- Email: [email protected]
Effect of mitral valve repair on exercise tolerance in asymptomatic patients with organic mitral regurgitation
Effect of mitral valve repair on exercise tolerance in asymptomatic patients with organic mitral regurgitation Juraj Madaric, MD,a Patrick Watripont, MD,b Jozef Bartunek, MD, PhD,a Filip Casselman, MD, PhD,c Marc Vanderheyden, MD,a Frank Van Praet, MD,c William Wijns, MD, PhD,a Ann Feys, MD,a Hugo Vanermen, MD,c and Bernard De Bruyne, MD, PhDa Aalst, Belgium
Background The aim of the study was to quantify the changes in cardiopulmonary function after minimally invasive video-assisted mitral valve repair for organic mitral regurgitation (MR) in asymptomatic or minimally symptomatic patients. Methods
Twenty-six patients (age 54 F 11 years) with severe organic MR (regurgitant volume of 94 F 37 mL, effective regurgitant orifice [ERO] of 0.73 F 0.35 cm2) and mild or no symptoms (New York Heart Association class 1.2 F 0.4) underwent exercise echocardiography and cardiopulmonary exercise testing 1 week before and 4 months after uncomplicated video-assisted mitral valve repair.
Results
During exercise, left ventricular ejection fraction increased from 68% F 7% to 74% F 6% ( P b .0001), but ERO did not change significantly. Four months after video-assisted mitral valve repair, a significant improvement was observed in peak oxygen uptake (Vo2max from 23 F 6 to 25 F 7 mL d kg1 d min1, P b .001), peak oxygen pulse (from 11 F 3 to 12 F 4 mL per beat, P b .005) as well as in maximal workload (from 143 F 49 to 159 F 55 W, P b .0001). When only patients without any symptoms (New York Heart Association class I, n = 20) were considered, these changes were even more pronounced (Vo2max from 24 F 7 to 27 F 7 mL d kg1 d min1, P b .001). Post-operative changes in Vo2max correlated with preoperative exercise-induced contractile reserve (r = 0.72, P b .0001), preoperative ERO (r = 0.49, P b .05), and preoperative ejection fraction at rest (r = 0.42, P b .05).
Conclusion
In patients with severe organic MR but mild or no symptoms, cardiopulmonary performance improves after successful minimally invasive video-assisted mitral valve repair. Improvement is directly related to preoperative left ventricular function and contractile reserve. (Am Heart J 2007;154:18025.)
The proper timing of surgery in asymptomatic patients with organic mitral regurgitation (MR) and preserved left ventricular (LV) dimensions and ejection fraction (EF) remains controversial. Traditionally, mitral valve surgery used to be proposed when patients started having symptoms, when indices of LV function started to deteriorate, or when atrial fibrillation or pulmonary hypertension occurred. It has been shown, however, that patients operated on before the occurrence of symptoms have a better survival than patients operated on with severe symptoms.1,2 Current guidelines suggest
From the aCardiovascular Center Aalst, bDepartments of Pneumology and cCardiovascular and Thoracic Surgery, OLV Clinic, Aalst, Belgium. Dr Madaric was the recipient of a Slovak Cardiology Society training scholarship. Submitted January 7, 2007; accepted March 21, 2007. Reprint requests: Bernard De Bruyne, MD, PhD, Cardiovascular Center, OLV Ziekenhuis, Moorselbaan 164, 9300 Aalst, Belgium. E-mail: [email protected] 0002-8703/$ - see front matter D 2007, Published by Mosby, Inc. doi:10.1016/j.ahj.2007.03.051
that in asymptomatic patients with severe MR and normal LV function, surgery should be considered when there is a high likelihood of valvular repair.3 The growing number of mitral valve repairs rather than mitral valve replacements4 and, more recently, the introduction of minimally invasive video-assisted mitral valve repair, further decreased the threshold for surgery.5,6 However, the effect of mitral valve repair on exercise capacity and cardiopulmonary testing in patients with no or little symptoms is unknown. Accordingly, we aimed at assessing the changes in cardiopulmonary functional capacity after minimally invasive video-assisted mitral valve repair in patients with severe organic MR but mild or no symptoms.
Methods Patients Between February 2004 and June 2005, 187 patients underwent video-assisted mitral valve repair for organic MR in our center. Among them, 35 had mild or no symptoms and
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were prospectively enrolled into the present study. All patients underwent cardiopulmonary exercise testing and exercise echocardiography including pulsed-wave tissue Doppler echocardiography within 1 week before operation. Four months after operation, we repeated cardiopulmonary exercise testing and resting echocardiography. Among these 35 patients, 9 were not included in the final analysis: 6 of them could not reach a maximal exercise level (respiratory exchange ratio b1) for extracardiac (orthopedic) reasons, and 3 patients refused to come back for follow-up. The remaining 26 patients had complete preoperative and postoperative testing and were eligible for final analysis. The study protocol was approved by the medical ethics committee of the OnzeLieve-Vrouw Clinic in Aalst, Belgium. All included patients were informed about the nature of the study and gave their oral informed consent.
