- Email: [email protected]
Effect of Elevated Pulmonary Vascular Resistance on Outcomes After Percutaneous Mitral Valvuloplasty
Effect of Elevated Pulmonary Vascular Resistance on Outcomes After Percutaneous Mitral Valvuloplasty Ignacio Cruz-Gonzalez, MD, PhDa,b,*, Marc J. Semigram, MDa, Ignacio Inglessis-Azuaje, MDa, Maria Sanchez-Ledesma, MDa,b, Javier Martin-Moreiras, MDb, Hani Jneid, MDc, Pablo Rengifo-Moreno, MDa, Roberto J. Cubeddu, MDd, Andrew O. Maree, MDe, Pedro L. Sanchez, MD, PhDf, and Igor F. Palacios, MDa Patients with mitral stenosis with severe pulmonary hypertension constitute a high-risk subset for surgical commissurotomy or valve replacement. The aim of the present study was to examine the effect of elevated pulmonary vascular resistance (PVR) on percutaneous mitral valvuloplasty (PMV) procedural success, short- and long-term clinical outcomes (i.e., mortality, mitral valve surgery, and redo PMV) in 926 patients. Of the 926 patients, 263 (28.4%) had PVR ‡4 Woods units (WU) and 663 (71.6%) had PVR <4 WU. Patients with PVR ‡4 WU were older and more symptomatic and had worse valve morphology for PMV. The patients with PVR ‡4 WU also had lower PMV procedural success than those with PVR <4 WU (78.2% vs 85.6%, p [ 0.006). However, after multivariate adjustment, PVR was no longer an independent predictor of PMV success nor an independent predictor of the combined end point at a median follow-up of 3.2 years. In conclusion, elevated PVR at PMV is not an independent predictor of procedural success or long-term outcomes. Therefore, appropriately selected patients with rheumatic mitral stenosis might benefit from PMV, even in the presence of elevated preprocedural PVR. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:580e584) Patients with mitral stenosis and severe pulmonary hypertension (PH) have a poor prognosis. Mortality among medically treated patients has been reported to be 48% at 1 year.1 Furthermore, PH has been considered a risk factor for poor outcomes in patients undergoing mitral valve replacement. In some studies, operative mortality has ranged from 15% to 31%1,2; however, other studies did not find an influence of PH on mortality.3,4 More recently, several reports have demonstrated improved outcomes in patients with PH undergoing mitral valve replacement. However, the periprocedural mortality has still ranged from 2.3% to 10%.5,6 Percutaneous mitral valvuloplasty (PMV) has been recommended in selected patients with moderate or severe mitral stenosis who are symptomatic.7,8 Previous longitudinal studies have confirmed that PMV in selected patients is a safe and well-tolerated procedure that is associated with short- and long-term benefits.9 However, the efficacy of PMV in patients with severe PH has not been fully elucidated, specifically with regard to the long-term outcomes. The present study was, a Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; bCardiology Division, University Hospital of Salamanca, Salamanca, Spain; cCardiology Division, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; dAventura Hospital and Medical Center, Miami, Florida; eCardiology Division, Waterford Regional Hospital, Waterford, Ireland; and fCardiology Division, Gregorio Marañón University Hospital, Madrid, Spain. Manuscript received February 21, 2013; revised manuscript received and accepted April 3, 2013. See page 583 for disclosure information. *Corresponding author: Tel: (þ34) 68-742-5695; fax: (þ34) 92-3270008. E-mail address: [email protected] (I. Cruz-Gonzalez).
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.04.022
therefore, designed to examine the effect of elevated pulmonary vascular resistance ([PVR] 4 Woods units [WU]) and PH on PMV procedural success and the short- and long-term clinical outcomes in patients with mitral stenosis. Methods Data were collected prospectively for 926 patients who had undergone PMV at the Massachusetts General Hospital (Boston, Massachusetts). The study subjects were divided into 2 groups: patients with PVR 4 WU (320 dyne$s/cm5) and those with PVR <4 WU. We also performed an extra analysis, dividing the population according a mean pulmonary artery pressure of 25 mm Hg at rest, as assessed by right heart catheterization. All participants provided informed consent, and the institutional review board approved the study protocol. PMV was performed using a transseptal antegrade technique, as previously described.10 Both double-balloon and Inoue techniques were used. PVR was calculated as follows: (mean pulmonary artery pressuremean pulmonary capillary wedge pressure)/cardiac index. The cardiac output was determined by thermodilution in all cases, when feasible. If evidence of left-to-right shunting was found or significant tricuspid regurgitation (TR) was present, the cardiac output was calculated according to the assumed Fick principle (oxygen consumption was estimated as 125 ml oxygen/min/m2). The mitral valve area was calculated using the Gorlin formula and 2-dimensional echocardiographic planimetry. The demographic and clinical variables, including age, gender, body surface area, New York Heart Association functional class at presentation, presence of atrial fibrillation, and previous surgical commissurotomy or PMV, were www.ajconline.org
Valvular Heart Disease/Mitral Valvuloplasty and Pulmonary Hypertension
581
Table 1 Baseline characteristics stratified pulmonary vascular resistance (PVR) severity
Table 2 Hemodynamic findings and procedure success stratified by pulmonary vascular resistance (PVR) severity
Variable
Variable
PVR (WU)
p Value
PVR (WU)
<4 (n ¼ 663) 4 (n ¼ 263) Female gender (%) Age (yrs) Atrial fibrillation (%) NYHA class (%) IeII IIIeIV Fluoroscopic calcium grade (%) 0e1 2 Echocardiographic score (%) 8 >8 Tricuspid regurgitation 3 (%) Previous commissurotomy (%)
80.4 53.4 14.9 44.5
87.5 59.8 15.58 58.4
32.3 67.7
14.4 85.6
77.4 22.6
61.1 38.9
73.4 26.6 4.5 15.4
53.8 46.2 11.9 17.5
<4 0.011 0.001 0.001 0.001
0.001
0.001
0.001 0.43
Data are presented as mean SD or %. NYHA ¼ New York Heart Association.
