coll Cardiol 2009;53: 1865–1873. Qureshi U, Nagueh SF, Afridi I, Vaduganathan P, Blaustein A, Verani MS, Winters WL Jr, Zoghbi WA. Dobutamine echocardiography and quantitative rest-redistribution 201TI tomography in myocardial hibernation: relation of contractile reserve to 201TI uptake and comparative prediction of recovery of function. Circulation 1997;95:626 – 635. Ramahi TM, Longo MD, Cadariu AR, Rohifs K, Slade M, Carolan S, Vallejo E, Wackers FJ. Dobutamine-induced augmentation of left ventricular ejection fraction predicts survival of heart failure patients with severe non-ischemic cardiomyopathy. Eur Heart J 2001;22:849456. Wahi S, Haluska B, Pasquet A, Case C, Rimmerman CM, Marwick TH. Exercise echocardiography predicts development of left ventricular dysfunction in medically and surgically treated patients with asymptomatic severe aortic regurgitation. Heart 2000;84:606 – 614. Eichhorn EI, Grayburn PA, Mayer SA, St John Sutton M, Appleton C, Plehn J, Oh J, Greenberg B, DeMaria A, Frantz R, Krause-Steinrauf H. Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with -blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST). Circulation 2003;108:2336 –2341.
a
Department of Cardiology, bDepartment of Cardiovascular Surgery, and cResearch Center, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada. Manuscript received April 14, 2011; revised manuscript received and accepted May 17, 2011. Dr. Sénéchal is recipient of a grant from the Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada. *Corresponding author: Tel: (418) 656-8711; fax: (418) 656-4581. E-mail address: [email protected] (M. Sénéchal). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.05.035
dergoing AVR for severe AR. The objective of the present study was to determine whether the preoperative stroke volume (SV) could be used to accurately predict early and late LV remodeling and outcomes in patients with chronic severe pure AR. Methods We studied patients with chronic severe pure AR who had undergone AVR from January 2005 to June 2010 in our institution. Patients with acute AR, coronary artery disease (coronary artery stenosis ⬎50%), atrial fibrillation, aortic stenosis, significant mitral disease (more than mild disease), previous aortic valve surgery, and previous or associated mitral valve replacement or repair were excluded. A total of 56 patients were included in the present study. The study was approved by the local hospital ethic and scientific committees. The patients were separated into 2 groups according to the presence or absence of early LV diastolic remodeling.9 Early diastolic remodeling was defined as an early postoperative LV diastolic dimension reduction of ⱖ10%. Postoperative cardiac events were defined as rehospitalization for congestive heart failure or cardiovascular-related death. The median duration of follow-up was 2.6 ⫾ 2.0 years. Two-dimensional and Doppler transthoracic echocardiographic examinations with commercially available echocardiographic systems (Sonos 5500 or 7500, Philips Medical Systems, Amsterdam, The Netherlands) were www.ajconline.org
Valvular Heart Disease/Postoperative Remodeling in Aortic Regurgitation
1009
Table 1 Clinical and echocardiographic characteristics according to early remodeling status Variable Age (years) Men Mean systolic pressure (mm Hg) Mean diastolic pressure (mm Hg) New York Heart Association functional class Body surface area Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Stroke volume (ml) Left ventricular end-diastolic volume (ml) Left ventricular end-systolic volume (ml) Left ventricular diameter/wall thickness Left ventricular systolic/wall thickness Systolic wall stress
Early Remodeling (n ⫽ 46)
No Remodeling (n ⫽ 10)
p Value
53 ⫾ 2 35 (76%) 125 ⫾ 3 66 ⫾ 1 3.0 ⫾ 0.3 2.0 ⫾ 0.2 47 ⫾ 10 65 ⫾ 6 45 ⫾ 7 130 ⫾ 27 134 ⫾ 31 82 ⫾ 28 6⫾1 4⫾1 128 ⫾ 32
61 ⫾ 4 8 (80%) 127 ⫾ 8 68 ⫾ 3 3.0 ⫾ 0.4 2.0 ⫾ 0.3 32 ⫾ 6 69 ⫾ 8 56 ⫾ 10 70 ⫾ 12 211 ⫾ 59 162 ⫾ 53 7⫾1 5⫾1 185 ⫾ 42
0.06 0.9 0.8 0.5 0.8 0.9 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.002 ⬍0.001 0.001 ⬍0.001 ⬍0.001
Figure 1. (A) Preoperative SV according to early remodeling status. (B) Preoperative LVEF according to early remodeling status. (C) Preoperative end-diastolic diameter (mm/m2) according to early remodeling status. (D) Preoperative end-systolic diameter (mm/m2) according to early remodeling status.