Surgical technique The surgical technique has been extensively reported elsewhere.5,6 The procedure was performed through a 4-cm working port located in the right inframammary groove, in the fourth intercostal space. No rib spreading was used, and the thoracic wall muscles and (sub)cutaneous tissues were spread with the use of a soft tissue retractor. This creates the necessary space for the working port through which all surgical maneuvers were performed. A left atrial retractor was introduced through a stab wound in the fourth intercostal space, just lateral to the right internal mammary artery. Another port in the fourth intercostal space at the anterior axillary line served to introduce a 5-mm endoscope for visualization. The carbon dioxide insufflations and suction were performed via another 5-mm port. A femoral-femoral extracorporeal circulation was used as well as an endoaortic balloon and antegrade cold crystalloid cardioplegia. The whole procedure was performed under transesophageal echocardiography guidance. When performing mitral valve repair, the annuloplasty stitches are put first, then the valve is analyzed and repaired using standard techniques. Our current contraindications for the applicability of this technique are pectus excavatus, dilated ascending aorta (N40 mm), aortic regurgitation Ngrade 1, severe peripheral vascular disease, and severe right pleural adhesions. The rheumatic mitral valve pathology is, for us, an indication for mitral valve replacement. All other pathologies (including Barlow disease and extensive calcifications) are repaired. In 21 patients in this study, the cause of MR was a prolaps of the posterior mitral leaflet, in 2 patients, a prolaps of the anterior mitral leaflet, and 3 patients had bileaflet mitral valve prolaps.
Echocardiography Two-dimensional and Doppler echocardiography were performed with a commercially available echocardiography unit (Acuson Sequoia C512 imaging system, Siemens Medical Solutions, Mountain View, CA). Images were acquired in semisupine position, and all parameters were first acquired at rest, and then during peak exercise. All patients underwent symptom-limited exercise echocardiography using semisupine bicycle exercise with an initial workload of 25 W for 2 minutes, followed by 10-W increments each minute. Blood pressure was
Madaric et al 181
measured by sphygmomanometer at rest and at peak exercise. Images were recorded on VHS videotapes and also captured in a digital format for off-line analysis. Left ventricular end-diastolic and end-systolic dimensions and EF (LVEF) were calculated at rest and at peak exercise by the biplane Simpson rule.7 The degree of MR was assessed by a qualitative grade of severity (0 to 4+) and by the size of the vena contracta (mm). In addition, the effective regurgitant orifice (ERO) and the regurgitant volume (RV) were assessed by quantitative Doppler method as well as by the proximal isovelocity surface area method as described previously.8,9 The results of ERO and RV obtained by the 2 approaches were averaged. Pulsed-wave tissue Doppler imaging signal was obtained from the medial and lateral mitral annulus. Myocardial systolic velocity and early diastolic velocity were acquired at rest and at peak exercise. Contractile reserve of the LV (LVCR) was assessed as the change in systolic mitral annulus velocity during the exercise.
Cardiopulmonary exercise testing One week before and 4 months after surgery, patients underwent maximal cardiopulmonary testing using a ramp protocol. Exercise tests were always performed at the same period of the day. Calibration of the mass flow sensor and gas analyzers was done on a daily basis. All patients exercised till exhaustion and stopped because of fatigue or shortness of breath. They all achieved a respiratory exchange ratio N1.1, indicating sufficient metabolic stress. The oxygen consumption, carbon dioxide output, and ventilation were continuously measured with a computerized breath-by-breath analyzer. Peak oxygen uptake (o2max) was defined as the highest value recorded during the last 30 seconds of exercise. Ventilatory anaerobic threshold was calculated using the V-slope method.10 The o2max at peak exercise was expressed both as mL d kg1 d min1 and as a percentage of the predicted o2max according to age, sex, race, and height. Oxygen pulse (volume of oxygen/heart rate [HR], mL per beat) was calculated by dividing volume of oxygen by the simultaneously measured HR.
Euro quality of life questionnaire The quality of life before and 4 months after surgery was assessed by the Euro quality of life (EuroQol) questionnaire.11 By a visual analogue scale, patients rated their overall health status from 0 (worst imaginable health) to 100 (best imaginable health). The questionnaire was composed of 5 items: mobility, self-care, usual activity, pain or discomfort, and anxiety or depression. These ratings were then summarized.
Statistical analysis All data are presented as mean F SD for continuous data and as a ratio for categorical data. Gaussian distributions of data were tested by Kolmogorov-Smirnov test. Linear regression analysis was applied to calculate the correlations between various parameters. Paired t test was used to compare values before and after surgery or at rest versus exercise. P V .05 was considered statistically significant. All statistical analysis was performed by GraphPad Prism 4 software (San Diego, CA).