recorded. Additional variables collected included the echocardiographic score,11 pre- and post-PMV degree of mitral regurgitation, and the presence of fluoroscopically visible mitral valve calcification (score 0 to 4).12 TR before PMV was qualitatively assessed from none to severe using echocardiography. The echocardiographic studies were performed in the standard manner, and the TR grade was estimated by integrating the continuous wave Doppler signal and color flow mapping.13 The procedural variables included the interventional technique (double balloon vs Inoue), effective balloon dilating area to body surface area, and pre- and postPMV hemodynamic values (mean pulmonary artery and left atrial pressures, mean mitral valve pressure gradient, mean pulmonary artery pressure, PVR, cardiac output, and calculated mitral valve area). Procedure-related complications included death, mitral valve surgery, pericardial tamponade, stroke, and post-PMV mitral regurgitation 3. Procedurerelated death was defined as in-hospital mortality directly related to PMV. Successful PMV was defined as a post-PMV mitral valve area of 1.5 cm2 or a 50% increase in valve area with post-PMV mitral regurgitation <3.14 The prespecified outcomes, including mortality, mitral valve surgery (mitral valve replacement), and redo PMV, were recorded at follow-up. A combine end point, including mortality, mitral valve replacement, and redo PMV, was defined, and each component of the combine end point was analyzed separately. Continuous and categorical variables are expressed as the mean SD and percentages, respectively. The follow-up time is reported as the median and interquartile range. Student’ t test and the chi-square test, or Fisher exact test when necessary, were used to compare the continuous and categorical variables, respectively. Multivariate logistic regression analyses were performed to determine whether an elevated PVR and mean pulmonary pressure were independently associated with PMV success (including the covariates gender, age, echocardiographic score, mitral valve area before PMV, mitral regurgitation before PMV, and previous
p Value 4
CO (L/min) Before PMV 4.2 1.07 3.4 0.9 After PMV 4.7 1.25 4.04 1.14 MG (mm Hg) Before PVM 13.62 5.68 15.02 5.81 After PMV 5.4 2.7 6.25 3.0 MVA (cm2) Before PMV 0.98 0.27 0.78 0.25 After PMV 1.96 0.66 1.63 0.61 PA (mm Hg) Before PMV 31.29 8.7 49.17 13.59 After PMV 26.30 8.27 38.24 12.55 Post-PMV MR grade 3þ (%) 8 10 PMV success* (%) 85.6 78.2
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.31 0.006
Data are presented as mean SD or %. CO ¼ cardiac output; MG ¼ transmitral gradient; MR ¼ mitral regurgitation; MVA ¼ mitral valve area; PA ¼ pulmonary artery pressure. * Procedural success was defined as MR <3 and MVA 1.5 cm2 or a 50% increase in MVA. Table 3 In-hospital complications grouped by pulmonary vascular resistance (PVR) severity Variable
PVR (WU) <4
Death (in hospital) Not procedure related Procedure related Total Tamponade Mitral valve replacement In-hospital (total) Emergent Atrioventricular block Stroke
p Value 4
3 3 6 3
(0.5) (0.5) (0.9) (0.5)
7 3 10 3
(2.7) (1) (3.8) (1)
0.003 0.241 0.002 0.241
21 8 4 11
(3.2) (1.2) (0.6) (1.7)
8 4 1 3
(3) (1.5) (0.4) (1.1)
0.91 0.70 0.67 0.55
Data are presented as n (%).
comissurotomy8). Kaplan-Meier estimates were used to determine the total survival and event-free survival (survival with freedom from death, mitral valve replacement, or redoPMV) for both groups and were compared using the log-rank test. Cox proportional hazards regression models were used to test the association between an elevated PVR and long-term outcomes (including the covariates age, echocardiographic score, mitral regurgitation after PMV of 3, mitral regurgitation before PMV of 2, and previous comissurotomy8). TR was also tested as an independent predictor of adverse longterm outcomes using the same covariates.8 All analyses were performed using the Statistical Package for Social Sciences, version 17.0, for Windows (SPSS, Chicago, Illinois). p Values <0.05 were considered statistically significant for all tests. Results The study population consisted of 926 consecutive patients who had undergone PMV at our institution. Of
582
The American Journal of Cardiology (www.ajconline.org)
Table 4 Cox proportional hazards regression for long-term combined end point (death, mitral valve replacement, redo PMV) Variable Mitral regurgitation grade 3 after PMV Mitral regurgitation grade 2 before PMV Age Pulmonary vascular resistance 4 WU Previous commissurotomy Echocardiographic score
Hazard Ratio 95% Confidence p Value Interval 3.54
2.66e4.77
<0.001
1.47
1.02e2.12
0.039
1.013 1.05
1.005e1.021 0.84e1.32
<0.001 0.61
1.53 1.162
1.19e1.96 1.099e1.230
0.01 <0.001
those, 663 (71.6%) had PVR <4 WU and 263 (28.4%) had PVR 4 WU. The baseline characteristics of the study groups are listed in Table 1. The hemodynamic findings in both groups before and after PMV are listed in Table 2. The hemodynamic parameters differed significantly between the 2 groups. The procedural success rate in patients with PVR 4 WU was significantly lower than in those with PVR <4 WU. However, on multivariate analysis, PVR 4 WU was not an independent predictor of PMV success (odds ratio 1.018, 95% confidence interval 0.70 to 1.48, p ¼ 0.925). Also, a mean pulmonary artery pressure of 25 mm Hg was not an independent predictor of PMV success (data shown in Supplementary Materials). The incidence of adverse events is listed in Table 3. The incidence of in-hospital adverse events did not differ significantly between the 2 groups, with the exception of higher nonprocedure-related deaths in patients with PVR 4 WU. Long-term clinical outcomes were available for 92% of the patients at a median follow-up of 3.2 years (interquartile range 1.0 to 5.9). A lower mortality for patients with PVR <4 WU compared with patients with PVR 4 during follow-up (logrank test, p ¼ 0.003) was recorded. No differences were found in the need for mitral valve replacement or redo-PMV between patients with PVR 4 WU and PVR <4 WU (logrank test, p ¼ 0.39 and p ¼ 0.89, respectively). Patients with PVR 4 WU experienced lower event-free survival (death, mitral valve replacement, redo PMV) than those with PVR <4 WU (p ¼ 0.003). However, in the Cox regression analysis, PVR 4 WU was no longer an independent predictor of event-free survival (hazards ratio 1.05, 95% confidence interval 0.84 to 1.32, p ¼ 0.61; Table 4). Also, a mean pulmonary artery pressure of 25 mm Hg was not an independent predictor of event-free survival (data shown in Supplementary Materials). Moderate and severe TR was observed in 23% and 6.4% of patients before PMV, respectively. Severe TR was an independent predictor of event-free survival (death, mitral valve replacement, redo PMV; hazard ratio 2.78, 95% confidence interval 1.87 to 4.13, p <0.001). Discussion Patients with mitral stenosis and severe PH have a poor prognosis.1 PH has long been considered a risk factor for poor outcomes in patients undergoing mitral valve replacement,1,2 although this topic has remained controversial because some