performed 5 ⫾ 2 days before AVR and 5 ⫾ 2 days (early) and 328 ⫾ 88 days (late) postoperatively. The degree of AR (grade 3⫹ to 4) was determined by analysis of color
flow Doppler. The heart diameter was measured using 2-dimensional echocardiographically guided M-mode, as previously described.10 The LV end-diastolic and end-
1010
The American Journal of Cardiology (www.ajconline.org)
Figure 3. Preoperative, early postoperative, and late postoperative LVEF changes in patients with and without significant early remodeling. *Significant difference (p ⬍0.01) compared to patients with early remodeling.
Results
Figure 2. (A) Preoperative, early postoperative, and late postoperative LV end-diastolic diameter changes in patients with and without significant early remodeling. *Significant difference (p ⬍0.01) compared to patients without early remodeling. (B) Preoperative, early postoperative, and late postoperative left ventricular end-systolic changes in patients with and without significant early remodeling. *Significant difference (p ⬍0.01) compared to patients without early remodeling.
systolic volumes and LVEF were determined using the modified biplane Simpson method. End-systolic wall stress was also calculated, as previously described.11 The SV was calculated using the outflow tract diameter measured at the base of the aortic leaflet in the parasternal long-axis view and the pulsed Doppler velocity integral obtained at the same level in the 5-chamber view.12 Continuous variables are presented as the mean ⫾ SD; discrete variables are presented as the frequency distribution. The mean values were compared using the 2-sample independent and paired t test, and categorical variables were compared using conventional chi-square testing. The correlations are reported with Pearson’s coefficient. All time-toevent distributions were estimated with the Kaplan-Meier methods. All reported time-to-event comparisons were made using the log-rank test.
The etiology of AR was a bicuspid valve in 23 patients (41%), rheumatic/degenerative disease in 16 patients (29%), aortic dilation in 15 (27%), and miscellaneous causes in 2 patients (3%). Thirty-two patients (57%) required concomitant ascending aortic surgery. Of the 56 patients, 46 (82%) had early significant LV remodeling (10% LV diastolic diameter reduction ⱕ2 weeks after AVR) and 10 (18%) had no early significant LV remodeling. No significant difference was found between patients with and without early remodeling in terms of preoperative demographic and clinical data (Table 1). In contrast, the echocardiographic characteristics were all different between the patients with and without early LV remodeling. On simple linear regression analysis, the preoperative SV (r ⫽ 0.44, p ⬍0.001), LVEF (r ⫽ 0.34, p ⬍0.01), and LV end-diastolic dimension (r ⫽ 0.26, p ⫽ 0.06) correlated with early LV diastolic remodeling. The preoperative presence of a SV of ⱖ97 ml had the best performance for the prediction of early LV remodeling compared to the preoperative LVEF and indexed LV diastolic or systolic diameter (Figure 1). The reduction in the LV end-diastolic dimension decreased by 14% (from 65 ⫾ 6 mm to 56 ⫾ 8 mm, p ⬍0.001) early after AVR, with an additional reduction of only 6% (relative to preoperative values) to 52 ⫾ 8 mm late after AVR. Thus, 69% of the overall reduction in end-diastolic dimension observed during the long-term postoperative evaluation occurred within 2 weeks of AVR. A reduction in the LV end-systolic diameter decreased by 9% (from 47 ⫾ 8 mm to 43 ⫾ 9 mm early after AVR, p ⬍0.001) with an additional reduction of 9% to 39 ⫾ 10 mm late after AVR. By definition, patients with significant early remodeling (ⱖ10% LV end-diastolic diameter early after AVR) had more important LV end-diastolic diameter reduction than patients without significant early remodeling (Figure 2). LV endsystolic reduction was also more important in the group of patients with significant early remodeling (Figure 2). In all patients, the LVEF decreased by 22% from 46 ⫾ 11% to 36 ⫾ 11% early after AVR (p ⬍0.001) with an additional