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Table I. Demographic characteristics N = 26 Age (y) Sex (M/F) BMI NYHA class (1-4) AF Arterial hypertension CAD
54 F 11 17/9 23.6 F 3.2 1.2 F 0.4 0 (0%) 1 (4%) 3 (12%)
AF, Atrial fibrillation; BMI, body mass index; CAD, coronary artery disease.
Results Baseline characteristics The mean age of the patients was 54 F 11 years (range 27-65 years). Their LVEF was 68% F 7% (range 55%80%). Twenty patients were in New York Heart Association (NYHA) class I, and 6 were in NYHA class II. All patients were in sinus rhythm. Five patients were treated with h-blockers, 4 with angiotensin-converting enzyme inhibitors, 1 with diuretics, and 1 with amiodarone. The demographic characteristics are given in Table I, and preoperative echocardiography characteristics at rest and during exercise are given in Table II. The degree of MR decreased from 3.1 F 0.4 before to 0.2 F 0.5 after mitral repair, P b .0001. Exercise echocardiography During exercise, systolic blood pressure increased from 125 F 16 to 174 F 18 mm Hg ( P b .0001), HR increased from 72 F 10 to 128 F 15 beat/min ( P b .001), and LVEF increased from 68% F 7% to 74 F 6% ( P b .0001). Transtricuspid pressure gradient increased from 24 F 7 to 41 F 12 mm Hg ( P b .0001), but there was no significant exercise-induced increase in MR severity: ERO varied from 0.73 F 0.35 to 0.78 F 0.42 cm2 (not significant [NS]); RV from 94 F 38 to 85 F 41 mL (NS) (Figure 1); vena contracta from 7.9 F 1.9 to 8.7 F 3.1 mm (NS); and qualitative grade of MR from 3.1 F 0.4 to 3.2 F 0.6 (NS), at rest and during peak exercise, respectively. Cardiopulmonary functional testing Changes in exercise tolerance after mitral valve repair are summarized in Table III. Four months after mitral valve repair, a significant improvement was observed in Vo2max (from 23.2 F 6.5 to 25.4 F 6.9 mL/kg/min, P b .001), in maximal workload (from 143 F 49 to 159 F 55 W, P b .0001), and in peak oxygen pulse (from 11 F 3 to 12 F 4 mL per beat, P b .005). When only patients with a preoperative LVEF z60% (n = 22) and in NYHA class I (n = 19) were considered, these functional improvements were even more pronounced (Figure 2). The anaerobic threshold did not change significantly.
Table II. Preoperative echocardiography characteristics at rest and during exercise
LA (mm) LVESV (mL) LVEF (%) Sm (cm/s) Transtricuspid pressure gradient (mm Hg) Grade of MR (I-IV) RV (mL) ERO (cm2) Vena contracta (mm)
Rest
Exercise
45 F 8 33 F 14 68 F 7 14.8 F 4 24 F 7
Not measured 27 F 114 74 F 6y 18.1 F 4y 41 F 12y
3.1 94 0.73 7.9
F F F F
0.4 38 0.35 1.9
3.2 F 0.6 85 F 41 0.78 F 0.42 8.7 F 3.1
LA, Left atrium; LVESV, LV end-systolic volume; Sm, systolic velocity of the mitral annulus. 4P b .05. yP b .0001.
Relation between changes in cardiopulmonary function and preoperative data Postoperative change in Vo2max correlated with preoperative LVEF at rest (r = 0.42, P b .05), preoperative exercise-induced LVCR (r = 0.72, P b .0001) (Figure 3), and preoperative MR severity expressed by ERO (r = 0.49, P b .05) and the increase in transtricuspid gradient during exercise (r = 0.45, P b .05). In all patients with preserved LVCR (N20%, n = 10) the improvement in o2max was N15%. There was no correlation between preoperative exercise-induced changes in indices of MR severity and the changes in cardiopulmonary function or in maximal workload. Euro quality of life questionnaire Based on the subjective scale of the EuroQol questionnaire, patients increased their overall health status from 78 F 17 to 86 F 12 ( P b .0005). This improvement did not correlate with preoperative functional data.
Discussion Opinions still diverge about the timing of mitral valve surgery in patients with MR and, in particular, about the benefit of mitral valve surgery in asymptomatic patients with preserved LV systolic function and dimensions. Recent studies showed that the clinical course of initially asymptomatic organic MR is not benign.12,13 EnriquezSarano et al12 showed that patients with medically managed asymptomatic MR who had an ERO z40 mm2 had an excess risk of death and cardiac events. In addition, these authors showed that the cardiac surgery markedly reduced the risk of heart failure and death and normalized patients’ life expectancy. Therefore, delaying surgical correction until symptoms appear carries an additional risk for the patient. Of note, the operative mortality of minimally invasive video-assisted mitral
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Figure 1
Individual values of ERO, RV, and transtricuspid pressure gradient before minimally invasive mitral valve repair at rest and at peak exercise.