conflicting data have been reported.3,4 The present report has demonstrated that an elevated PVR at PMV does not independently determine procedural success or long-term eventfree survival and should not be regarded as a contraindication for PMV. Our results support the role of PMV in the treatment of appropriately selected patients with mitral stenosis and PVR. Chronic PH in patients with mitral stenosis has been associated with an elevated PVR, impedance, and highamplitude arterial wave reflections.15 At least 3 mechanisms contribute to PH in mitral valve disease: passive transmission of elevated left atrial pressure, reactive pulmonary arteriolar vasoconstriction, and morphologic changes in the pulmonary vasculature. Because of the latter 2 mechanisms, the increase in pulmonary artery pressure is often disproportionate to the left atrial hypertension, resulting in a significant increase in PVR.16,17 The reactive component is known to decrease immediately after mitral valve surgery; furthermore, it has been shown that pulmonary vasoconstriction can be alleviated in the short term using inhaled nitric oxide18 and might have short-term clinical benefits.18 However, medial hypertrophy or intimal fibrosis in the pulmonary arterioles might or might not regress after mitral valve replacement19; thus, PH can persist or recur. It has been shown that the PVR can fall after mitral valve replacement20; however, the data are limited regarding PVR regression after PMV. The PVR can remain elevated despite the relief of mitral stenosis,21,22 but others have shown a reduction in PVR either immediately after PMV17,23 or a few months later.24 It might be that the passive increase in pulmonary pressure regresses immediately after PMV but that regression of pulmonary pressure secondary to an increase in pulmonary artery resistance takes longer. PMV has become the procedure of choice for many patients with mitral stenosis.7 Follow-up studies have indicated that PMV is safe and well tolerated and associated with good short- and long-term outcomes.8,9 However, PMV success and the subsequent outcomes depend on appropriate patient selection. Despite the existence of several studies that assessed the role of preprocedural variables in determining the PMV outcome,8 only a few studies17,21,23,25 have evaluated the effect of elevated PVR on procedural success and the short- or long-term outcome. Large-scale studies of patients undergoing PMV with elevated PVR with long-term followup data are lacking. In the present study, patients with elevated PVR at PMV were older, more symptomatic, and had less favorable valve morphology. Accordingly, the rate of PMV success was lower. However, on multivariate analysis, PVR was not an independent predictor of PMV success, supporting a role for PMV in patients with mitral stenosis and elevated PVR. Furthermore, elevated PVR did not determine the in-hospital event rate, except in the case of nonprocedure-related death. Finally, elevated PVR was associated with lower long-term event-free survival but did not remain significant on multivariate analysis. It is intuitive to assume that the presence of severe PH reflects more severe or long-standing mitral stenosis and will be associated with clinical and morphologic features that adversely affect the hemodynamic outcome after PMV. However, the immediate and long-term outcomes for this group of patients can be comparable to those with lower PH. From our results, we suggest that
Valvular Heart Disease/Mitral Valvuloplasty and Pulmonary Hypertension
PMV remains a treatment option for appropriately selected patients with mitral stenosis, despite the presence of elevated PVR. This strategy has been associated with lower mortality compared with previously reported surgical mitral valve replacement data.5,6 TR is frequently present in patients with mitral valve disease, and >1/3 of patients with mitral stenosis have at least moderate TR.26 The pathogenesis of TR in patients with mitral valve disease is complex and multifactorial. Longstanding PH can lead to right ventricular dysfunction and remodeling and thereby TR. PH can decrease after PMV or mitral valve surgery; however, our group has previously reported that in many patients, TR has not resolved after PMV.27 Furthermore, we have previously reported that severe TR is an independent risk factor for adverse outcomes in patients undergoing PMV.13 Therefore, it has been suggested that tricuspid valve repair combined with mitral valve surgery should be considered preferentially in patients with severe mitral stenosis and severe TR, especially if atrial fibrillation or an enlarged right ventricle is present.28 We again identified TR as an independent predictor of adverse immediate and long-term outcomes. Thus, patients with mitral stenosis and severe TR should be considered high-risk patients for PMV, irrespective of the presence of PH. The present study was a retrospective, single-center study. The findings of the present study, just as with any observational cohort, might not necessarily be generalizable to all patients with mitral stenosis and elevated PVR who undergo PMV. Follow-up echocardiographic data could not be collected for a proportion of patients owing to the referral nature of our clinical practice and therefore were not included. The vasoreactivity of the PH and the postprocedural PVR data were not available. We also acknowledge that the lack of follow-up data for pulmonary dynamics by catheterization after PMV was a limitation. Nevertheless, our study has provided data from a real-world cohort of unselected patients and is the largest study to date of the effect of PVR on outcomes after PMV. Acknowledgment: Dr. Cruz-Gonzalez acknowledges the support of the Spanish Society of Cardiology and Medtronic Iberia S.A. Disclosures The authors have no conflicts of interest to disclose. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2013.04.022. 1. Ward C, Hancock BW. Extreme pulmonary hypertension caused by mitral valve disease: natural history and results of surgery. Br Heart J 1975;37:74e78. 2. Chaffin JS, Daggett WM. Mitral valve replacement: a nine-year followup of risks and survivals. Ann Thorac Surg 1979;27:312e319. 3. Scott WC, Miller DC, Haverich A, Mitchell RS, Oyer PE, Stinson EB, Jamieson SW, Baldwin JC, Shumway NE. Operative risk of mitral valve replacement: discriminant analysis of 1329 procedures. Circulation 1985;72:II108eII119.