Valvular Heart Disease/Postoperative Remodeling in Aortic Regurgitation
1011
Table 2 Sensitivity and specificity of diagnostic cutoff values for preoperative variables in predicting late postoperative left ventricular ejection fraction ⱖ45% Variable Stroke volume (ml) Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm/m2) Left ventricular end-systolic diameter (mm/m2)
Diagnostic Cutoff Value
Sensitivity (%)
Specificity (%)
AUC
CCOC (%)
97 40 32 21
98% 87% 74% 85%
100% 89% 30% 10%
0.99 0.94 0.47 0.26
98% 88% 66% 71%
AUC ⫽ area under the curve; CCOC ⫽ correctly classified observations using cutoff value.
Figure 4. Kaplan-Meier survival estimation in patients with or without early remodeling.
increase of 11% (relative to the preoperative values) to 51 ⫾ 13% late after AVR. The patients with significant early remodeling also had a decrease in LVEF early after AVR; however, the LVEF increased significantly late after AVR (Figure 3). In patients without significant early remodeling, the LVEF decreased significantly late after AVR compared to the preoperative values (32% vs 26%, p ⫽ 0.03). The preoperative presence of a SV of ⱖ97 ml had the best performance for the prediction of a LVEF of ⱖ45% late after AVR (Table 2). The patients with a preoperative SV ⬍97 ml had a markedly lower cardiac event-free survival at 3 years compared to those with a preoperative SV of ⱖ97 ml (Figure 4). The outcomes for patients with a SV of ⬍97 ml are presented in Table 3. Discussion In the present study, we have shown that the preoperative SV accurately predicts LV remodeling and the outcomes in patients with chronic severe pure AR. An elevated preoperative SV (i.e., ⱖ97 ml) was present in all patients with significant early remodeling after AVR and was a better predictor of LVEF normalization (ⱖ45%) at the long-term follow-up examination compare to the preoperative LVEF or indexed ventricular dimensions. This is the first study to investigate the utility of preoperative SV in this patient population. Our results suggest that improvement in LVEF during long-term follow-up represents the combined result of an early predominant and late remodeling process occurring
after AVR. Patients with normal preoperative LVEF manifested an impressive early decrease in the LV end-diastolic dimension early postoperatively and significant, but less important, late remodeling. In the same line, Bonow et al9 have also suggested that early remodeling after AVR is important because only a few patients with persistent LV end-diastolic dilation 6 to 12 months after AVR will present a subsequent reduction in the ventricular cavity size to normal.9 Our study has demonstrated that data relevant to long-term prognosis can be obtained in all patients by the simple measurement of preoperative SV and early postoperative LV diameter diastolic reduction. Patients with AR and depressed ventricular function are often considered at very high risk of AVR, and some of them are even denied an intervention because they are believed to be at an irreversible stage of deterioration. Our data underline the importance of considering the SV in assessing the potential for recuperation in these patients, both in terms of ventricular function and survival. In our series, the patients manifesting the greatest reduction in LV end-diastolic dimension after AVR were either those with a normal preoperative LVEF or those with a depressed LVEF but an elevated SV. In contrast, among the patients with preoperative LV dysfunction and reduced SV, the magnitude of decrease in LV end-diastolic dimension was less pronounced, and there was also a significant decrease of LVEF late after AVR. Previous studies have shown that patients with severe AR and markedly low LVEF have greater operative and postoperative mortality rates and greater heart failure risks than patients with mild or no decrease in preoperative LVEF.13 Our study included 