Table III. Changes in exercise tolerance and in cardiopulmonary function after endoscopic mitral valve repair Vo o2max (mL ! kg1 ! min1)
All patients (N = 26) Patients with LVEF N 60% (n = 22) Patients in NYHA I (n = 20) Patients with LVEF N 60% and NYHA I (n = 19) Patients b55 y (n = 13)
Workload (W)
Peak oxygen pulse (mL/beat)
Before surgery
After surgery
P
Before surgery
After surgery
P
Before surgery
After surgery
P
23 F 6 24 F 6
25 F 7 27 F 6
b.001 b.0001
143 F 49 154 F 45
159 F 55 173 F 48
b.0001 b.0001
11 F 3 12 F 3
12 F 4 13 F 3
b.005 b.001
24 F 7 25 F 7
27 F 7 28 F 6
b.001 b.0005
154 F 48 159 F 46
173 F 52 178 F 47
b.0001 b.0001
12 F 3 12 F 3
13 F 4 14 F 4
b.005 b.0005
26 F 7
28 F 7
b.05
170 F 44
185 F 53
b.01
12 F 3
14 F 4
b.005
valve repair of 1% seems to be substantially lower than the operative mortality rates for standard mitral valve repair (approximately 2%) and mitral valve replacement (approximately 6%) reported by the Society of Thoracic Surgeons.6,14 On the other hand, to operate on asymptomatic patients in whom MR has been found incidentally and in whom LV function and dimensions are normal remains a difficult decision. This difficulty is mainly related to the belief that the operation bcannot make the patient better.Q
Cardiopulmonary functional testing In the present study, we quantified the changes in cardiopulmonary functional capacity and in exercise tolerance in candidates for minimally invasive videoassisted mitral valve repair for severe MR before and 4 months after operation. Before surgery, all patients were in sinus rhythm and had a normal EF, and 80% percent of patients claimed to be completely asymptomatic. Despite these very favorable baseline clinical characteristics, a significant improvement in peak oxygen uptake, maximal workload, and peak oxygen
pulse was observed in the group as a whole. These improvements were even more pronounced in completely asymptomatic patients. Moreover, there was no increase in anaerobic threshold after mitral valve repair, suggesting that the improvement was not due to training. In addition, patients’ rating of their overall quality of life was significantly better 4 months after than before the operation. Taken together, these results suggest that most patients with a severe MR are not truly asymptomatic, or, at least, that they tend to minimize their complaints, which appear and progress very slowly. This aspect also emphasizes the difficulty of the clinical follow-up of patients with a severe MR. Symptoms are masked by their insidious appearance and progression. The statistically significant increase in some indices of exercise tolerance indicates that patients with severe MR have an exercise tolerance that is abnormal, although they claim the contrary.
Predictors of cardiopulmonary functional status improvement Among the conventional echocardiographic preoperative measurements, only resting LVEF and the ERO
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184 Madaric et al
Figure 2
Figure 3
Correlation between the postoperative changes in Vo2max and preoperative LV EF (left panel) and preoperative LVCR (right panel). Individual values of preoperative (Pre OP) and postoperative (Post OP) Vo2max in overall group of patients (N = 26, left panel) and in subgroup with LV EF N60% and NYHA class I (n = 19, right panel).
were related—albeit modestly—to the improvement in o2max. In contrast, a strong relationship was found between LVCR during exercise and the improvement of o2max after minimally invasive mitral valve repair. Leung et al15,16 have previously shown that LVCR (ie, the ability of the LV to increase EF during exercise) predicts functional recovery after mitral valve repair in patients with MR. Hence, the latent LV dysfunction, often underestimated in patients with chronic MR, may be unmasked during exercise. The present data extend the findings of Leung et al15,16 because patients with a low LVCR did not improve their cardiopulmonary capacity nor their exercise tolerance. More generally, these results are in line with the concept that mitral valve repair performed at an early stage—when the damage to the LV is absent or minimal—provides the greatest benefit.
Exercise-induced changes in MR severity In patients with an MR secondary to an ischemic cardiomyopathy, the RV has been shown to increase during exercise regardless of the degree of MR at rest.17 In addition, these changes in RV are paralleled by changes in pulmonary pressure. They carry a poor prognosis18 and represent a major mechanism leading to acute pulmonary edema in these patients with depressed LV function.19 In contrast, the present data indicate that in patients with primary MR, exercise is not accompanied by an increase in RV or ERO. This emphasizes the difference in mechanisms underlying primary and secondary MR. Limitations Patients included in the present study represent a selected patient population with severe MR who underwent an uncomplicated minimally invasive video-
assisted mitral valve repair. The present result should indeed be considered as a proof of concept and cannot necessarily be extrapolated to all patients with severe MR in whom mitral repair is contemplated. Although not supported by any data so far, it might be speculated that the minimally invasive nature of the procedure contributes to the restoration of the cardiopulmonary function. Indeed, unlike a standard sternotomy, an endoscopic procedure totally preserves the integrity of the thoracic cavity. Moreover, the absence of active rib spreading (unlike a true thoracotomy procedure) markedly reduces postoperative pain.6 Second, the present study did not aim at comparing the different surgical approaches for mitral valve repair because all patients were operated by video-assisted surgery. Third, the absence of exercise-induced increase in RV and ERO might at least partially be explained by the fact that patients in the present study had very large RVs and ERO at baseline. Whether patients with moderate primary MR might exhibit exercise-induced increase in RV requires further studies.