583
4. Christakis GT, Kormos RL, Weisel RD, Fremes SE, Tong CP, Herst JA, Schwartz L, Mickleborough LL, Scully HE, Goldman BS. Morbidity and mortality in mitral valve surgery. Circulation 1985;72:II120eII128. 5. Cesnjevar RA, Feyrer R, Walther F, Mahmoud FO, Lindemann Y, von der Emde J. High-risk mitral valve replacement in severe pulmonary hypertension—30 years experience. Eur J Cardiothorac Surg 1998;13: 344e351 [discussion 351e352]. 6. Jegaden O, Rossi R, Delahaye F, Montagna P, Delaye J, Delahaye JP, Mikaeloff P. Mitral valve replacement in severe pulmonary hypertension. Long-term results. Arch Mal Coeur Vaiss 1991;84:1297e1301. 7. Bonow RO, Carabello BA, Kanu C, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84ee231. 8. Palacios IF, Sanchez PL, Harrell LC, Weyman AE, Block PC. Which patients benefit from percutaneous mitral balloon valvuloplasty? Prevalvuloplasty and postvalvuloplasty variables that predict long-term outcome. Circulation 2002;105:1465e1471. 9. Tuzcu EM, Block PC, Griffin BP, Newell JB, Palacios IF. Immediate and long-term outcome of percutaneous mitral valvotomy in patients 65 years and older. Circulation 1992;85:963e971. 10. Palacios I, Block PC, Brandi S, Blanco P, Casal H, Pulido JI, Munoz S, D’Empaire G, Ortega MA, Jacobs M, Vlahakes G. Percutaneous balloon valvotomy for patients with severe mitral stenosis. Circulation 1987;75:778e784. 11. Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J 1988;60:299e308. 12. Tuzcu EM, Block PC, Griffin B, Dinsmore R, Newell JB, Palacios IF. Percutaneous mitral balloon valvotomy in patients with calcific mitral stenosis: immediate and long-term outcome. J Am Coll Cardiol 1994;23: 1604e1609. 13. Sagie A, Schwammenthal E, Newell JB, Harrell L, Joziatis TB, Weyman AE, Levine RA, Palacios IF. Significant tricuspid regurgitation is a marker for adverse outcome in patients undergoing percutaneous balloon mitral valvuloplasty. J Am Coll Cardiol 1994;24: 696e702. 14. Block PC, Tuzcu EM, Palacios IF. Percutaneous mitral balloon valvotomy. Cardiol Clin 1991;9:271e287. 15. Kussmaul WG III, Altschuler JA, Herrmann HC, Laskey WK. Effects of pacing tachycardia and balloon valvuloplasty on pulmonary artery impedance and hydraulic power in mitral stenosis. Circulation 1992;86:1770e1779. 16. Levine MJ, Weinstein JS, Diver DJ, Berman AD, Wyman RM, Cunningham MJ, Safian RD, Grossman W, McKay RG. Progressive improvement in pulmonary vascular resistance after percutaneous mitral valvuloplasty. Circulation 1989;79:1061e1067. 17. Fawzy ME, Osman A, Nambiar V, Nowayhed O, El DA, Badr A, Canver CC. Immediate and long-term results of mitral balloon valvuloplasty in patients with severe pulmonary hypertension. J Heart Valve Dis 2008;17:485e491. 18. Fernandes JL, Sampaio RO, Brandao CM, Accorsi TA, Cardoso LF, Spina GS, Tarasoutchi F, Pomerantzeff P, Auler JO Jr, Grinberg M. Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery. Am J Cardiol 2011;107:1040e1045. 19. Foltz BD, Hessel EA II, Ivey TD. The early course of pulmonary artery hypertension in patients undergoing mitral valve replacement with cardioplegic arrest. J Thorac Cardiovasc Surg 1984;88:238e247. 20. Zener JC, Hancock EW, Shumway NE, Harrison DC. Regression of extreme pulmonary hypertension after mitral valve surgery. Am J Cardiol 1972;30:820e826. 21. Maoqin S, Guoxiang H, Zhiyuan S, Luxiang C, Houyuan H, Liangyi S, Ling Z, Guoqiang Z. The clinical and hemodynamic results of mitral
584
22. 23.
24.
25.