35 patients (63%) with systolic dysfunction (LVEF of ⱕ50%); 14 (40%) had severe systolic dysfunction (LVEF of ⱕ35%). Eight patients with severe systolic dysfunction had a preoperative SV of ⬍97 ml (70 ⫾ 12 ml), and 7 (88%) with severe systolic dysfunction and SV ⬍97 ml died or were rehospitalized for heart failure during follow-up. In the group of patients with severe systolic dysfunction but elevated SV (i.e., ⱖ97 ml), the LVEF on last follow-up was 52 ⫾ 6% and no mortality or hospitalization was recorded. Chronic AR is both a volume and a pressure overload condition. Initially, hypertrophy and dilation compensate for the overload, and, thus, the LV systolic function remains normal. However, progressive LV dilation is followed by LV systolic dysfunction, presumably without irreversible myocardial dysfunction at first. Eventually, severe and chronic LV volume overload increases the wall stress, leading to deposition of collagen and subendocardial fibrosis,
1012
The American Journal of Cardiology (www.ajconline.org)
Table 3 Postoperative outcomes of patients with preoperative stroke volume (SV) ⬍97 ml Age (years)
SV (ml)
Clinical Outcomes NYHA
37 52 64 69 81 57 63 54 69 68
52 53 63 63 68 73 73 83 83 84
Follow-Up (d) Events
Preoperative
Postoperative
III III III III III III III III III III
III III III III Death II II III III III
HF hospitalization — HF hospitalization HF hospitalization Death from cardiac cause — — HF hospitalization HF hospitalization HF hospitalization
580 128 427 650 12 1670 214 252 164 565
HF ⫽ heart failure; NYHA ⫽ New York Heart Association.
and resulting in progressive LV dysfunction in patients with AR. Invasive and noninvasive techniques have suggested that dP/dt might be the reference standard in the evaluation of LV contractility.14 –17 The prediction of postoperative LV systolic function with Doppler-derived dP/dt in patients with chronic AR has been proposed by Kang et al.4 Doppler-derived dP/dt showed a significant independent correlation with late postoperative LVEF.4 Using a micromanometer catheter for the measurement of LV dP/dt in patients with advanced heart failure, Gold et al18 demonstrated an excellent correlation between SV and LV dP/dt maximum (r ⬎0.98). Many studies have demonstrated the correlation between the SV and other parameters of LV performance. In cardiac resynchronization therapy, the correlation between changes in the wall motion stress index and SV has been validated.19 Furthermore, investigators have demonstrated that the variation in the SV with dobutamine infusion correlated with the contractile reserve and LV remodeling.19 –22 In patients with low-gradient aortic stenosis, the assessment of an increase in SV by dobutamine stress echocardiography has the potential to stratify operative risks.20 Those studies are clearly suggesting a link between the SV and the presence and extent of viable myocardium in patients with heart failure from systolic dysfunction. In a population of 61 patients with chronic severe pure AR, Wahi et al23 have performed exercise echocardiography to evaluate contractile reserve (increment of LVEF after exercise). Their findings indicate that contractile reserve identified by exercise echocardiography was useful in the prediction of progressive deterioration of LV function after AVR. In the same line, Bonow et al1 have demonstrated that patients with severe pure AR who manifested the greatest reduction in LV end-diastolic dimension after AVR were either those with normal preoperative LVEF or those with depressed LVEF but preserved exercise tolerance, presuming the presence of contractile reserve in both populations. Accordingly, the clinical response to treatment such as  blockade or revascularization in patients with LV systolic dysfunction has been shown to be dependent on the presence and extent of viable myocardium.24 In the presence of severe pure AR, the SV depends on the regurgitant volume and also on the capacity of the left