Conclusion Minimally invasive video-assisted mitral valve repair improves exercise capacity of patients with severe MR but no or mild symptoms, especially in patients with preserved LV contractility.
References 1. Enriquez-Sarano M, Tajik AJ, Schaff HV, et al. Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation 1994;90:830 - 7. 2. Tribouilloy CM, Enriquez-Sarano M, Schaff HV, et al. Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications. Circulation 1999;99:400 - 5. 3. Bonow RO, Carabello B, Chaterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart
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4.
5.
6.
7.
8.
9.
10. 11.
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. J Am Coll Cardiol 2006;48:e1-e148. Akins CW, Hilgenber AD, Buckley MJ, et al. Mitral valve reconstruction versus replacement for degenerative or ischemic mitral regurgitation. Ann Thorac Surg 1994;58:668 - 75. Schoeyers P, Wellens F, De Geest R, et al. Minimally invasive videoassisted mitral valve surgery: our lessons after a 4-year experience. Ann Thorac Surg 2001;72:S1050 -4. Casselman FP, Van Slycke S, Wellens F, et al. Mitral valve surgery can now routinely be performed endoscopically. Circulation 2003;108(Suppl ll):II-48-II-54. Schiller NB, Shah P, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 - 67. Enriquez-Sarano M, Bailey KR, Seward JB, et al. Quantitative Doppler assessment of valvular regurgitation. Circulation 1993;87:841 - 8. Enriquez-Sarano M, Miller Jr FA, Hayes SN, et al. Effective regurgitant orifice area: clinical use and pitfalls of the proximal isovelocity surface area method. J Am Colll Cardiol 1995;25:703 - 9. Wasserman K, Hansen JE, Sue DY, et al. Principles of exercise testing and interpretation. 4th ed.. Lipincott Williams and Wilkins Edts. Dolan P. Modeling valuations for EuroQol health states. Med Care 1997;35:1095 - 108.
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12. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:875 - 83. 13. Ling LH, Enriquez-Sarano M, Seward JB, et al. Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335: 1417 - 23. 14. Grossi EA, Galloway AC, LaPietra A, et al. Minimally invasive mitral valve surgery: a 6-year experience with 714 patients. Ann Thorac Surg 2002;74:660 - 4. 15. Leung DY, Armstrong G, Griffin BP, et al. Latent left ventricular dysfunction in patients with mitral regurgitation: feasibility of measuring diminished contractile reserve from a simplified model of non-invasively derived left ventricular pressure-volume loops. Am Heart J 1999;137:427 - 34. 16. Leung DY, Griffin BP, Stewart WJ, et al. Left ventricular function after valve repair for chronic mitral regurgitation: predictive value of preoperative assessment of contractile reserve by exercise echocardiography. J Am Coll Cardiol 1996;28:1198 - 205. 17. Lancellotti P, Lebrun F, Pierard LA. Determinants of exercise-induced changes in mitral regurgitation in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2003;42:1921 - 8. 18. Lancellotti P, Troisfontaines P, Toussaint A-C, et al. Prognostic importance of exercise-induced changes in mitral regurgitation in patients with chronic ischemic left ventricular dysfunction. Circulation 2003;108:1713 - 7. 19. Pierard LA, Lancellotti P. The role of ischemic mitral regurgitation in the pathogenesis of acute pulmonary edema. N Engl J Med 2004;351:1627 - 34.
Background The aim of the study was to quantify the changes in cardiopulmonary function after minimally invasive video-assisted mitral valve repair for organic mitral regurgitation (MR) in asymptomatic or minimally symptomatic patients. Methods
Twenty-six patients (age 54 F 11 years) with severe organic MR (regurgitant volume of 94 F 37 mL, effective regurgitant orifice [ERO] of 0.73 F 0.35 cm2) and mild or no symptoms (New York Heart Association class 1.2 F 0.4) underwent exercise echocardiography and cardiopulmonary exercise testing 1 week before and 4 months after uncomplicated video-assisted mitral valve repair.