The American Journal of Cardiology (www.ajconline.org) balloon valvuloplasty for patients with mitral stenosis complicated by severe pulmonary hypertension. Eur J Intern Med 2005;16:413e418. Block PC, Palacios IF. Pulmonary vascular dynamics after percutaneous mitral valvotomy. J Thorac Cardiovasc Surg 1988;96:39e43. Alfonso F, Macaya C, Hernandez R, Banuelos C, Iniguez A, Goicolea J, Fernandez-Ortiz A, Zamorano J, Zarco P. Percutaneous mitral valvuloplasty with severe pulmonary artery hypertension. Am J Cardiol 1993;72:325e330. Dev V, Shrivastava S. Time course of changes in pulmonary vascular resistance and the mechanism of regression of pulmonary arterial hypertension after balloon mitral valvuloplasty. Am J Cardiol 1991;67: 439e442. Fawzy ME, Mimish L, Sivanandam V, Lingamanaicker J, Patel A, Khan B, Duran CM. Immediate and long-term effect of mitral balloon
valvotomy on severe pulmonary hypertension in patients with mitral stenosis. Am Heart J 1996;131:89e93. 26. Sagie A, Freitas N, Chen MH, Marshall JE, Weyman AE, Levine RA. Echocardiographic assessment of mitral stenosis and its associated valvular lesions in 205 patients and lack of association with mitral valve prolapse. J Am Soc Echocardiogr 1997;10:141e148. 27. Sagie A, Schwammenthal E, Palacios IF, King ME, Leavitt M, Freitas N, Weyman AE, Levine RA. Significant tricuspid regurgitation does not resolve after percutaneous balloon mitral valvotomy. J Thorac Cardiovasc Surg 1994;108:727e735. 28. Song H, Kang DH, Kim JH, Park KM, Song JM, Choi KJ, Hong MK, Chung CH, Song JK, Lee JW, Park SW, Park SJ. Percutaneous mitral valvuloplasty versus surgical treatment in mitral stenosis with severe tricuspid regurgitation. Circulation 2007;116:I246eI250.
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.04.022
therefore, designed to examine the effect of elevated pulmonary vascular resistance ([PVR] 4 Woods units [WU]) and PH on PMV procedural success and the short- and long-term clinical outcomes in patients with mitral stenosis. Methods Data were collected prospectively for 926 patients who had undergone PMV at the Massachusetts General Hospital (Boston, Massachusetts). The study subjects were divided into 2 groups: patients with PVR 4 WU (320 dyne$s/cm5) and those with PVR <4 WU. We also performed an extra analysis, dividing the population according a mean pulmonary artery pressure of 25 mm Hg at rest, as assessed by right heart catheterization. All participants provided informed consent, and the institutional review board approved the study protocol. PMV was performed using a transseptal antegrade technique, as previously described.10 Both double-balloon and Inoue techniques were used. PVR was calculated as follows: (mean pulmonary artery pressuremean pulmonary capillary wedge pressure)/cardiac index. The cardiac output was determined by thermodilution in all cases, when feasible. If evidence of left-to-right shunting was found or significant tricuspid regurgitation (TR) was present, the cardiac output was calculated according to the assumed Fick principle (oxygen consumption was estimated as 125 ml oxygen/min/m2). The mitral valve area was calculated using the Gorlin formula and 2-dimensional echocardiographic planimetry. The demographic and clinical variables, including age, gender, body surface area, New York Heart Association functional class at presentation, presence of atrial fibrillation, and previous surgical commissurotomy or PMV, were www.ajconline.org
Valvular Heart Disease/Mitral Valvuloplasty and Pulmonary Hypertension
581
Table 1 Baseline characteristics stratified pulmonary vascular resistance (PVR) severity
Table 2 Hemodynamic findings and procedure success stratified by pulmonary vascular resistance (PVR) severity
Variable
Variable
PVR (WU)
p Value
PVR (WU)
<4 (n ¼ 663) 4 (n ¼ 263) Female gender (%) Age (yrs) Atrial fibrillation (%) NYHA class (%) IeII IIIeIV Fluoroscopic calcium grade (%) 0e1 2 Echocardiographic score (%) 8 >8 Tricuspid regurgitation 3 (%) Previous commissurotomy (%)
80.4 53.4 14.9 44.5
87.5 59.8 15.58 58.4
32.3 67.7
14.4 85.6
77.4 22.6
61.1 38.9
73.4 26.6 4.5 15.4
53.8 46.2 11.9 17.5
<4 0.011 0.001 0.001 0.001
0.001
0.001
0.001 0.43
Data are presented as mean SD or %. NYHA ¼ New York Heart Association.