ventricle of “pumping” this volume overload. In these conditions, preservation of an elevated SV despite a severe systolic dysfunction (LVEF ⱕ35%) suggests that sufficient viable myocardium is present to allow eventual favorable remodeling after AVR. In patients with chronic severe pure AR, the left ventricle adapts to a slowly increasing load by undergoing so-called eccentric hypertrophy. The LV chamber size increases in proportion to the regurgitant volume, the LV wall thickness increases proportionally to maintain the wall stress within physiologic limits, and LV function is maintained at normal or near-normal levels. Eventually, however, hypertrophy cannot keep pace with the increasing regurgitant volume, and, with time, dilation of the LV chamber will be out of proportion to its degree of hypertrophy and LV function fails. We suggest that when LVEF decreases, there is a subgroup of patients whose myocardial dysfunction remains reversible, characterized by a “preserved SV.” In these patients, systolic function responds favorably to surgical removal of valvular regurgitation and to the reversal of ventricular dilation. In contrast, when compensatory mechanisms become exhausted, irreversible myocardial dysfunction supervenes in the subgroup of patients “without preserved SV.” The present study had several limitations. The number of patients in the present cohort was relatively small. Also, the duration of follow-up was relatively short, and the additional alteration in LV function (and especially the clinical condition) might have been seen if the cohort had been followed up for a longer period. The retrospective analysis of the data was another shortcoming. Finally, we did not perform any viability study to allow us to confirm our hypothesis on the possible relation between preoperative SV and contractile reserve. 1. Bonow RO, Borer JS, Rosing DR, Henry WL, Pearlman AS, McIntosh CL, Morrow AG, Epstein SE. Preoperative exercise capacity in symptomatic patients with aortic regurgitation as a predictor of postoperative left ventricular function and long-term prognosis. Circulation 1980;62:1280 –1290. 2. Hirshfeld JW, Epstein SE, Roberts AJ, Glancy DL, Morrow AG. Indices predicting long-term survival after valve replacement in pa-
Valvular Heart Disease/Postoperative Remodeling in Aortic Regurgitation
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
tients with aortic regurgitation and patients with aortic stenosis. Circulation 1974;50:1190 –1199. Henry WL, Bonow RO, Borer JS, Ware JH, Kent KM, Redwood DR, McIntosh CL, Morrow AG, Epstein SE. Observations on the optimum time for operative intervention for aortic regurgitation. I. Evaluation of the results of aortic valve replacement in symptomatic patients. Circulation 1980;61:471– 483. Kang HJ, Kim YJ, Sohn DW, Oh BH, Lee MM, Park YB, Choi YS. Prediction of postoperative left ventricular systolic function with Doppler-derived dP/dt in patients with chronic aortic regurgitation. J Am Soc Echocardiogr 2003;16:1111–1115. Hwang MH, Hammermeister KE, Oprian C, Henderson W, Bousvaros G, Wong MJ, Miller DC, Folland E, Sethy G. Preoperative identification of patients likely to have left ventricular dysfunction after aortic valve replacement: participants in the Veterans Administration cooperative study on valvular heart disease. Circulation 1989;80:165–176. Klodas E, Enriquez-Sarano M, Tajik AJ, Mullany CJ, Bayley KR, Seward JB. Aortic regurgitation complicated by extreme left ventricular dilation: long-term outcome after surgical correction. J Am Coll Cardiol 1996;27:670 – 677. Onishi T, Kawai H, Tatsumi K, Kataoka T, Sugiyama D, Tanaka H, Okita Y, Hirata KI. Preoperative systolic strain rate predicts postoperative left ventricular dysfunction in patients with chronic aortic regurgitation. Circ Cardiovasc Img 2010;3:134 –141. Paraskevaidis IA, Kyrzopoulos S, Farmakis D, Parissis J, Tsiapras D, Iliodromitis K, Kremastinos DT. Ventricular long-axis contraction as an earlier predictor of outcome in asymptomatic aortic regurgitation. Am