Results
During exercise, left ventricular ejection fraction increased from 68% F 7% to 74% F 6% ( P b .0001), but ERO did not change significantly. Four months after video-assisted mitral valve repair, a significant improvement was observed in peak oxygen uptake (Vo2max from 23 F 6 to 25 F 7 mL d kg1 d min1, P b .001), peak oxygen pulse (from 11 F 3 to 12 F 4 mL per beat, P b .005) as well as in maximal workload (from 143 F 49 to 159 F 55 W, P b .0001). When only patients without any symptoms (New York Heart Association class I, n = 20) were considered, these changes were even more pronounced (Vo2max from 24 F 7 to 27 F 7 mL d kg1 d min1, P b .001). Post-operative changes in Vo2max correlated with preoperative exercise-induced contractile reserve (r = 0.72, P b .0001), preoperative ERO (r = 0.49, P b .05), and preoperative ejection fraction at rest (r = 0.42, P b .05).
Conclusion
In patients with severe organic MR but mild or no symptoms, cardiopulmonary performance improves after successful minimally invasive video-assisted mitral valve repair. Improvement is directly related to preoperative left ventricular function and contractile reserve. (Am Heart J 2007;154:18025.)
The proper timing of surgery in asymptomatic patients with organic mitral regurgitation (MR) and preserved left ventricular (LV) dimensions and ejection fraction (EF) remains controversial. Traditionally, mitral valve surgery used to be proposed when patients started having symptoms, when indices of LV function started to deteriorate, or when atrial fibrillation or pulmonary hypertension occurred. It has been shown, however, that patients operated on before the occurrence of symptoms have a better survival than patients operated on with severe symptoms.1,2 Current guidelines suggest
From the aCardiovascular Center Aalst, bDepartments of Pneumology and cCardiovascular and Thoracic Surgery, OLV Clinic, Aalst, Belgium. Dr Madaric was the recipient of a Slovak Cardiology Society training scholarship. Submitted January 7, 2007; accepted March 21, 2007. Reprint requests: Bernard De Bruyne, MD, PhD, Cardiovascular Center, OLV Ziekenhuis, Moorselbaan 164, 9300 Aalst, Belgium. E-mail: [email protected] 0002-8703/$ - see front matter D 2007, Published by Mosby, Inc. doi:10.1016/j.ahj.2007.03.051
that in asymptomatic patients with severe MR and normal LV function, surgery should be considered when there is a high likelihood of valvular repair.3 The growing number of mitral valve repairs rather than mitral valve replacements4 and, more recently, the introduction of minimally invasive video-assisted mitral valve repair, further decreased the threshold for surgery.5,6 However, the effect of mitral valve repair on exercise capacity and cardiopulmonary testing in patients with no or little symptoms is unknown. Accordingly, we aimed at assessing the changes in cardiopulmonary functional capacity after minimally invasive video-assisted mitral valve repair in patients with severe organic MR but mild or no symptoms.
Methods Patients Between February 2004 and June 2005, 187 patients underwent video-assisted mitral valve repair for organic MR in our center. Among them, 35 had mild or no symptoms and
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were prospectively enrolled into the present study. All patients underwent cardiopulmonary exercise testing and exercise echocardiography including pulsed-wave tissue Doppler echocardiography within 1 week before operation. Four months after operation, we repeated cardiopulmonary exercise testing and resting echocardiography. Among these 35 patients, 9 were not included in the final analysis: 6 of them could not reach a maximal exercise level (respiratory exchange ratio b1) for extracardiac (orthopedic) reasons, and 3 patients refused to come back for follow-up. The remaining 26 patients had complete preoperative and postoperative testing and were eligible for final analysis. The study protocol was approved by the medical ethics committee of the OnzeLieve-Vrouw Clinic in Aalst, Belgium. All included patients were informed about the nature of the study and gave their oral informed consent.
Surgical technique The surgical technique has been extensively reported elsewhere.5,6 The procedure was performed through a 4-cm working port located in the right inframammary groove, in the fourth intercostal space. No rib spreading was used, and the thoracic wall muscles and (sub)cutaneous tissues were spread with the use of a soft tissue retractor. This creates the necessary space for the working port through which all surgical maneuvers were performed. A left atrial retractor was introduced through a stab wound in the fourth intercostal space, just lateral to the right internal mammary artery. Another port in the fourth intercostal space at the anterior axillary line served to introduce a 5-mm endoscope for visualization. The carbon dioxide insufflations and suction were performed via another 5-mm port. A femoral-femoral extracorporeal circulation was used as well as an endoaortic balloon and antegrade cold crystalloid cardioplegia. The whole procedure was performed under transesophageal echocardiography guidance. When performing mitral valve repair, the annuloplasty stitches are put first, then the valve is analyzed and repaired using standard techniques. Our current contraindications for the applicability of this technique are pectus excavatus, dilated ascending aorta (N40 mm), aortic regurgitation Ngrade 1, severe peripheral vascular disease, and severe right pleural adhesions. The rheumatic mitral valve pathology is, for us, an indication for mitral valve replacement. All other pathologies (including Barlow disease and extensive calcifications) are repaired. In 21 patients in this study, the cause of MR was a prolaps of the posterior mitral leaflet, in 2 patients, a prolaps of the anterior mitral leaflet, and 3 patients had bileaflet mitral valve prolaps.