recorded. Additional variables collected included the echocardiographic score,11 pre- and post-PMV degree of mitral regurgitation, and the presence of fluoroscopically visible mitral valve calcification (score 0 to 4).12 TR before PMV was qualitatively assessed from none to severe using echocardiography. The echocardiographic studies were performed in the standard manner, and the TR grade was estimated by integrating the continuous wave Doppler signal and color flow mapping.13 The procedural variables included the interventional technique (double balloon vs Inoue), effective balloon dilating area to body surface area, and pre- and postPMV hemodynamic values (mean pulmonary artery and left atrial pressures, mean mitral valve pressure gradient, mean pulmonary artery pressure, PVR, cardiac output, and calculated mitral valve area). Procedure-related complications included death, mitral valve surgery, pericardial tamponade, stroke, and post-PMV mitral regurgitation 3. Procedurerelated death was defined as in-hospital mortality directly related to PMV. Successful PMV was defined as a post-PMV mitral valve area of 1.5 cm2 or a 50% increase in valve area with post-PMV mitral regurgitation <3.14 The prespecified outcomes, including mortality, mitral valve surgery (mitral valve replacement), and redo PMV, were recorded at follow-up. A combine end point, including mortality, mitral valve replacement, and redo PMV, was defined, and each component of the combine end point was analyzed separately. Continuous and categorical variables are expressed as the mean SD and percentages, respectively. The follow-up time is reported as the median and interquartile range. Student’ t test and the chi-square test, or Fisher exact test when necessary, were used to compare the continuous and categorical variables, respectively. Multivariate logistic regression analyses were performed to determine whether an elevated PVR and mean pulmonary pressure were independently associated with PMV success (including the covariates gender, age, echocardiographic score, mitral valve area before PMV, mitral regurgitation before PMV, and previous
p Value 4
CO (L/min) Before PMV 4.2 1.07 3.4 0.9 After PMV 4.7 1.25 4.04 1.14 MG (mm Hg) Before PVM 13.62 5.68 15.02 5.81 After PMV 5.4 2.7 6.25 3.0 MVA (cm2) Before PMV 0.98 0.27 0.78 0.25 After PMV 1.96 0.66 1.63 0.61 PA (mm Hg) Before PMV 31.29 8.7 49.17 13.59 After PMV 26.30 8.27 38.24 12.55 Post-PMV MR grade 3þ (%) 8 10 PMV success* (%) 85.6 78.2
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.31 0.006
Data are presented as mean SD or %. CO ¼ cardiac output; MG ¼ transmitral gradient; MR ¼ mitral regurgitation; MVA ¼ mitral valve area; PA ¼ pulmonary artery pressure. * Procedural success was defined as MR <3 and MVA 1.5 cm2 or a 50% increase in MVA. Table 3 In-hospital complications grouped by pulmonary vascular resistance (PVR) severity Variable
PVR (WU) <4
Death (in hospital) Not procedure related Procedure related Total Tamponade Mitral valve replacement In-hospital (total) Emergent Atrioventricular block Stroke
p Value 4
3 3 6 3
(0.5) (0.5) (0.9) (0.5)
7 3 10 3
(2.7) (1) (3.8) (1)
0.003 0.241 0.002 0.241
21 8 4 11
(3.2) (1.2) (0.6) (1.7)
8 4 1 3
(3) (1.5) (0.4) (1.1)
0.91 0.70 0.67 0.55
Data are presented as n (%).
comissurotomy8). Kaplan-Meier estimates were used to determine the total survival and event-free survival (survival with freedom from death, mitral valve replacement, or redoPMV) for both groups and were compared using the log-rank test. Cox proportional hazards regression models were used to test the association between an elevated PVR and long-term outcomes (including the covariates age, echocardiographic score, mitral regurgitation after PMV of 3, mitral regurgitation before PMV of 2, and previous comissurotomy8). TR was also tested as an independent predictor of adverse longterm outcomes using the same covariates.8 All analyses were performed using the Statistical Package for Social Sciences, version 17.0, for Windows (SPSS, Chicago, Illinois). p Values <0.05 were considered statistically significant for all tests. Results The study population consisted of 926 consecutive patients who had undergone PMV at our institution. Of
582
The American Journal of Cardiology (www.ajconline.org)
Table 4 Cox proportional hazards regression for long-term combined end point (death, mitral valve replacement, redo PMV) Variable Mitral regurgitation grade 3 after PMV Mitral regurgitation grade 2 before PMV Age Pulmonary vascular resistance 4 WU Previous commissurotomy Echocardiographic score
Hazard Ratio 95% Confidence p Value Interval 3.54
2.66e4.77
<0.001
1.47
1.02e2.12
0.039
1.013 1.05
1.005e1.021 0.84e1.32
<0.001 0.61
1.53 1.162
1.19e1.96 1.099e1.230
0.01 <0.001
those, 663 (71.6%) had PVR <4 WU and 263 (28.4%) had PVR 4 WU. The baseline characteristics of the study groups are listed in Table 1. The hemodynamic findings in both groups before and after PMV are listed in Table 2. The hemodynamic parameters differed significantly between the 2 groups. The procedural success rate in patients with PVR 4 WU was significantly lower than in those with PVR <4 WU. However, on multivariate analysis, PVR 4 WU was not an independent predictor of PMV success (odds ratio 1.018, 95% confidence interval 0.70 to 1.48, p ¼ 0.925). Also, a mean pulmonary artery pressure of 25 mm Hg was not an independent predictor of PMV success (data shown in Supplementary Materials). The incidence of adverse events is listed in Table 3. The incidence of in-hospital adverse events did not differ significantly between the 2 groups, with the exception of higher nonprocedure-related deaths in patients with PVR 4 WU. Long-term clinical outcomes were available for 92% of the patients at a median follow-up of 3.2 years (interquartile range 1.0 to 5.9). A lower mortality for patients with PVR <4 WU compared with patients with PVR 4 during follow-up (logrank test, p ¼ 0.003) was recorded. No differences were found in the need for mitral valve replacement or redo-PMV between patients with PVR 4 WU and PVR <4 WU (logrank test, p ¼ 0.39 and p ¼ 0.89, respectively). Patients with PVR 4 WU experienced lower event-free survival (death, mitral valve replacement, redo PMV) than those with PVR <4 WU (p ¼ 0.003). However, in the Cox regression analysis, PVR 4 WU was no longer an independent predictor of event-free survival (hazards ratio 1.05, 95% confidence interval 0.84 to 1.32, p ¼ 0.61; Table 4). Also, a mean pulmonary artery pressure of 25 mm Hg was not an independent predictor of event-free survival (data shown in Supplementary Materials). Moderate and severe TR was observed in 23% and 6.4% of patients before PMV, respectively. Severe TR was an independent predictor of event-free survival (death, mitral valve replacement, redo PMV; hazard ratio 2.78, 95% confidence interval 1.87 to 4.13, p <0.001). Discussion Patients with mitral stenosis and severe PH have a poor prognosis.1 PH has long been considered a risk factor for poor outcomes in patients undergoing mitral valve replacement,1,2 although this topic has remained controversial because some