J Cardiol 2007;100:1677–1682. Bonow RO, Dodd JT, Maron BJ, O’Gara PT, White GG, McIntosh CL, Clark RE, Epstein SE. Long-term serial changes in left ventricular function and reversal of ventricular dilatation after valve replacement for chronic aortic regurgitation. Circulation 1988;78:1108 –1120. Tajik AJ, Seward JB, Hagler DJ, Mair DD, Lie JT. Two-dimensional real-time ultrasonic imaging of the heart and great vessels: technique, image orientation, structure identification, and validation. Mayo Clin Proc 1978;53:271–303. Reichek N, Wilson J, St John Sutton M, Plappert TA, Goldberg S, Hirshfeld JW. Noninvasive determination of left ventricular end-systolic stress: validation of the method and initial application. Circulation 1982;65:99 –108. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984;79:425– 431. Chaliki HP, Mohty D, Avierinos JF, Scott CG, Schaff HV, Tajik AJ, Enriquez-Sarano M. Outcomes after aortic valve replacement in patients with severe aortic regurgitation and markedly reduced left ventricular function. Circulation 2002;106:2687–2693. Daniel WG, Hood WP, Siart A, Hausmann D, Nellessen U, Oelert H, Lichtien PR. Chronic aortic regurgitation: reassessment of the prog-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
1013
nostic value of preoperative left ventricular end-systolic dimension and fractional shortening. Circulation 1985;71:669 – 680. Greves J, Rahimtoola SH, McAnultry JH, DeMots H, Clark DG, Greenberg B, Starr A. Preoperative criteria predictive of late survival following valve replacement for severe aortic regurgitation. Am Heart J 1981;101:300 –308. Siemienczuk D, Greenberg B, Morris C, Massie B, Wilson RA, Topic N, Bristow JD, Cheitlin M. Chronic aortic insufficiency: factors associated with progression to aortic valve replacement. Ann Intern Med 1989;110:587–592. Rahimtoola SH. Valve replacement should not be performed in all asymptomatic patients with severe aortic incompetence. J Thorac Cardiovasc Surg 1980;79:163–172. Gold MR, Niazi I, Giudici M, Leman RB, Sturdivant JL, Kim MH, Waggoner AD, Ding J, Arcot-Krishnamurthy S, Daum D, Yu Y. Acute hemodynamic effects of atrial pacing with cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2009;20:894 –900. Sénéchal M, Lancellotti P, Garceau P, Champagne J, Dubois M, Blier L, Molin F, Philippon F, Dumesnil JG, Pierard L, O’Hara G. Usefulness and limitation of dobutamine stress echocardiography to predict acute response to cardiac resynchronization therapy. Echocardiography 2010;27:50 –57. Tribouilloy C, Lévy F, Rusinaru D, Guéret P, Petit-Eisenmann H, Baleynaud S, Jobic Y, Adams C, Lelong B, Pasquet A, Chauvel C, Metz D, Quéré JP, Monin JL. Outcome after aortic valve replacement for low-flow/low-gradient aortic stenosis without contractile reserve on dobutamine stress echocardiography. J Am Coll Cardiol 2009;53: 1865–1873. Qureshi U, Nagueh SF, Afridi I, Vaduganathan P, Blaustein A, Verani MS, Winters WL Jr, Zoghbi WA. Dobutamine echocardiography and quantitative rest-redistribution 201TI tomography in myocardial hibernation: relation of contractile reserve to 201TI uptake and comparative prediction of recovery of function. Circulation 1997;95:626 – 635. Ramahi TM, Longo MD, Cadariu AR, Rohifs K, Slade M, Carolan S, Vallejo E, Wackers FJ. Dobutamine-induced augmentation of left ventricular ejection fraction predicts survival of heart failure patients with severe non-ischemic cardiomyopathy. Eur Heart J 2001;22:849456. Wahi S, Haluska B, Pasquet A, Case C, Rimmerman CM, Marwick TH. Exercise echocardiography predicts development of left ventricular dysfunction in medically and surgically treated patients with asymptomatic severe aortic regurgitation. Heart 2000;84:606 – 614. Eichhorn EI, Grayburn PA, Mayer SA, St John Sutton M, Appleton C, Plehn J, Oh J, Greenberg B, DeMaria A, Frantz R, Krause-Steinrauf H. Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with -blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST). Circulation 2003;108:2336 –2341.