Echocardiography Two-dimensional and Doppler echocardiography were performed with a commercially available echocardiography unit (Acuson Sequoia C512 imaging system, Siemens Medical Solutions, Mountain View, CA). Images were acquired in semisupine position, and all parameters were first acquired at rest, and then during peak exercise. All patients underwent symptom-limited exercise echocardiography using semisupine bicycle exercise with an initial workload of 25 W for 2 minutes, followed by 10-W increments each minute. Blood pressure was
Madaric et al 181
measured by sphygmomanometer at rest and at peak exercise. Images were recorded on VHS videotapes and also captured in a digital format for off-line analysis. Left ventricular end-diastolic and end-systolic dimensions and EF (LVEF) were calculated at rest and at peak exercise by the biplane Simpson rule.7 The degree of MR was assessed by a qualitative grade of severity (0 to 4+) and by the size of the vena contracta (mm). In addition, the effective regurgitant orifice (ERO) and the regurgitant volume (RV) were assessed by quantitative Doppler method as well as by the proximal isovelocity surface area method as described previously.8,9 The results of ERO and RV obtained by the 2 approaches were averaged. Pulsed-wave tissue Doppler imaging signal was obtained from the medial and lateral mitral annulus. Myocardial systolic velocity and early diastolic velocity were acquired at rest and at peak exercise. Contractile reserve of the LV (LVCR) was assessed as the change in systolic mitral annulus velocity during the exercise.
Cardiopulmonary exercise testing One week before and 4 months after surgery, patients underwent maximal cardiopulmonary testing using a ramp protocol. Exercise tests were always performed at the same period of the day. Calibration of the mass flow sensor and gas analyzers was done on a daily basis. All patients exercised till exhaustion and stopped because of fatigue or shortness of breath. They all achieved a respiratory exchange ratio N1.1, indicating sufficient metabolic stress. The oxygen consumption, carbon dioxide output, and ventilation were continuously measured with a computerized breath-by-breath analyzer. Peak oxygen uptake (o2max) was defined as the highest value recorded during the last 30 seconds of exercise. Ventilatory anaerobic threshold was calculated using the V-slope method.10 The o2max at peak exercise was expressed both as mL d kg1 d min1 and as a percentage of the predicted o2max according to age, sex, race, and height. Oxygen pulse (volume of oxygen/heart rate [HR], mL per beat) was calculated by dividing volume of oxygen by the simultaneously measured HR.
Euro quality of life questionnaire The quality of life before and 4 months after surgery was assessed by the Euro quality of life (EuroQol) questionnaire.11 By a visual analogue scale, patients rated their overall health status from 0 (worst imaginable health) to 100 (best imaginable health). The questionnaire was composed of 5 items: mobility, self-care, usual activity, pain or discomfort, and anxiety or depression. These ratings were then summarized.
Statistical analysis All data are presented as mean F SD for continuous data and as a ratio for categorical data. Gaussian distributions of data were tested by Kolmogorov-Smirnov test. Linear regression analysis was applied to calculate the correlations between various parameters. Paired t test was used to compare values before and after surgery or at rest versus exercise. P V .05 was considered statistically significant. All statistical analysis was performed by GraphPad Prism 4 software (San Diego, CA).
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Table I. Demographic characteristics N = 26 Age (y) Sex (M/F) BMI NYHA class (1-4) AF Arterial hypertension CAD
54 F 11 17/9 23.6 F 3.2 1.2 F 0.4 0 (0%) 1 (4%) 3 (12%)
AF, Atrial fibrillation; BMI, body mass index; CAD, coronary artery disease.
Results Baseline characteristics The mean age of the patients was 54 F 11 years (range 27-65 years). Their LVEF was 68% F 7% (range 55%80%). Twenty patients were in New York Heart Association (NYHA) class I, and 6 were in NYHA class II. All patients were in sinus rhythm. Five patients were treated with h-blockers, 4 with angiotensin-converting enzyme inhibitors, 1 with diuretics, and 1 with amiodarone. The demographic characteristics are given in Table I, and preoperative echocardiography characteristics at rest and during exercise are given in Table II. The degree of MR decreased from 3.1 F 0.4 before to 0.2 F 0.5 after mitral repair, P b .0001. Exercise echocardiography During exercise, systolic blood pressure increased from 125 F 16 to 174 F 18 mm Hg ( P b .0001), HR increased from 72 F 10 to 128 F 15 beat/min ( P b .001), and LVEF increased from 68% F 7% to 74 F 6% ( P b .0001). Transtricuspid pressure gradient increased from 24 F 7 to 41 F 12 mm Hg ( P b .0001), but there was no significant exercise-induced increase in MR severity: ERO varied from 0.73 F 0.35 to 0.78 F 0.42 cm2 (not significant [NS]); RV from 94 F 38 to 85 F 41 mL (NS) (Figure 1); vena contracta from 7.9 F 1.9 to 8.7 F 3.1 mm (NS); and qualitative grade of MR from 3.1 F 0.4 to 3.2 F 0.6 (NS), at rest and during peak exercise, respectively. Cardiopulmonary functional testing Changes in exercise tolerance after mitral valve repair are summarized in Table III. Four months after mitral valve repair, a significant improvement was observed in Vo2max (from 23.2 F 6.5 to 25.4 F 6.9 mL/kg/min, P b .001), in maximal workload (from 143 F 49 to 159 F 55 W, P b .0001), and in peak oxygen pulse (from 11 F 3 to 12 F 4 mL per beat, P b .005). When only patients with a preoperative LVEF z60% (n = 22) and in NYHA class I (n = 19) were considered, these functional improvements were even more pronounced (Figure 2). The anaerobic threshold did not change significantly.