conflicting data have been reported.3,4 The present report has demonstrated that an elevated PVR at PMV does not independently determine procedural success or long-term eventfree survival and should not be regarded as a contraindication for PMV. Our results support the role of PMV in the treatment of appropriately selected patients with mitral stenosis and PVR. Chronic PH in patients with mitral stenosis has been associated with an elevated PVR, impedance, and highamplitude arterial wave reflections.15 At least 3 mechanisms contribute to PH in mitral valve disease: passive transmission of elevated left atrial pressure, reactive pulmonary arteriolar vasoconstriction, and morphologic changes in the pulmonary vasculature. Because of the latter 2 mechanisms, the increase in pulmonary artery pressure is often disproportionate to the left atrial hypertension, resulting in a significant increase in PVR.16,17 The reactive component is known to decrease immediately after mitral valve surgery; furthermore, it has been shown that pulmonary vasoconstriction can be alleviated in the short term using inhaled nitric oxide18 and might have short-term clinical benefits.18 However, medial hypertrophy or intimal fibrosis in the pulmonary arterioles might or might not regress after mitral valve replacement19; thus, PH can persist or recur. It has been shown that the PVR can fall after mitral valve replacement20; however, the data are limited regarding PVR regression after PMV. The PVR can remain elevated despite the relief of mitral stenosis,21,22 but others have shown a reduction in PVR either immediately after PMV17,23 or a few months later.24 It might be that the passive increase in pulmonary pressure regresses immediately after PMV but that regression of pulmonary pressure secondary to an increase in pulmonary artery resistance takes longer. PMV has become the procedure of choice for many patients with mitral stenosis.7 Follow-up studies have indicated that PMV is safe and well tolerated and associated with good short- and long-term outcomes.8,9 However, PMV success and the subsequent outcomes depend on appropriate patient selection. Despite the existence of several studies that assessed the role of preprocedural variables in determining the PMV outcome,8 only a few studies17,21,23,25 have evaluated the effect of elevated PVR on procedural success and the short- or long-term outcome. Large-scale studies of patients undergoing PMV with elevated PVR with long-term followup data are lacking. In the present study, patients with elevated PVR at PMV were older, more symptomatic, and had less favorable valve morphology. Accordingly, the rate of PMV success was lower. However, on multivariate analysis, PVR was not an independent predictor of PMV success, supporting a role for PMV in patients with mitral stenosis and elevated PVR. Furthermore, elevated PVR did not determine the in-hospital event rate, except in the case of nonprocedure-related death. Finally, elevated PVR was associated with lower long-term event-free survival but did not remain significant on multivariate analysis. It is intuitive to assume that the presence of severe PH reflects more severe or long-standing mitral stenosis and will be associated with clinical and morphologic features that adversely affect the hemodynamic outcome after PMV. However, the immediate and long-term outcomes for this group of patients can be comparable to those with lower PH. From our results, we suggest that
Valvular Heart Disease/Mitral Valvuloplasty and Pulmonary Hypertension
PMV remains a treatment option for appropriately selected patients with mitral stenosis, despite the presence of elevated PVR. This strategy has been associated with lower mortality compared with previously reported surgical mitral valve replacement data.5,6 TR is frequently present in patients with mitral valve disease, and >1/3 of patients with mitral stenosis have at least moderate TR.26 The pathogenesis of TR in patients with mitral valve disease is complex and multifactorial. Longstanding PH can lead to right ventricular dysfunction and remodeling and thereby TR. PH can decrease after PMV or mitral valve surgery; however, our group has previously reported that in many patients, TR has not resolved after PMV.27 Furthermore, we have previously reported that severe TR is an independent risk factor for adverse outcomes in patients undergoing PMV.13 Therefore, it has been suggested that tricuspid valve repair combined with mitral valve surgery should be considered preferentially in patients with severe mitral stenosis and severe TR, especially if atrial fibrillation or an enlarged right ventricle is present.28 We again identified TR as an independent predictor of adverse immediate and long-term outcomes. Thus, patients with mitral stenosis and severe TR should be considered high-risk patients for PMV, irrespective of the presence of PH. The present study was a retrospective, single-center study. The findings of the present study, just as with any observational cohort, might not necessarily be generalizable to all patients with mitral stenosis and elevated PVR who undergo PMV. Follow-up echocardiographic data could not be collected for a proportion of patients owing to the referral nature of our clinical practice and therefore were not included. The vasoreactivity of the PH and the postprocedural PVR data were not available. We also acknowledge that the lack of follow-up data for pulmonary dynamics by catheterization after PMV was a limitation. Nevertheless, our study has provided data from a real-world cohort of unselected patients and is the largest study to date of the effect of PVR on outcomes after PMV. Acknowledgment: Dr. Cruz-Gonzalez acknowledges the support of the Spanish Society of Cardiology and Medtronic Iberia S.A. Disclosures The authors have no conflicts of interest to disclose. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2013.04.022. 1. Ward C, Hancock BW. Extreme pulmonary hypertension caused by mitral valve disease: natural history and results of surgery. Br Heart J 1975;37:74e78. 2. Chaffin JS, Daggett WM. Mitral valve replacement: a nine-year followup of risks and survivals. Ann Thorac Surg 1979;27:312e319. 3. Scott WC, Miller DC, Haverich A, Mitchell RS, Oyer PE, Stinson EB, Jamieson SW, Baldwin JC, Shumway NE. Operative risk of mitral valve replacement: discriminant analysis of 1329 procedures. Circulation 1985;72:II108eII119.
583
4. Christakis GT, Kormos RL, Weisel RD, Fremes SE, Tong CP, Herst JA, Schwartz L, Mickleborough LL, Scully HE, Goldman BS. Morbidity and mortality in mitral valve surgery. Circulation 1985;72:II120eII128. 5. Cesnjevar RA, Feyrer R, Walther F, Mahmoud FO, Lindemann Y, von der Emde J. High-risk mitral valve replacement in severe pulmonary hypertension—30 years experience. Eur J Cardiothorac Surg 1998;13: 344e351 [discussion 351e352]. 6. Jegaden O, Rossi R, Delahaye F, Montagna P, Delaye J, Delahaye JP, Mikaeloff P. Mitral valve replacement in severe pulmonary hypertension. Long-term results. Arch Mal Coeur Vaiss 1991;84:1297e1301. 7. Bonow RO, Carabello BA, Kanu C, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84ee231. 8. Palacios IF, Sanchez PL, Harrell LC, Weyman AE, Block PC. Which patients benefit from percutaneous mitral balloon valvuloplasty? Prevalvuloplasty and postvalvuloplasty variables that predict long-term outcome. Circulation 2002;105:1465e1471. 9. Tuzcu EM, Block PC, Griffin BP, Newell JB, Palacios IF. Immediate and long-term outcome of percutaneous mitral valvotomy in patients 65 years and older. Circulation 1992;85:963e971. 10. Palacios I, Block PC, Brandi S, Blanco P, Casal H, Pulido JI, Munoz S, D’Empaire G, Ortega MA, Jacobs M, Vlahakes G. Percutaneous balloon valvotomy for patients with severe mitral stenosis. Circulation 1987;75:778e784. 11. Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J 1988;60:299e308. 12. Tuzcu EM, Block PC, Griffin B, Dinsmore R, Newell JB, Palacios IF. Percutaneous mitral balloon valvotomy in patients with calcific mitral stenosis: immediate and long-term outcome. J Am Coll Cardiol 1994;23: 1604e1609. 13. Sagie A, Schwammenthal E, Newell JB, Harrell L, Joziatis TB, Weyman AE, Levine RA, Palacios IF. Significant tricuspid regurgitation is a marker for adverse outcome in patients undergoing percutaneous balloon mitral valvuloplasty. J Am Coll Cardiol 1994;24: 696e702. 14. Block PC, Tuzcu EM, Palacios IF. Percutaneous mitral balloon valvotomy. Cardiol Clin 1991;9:271e287. 15. Kussmaul WG III, Altschuler JA, Herrmann HC, Laskey WK. Effects of pacing tachycardia and balloon valvuloplasty on pulmonary artery impedance and hydraulic power in mitral stenosis. Circulation 1992;86:1770e1779. 16. Levine MJ, Weinstein JS, Diver DJ, Berman AD, Wyman RM, Cunningham MJ, Safian RD, Grossman W, McKay RG. Progressive improvement in pulmonary vascular resistance after percutaneous mitral valvuloplasty. Circulation 1989;79:1061e1067. 17. Fawzy ME, Osman A, Nambiar V, Nowayhed O, El DA, Badr A, Canver CC. Immediate and long-term results of mitral balloon valvuloplasty in patients with severe pulmonary hypertension. J Heart Valve Dis 2008;17:485e491. 18. Fernandes JL, Sampaio RO, Brandao CM, Accorsi TA, Cardoso LF, Spina GS, Tarasoutchi F, Pomerantzeff P, Auler JO Jr, Grinberg M. Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery. Am J Cardiol 2011;107:1040e1045. 19. Foltz BD, Hessel EA II, Ivey TD. The early course of pulmonary artery hypertension in patients undergoing mitral valve replacement with cardioplegic arrest. J Thorac Cardiovasc Surg 1984;88:238e247. 20. Zener JC, Hancock EW, Shumway NE, Harrison DC. Regression of extreme pulmonary hypertension after mitral valve surgery. Am J Cardiol 1972;30:820e826. 21. Maoqin S, Guoxiang H, Zhiyuan S, Luxiang C, Houyuan H, Liangyi S, Ling Z, Guoqiang Z. The clinical and hemodynamic results of mitral
584
22. 23.
24.
25.
The American Journal of Cardiology (www.ajconline.org) balloon valvuloplasty for patients with mitral stenosis complicated by severe pulmonary hypertension. Eur J Intern Med 2005;16:413e418. Block PC, Palacios IF. Pulmonary vascular dynamics after percutaneous mitral valvotomy. J Thorac Cardiovasc Surg 1988;96:39e43. Alfonso F, Macaya C, Hernandez R, Banuelos C, Iniguez A, Goicolea J, Fernandez-Ortiz A, Zamorano J, Zarco P. Percutaneous mitral valvuloplasty with severe pulmonary artery hypertension. Am J Cardiol 1993;72:325e330. Dev V, Shrivastava S. Time course of changes in pulmonary vascular resistance and the mechanism of regression of pulmonary arterial hypertension after balloon mitral valvuloplasty. Am J Cardiol 1991;67: 439e442. Fawzy ME, Mimish L, Sivanandam V, Lingamanaicker J, Patel A, Khan B, Duran CM. Immediate and long-term effect of mitral balloon
valvotomy on severe pulmonary hypertension in patients with mitral stenosis. Am Heart J 1996;131:89e93. 26. Sagie A, Freitas N, Chen MH, Marshall JE, Weyman AE, Levine RA. Echocardiographic assessment of mitral stenosis and its associated valvular lesions in 205 patients and lack of association with mitral valve prolapse. J Am Soc Echocardiogr 1997;10:141e148. 27. Sagie A, Schwammenthal E, Palacios IF, King ME, Leavitt M, Freitas N, Weyman AE, Levine RA. Significant tricuspid regurgitation does not resolve after percutaneous balloon mitral valvotomy. J Thorac Cardiovasc Surg 1994;108:727e735. 28. Song H, Kang DH, Kim JH, Park KM, Song JM, Choi KJ, Hong MK, Chung CH, Song JK, Lee JW, Park SW, Park SJ. Percutaneous mitral valvuloplasty versus surgical treatment in mitral stenosis with severe tricuspid regurgitation. Circulation 2007;116:I246eI250.