Table II. Preoperative echocardiography characteristics at rest and during exercise
LA (mm) LVESV (mL) LVEF (%) Sm (cm/s) Transtricuspid pressure gradient (mm Hg) Grade of MR (I-IV) RV (mL) ERO (cm2) Vena contracta (mm)
Rest
Exercise
45 F 8 33 F 14 68 F 7 14.8 F 4 24 F 7
Not measured 27 F 114 74 F 6y 18.1 F 4y 41 F 12y
3.1 94 0.73 7.9
F F F F
0.4 38 0.35 1.9
3.2 F 0.6 85 F 41 0.78 F 0.42 8.7 F 3.1
LA, Left atrium; LVESV, LV end-systolic volume; Sm, systolic velocity of the mitral annulus. 4P b .05. yP b .0001.
Relation between changes in cardiopulmonary function and preoperative data Postoperative change in Vo2max correlated with preoperative LVEF at rest (r = 0.42, P b .05), preoperative exercise-induced LVCR (r = 0.72, P b .0001) (Figure 3), and preoperative MR severity expressed by ERO (r = 0.49, P b .05) and the increase in transtricuspid gradient during exercise (r = 0.45, P b .05). In all patients with preserved LVCR (N20%, n = 10) the improvement in o2max was N15%. There was no correlation between preoperative exercise-induced changes in indices of MR severity and the changes in cardiopulmonary function or in maximal workload. Euro quality of life questionnaire Based on the subjective scale of the EuroQol questionnaire, patients increased their overall health status from 78 F 17 to 86 F 12 ( P b .0005). This improvement did not correlate with preoperative functional data.
Discussion Opinions still diverge about the timing of mitral valve surgery in patients with MR and, in particular, about the benefit of mitral valve surgery in asymptomatic patients with preserved LV systolic function and dimensions. Recent studies showed that the clinical course of initially asymptomatic organic MR is not benign.12,13 EnriquezSarano et al12 showed that patients with medically managed asymptomatic MR who had an ERO z40 mm2 had an excess risk of death and cardiac events. In addition, these authors showed that the cardiac surgery markedly reduced the risk of heart failure and death and normalized patients’ life expectancy. Therefore, delaying surgical correction until symptoms appear carries an additional risk for the patient. Of note, the operative mortality of minimally invasive video-assisted mitral
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Figure 1
Individual values of ERO, RV, and transtricuspid pressure gradient before minimally invasive mitral valve repair at rest and at peak exercise.
Table III. Changes in exercise tolerance and in cardiopulmonary function after endoscopic mitral valve repair Vo o2max (mL ! kg1 ! min1)
All patients (N = 26) Patients with LVEF N 60% (n = 22) Patients in NYHA I (n = 20) Patients with LVEF N 60% and NYHA I (n = 19) Patients b55 y (n = 13)
Workload (W)
Peak oxygen pulse (mL/beat)
Before surgery
After surgery
P
Before surgery
After surgery
P
Before surgery
After surgery
P
23 F 6 24 F 6
25 F 7 27 F 6
b.001 b.0001
143 F 49 154 F 45
159 F 55 173 F 48
b.0001 b.0001
11 F 3 12 F 3
12 F 4 13 F 3
b.005 b.001
24 F 7 25 F 7
27 F 7 28 F 6
b.001 b.0005
154 F 48 159 F 46
173 F 52 178 F 47
b.0001 b.0001
12 F 3 12 F 3
13 F 4 14 F 4
b.005 b.0005
26 F 7
28 F 7
b.05
170 F 44
185 F 53
b.01
12 F 3
14 F 4
b.005
valve repair of 1% seems to be substantially lower than the operative mortality rates for standard mitral valve repair (approximately 2%) and mitral valve replacement (approximately 6%) reported by the Society of Thoracic Surgeons.6,14 On the other hand, to operate on asymptomatic patients in whom MR has been found incidentally and in whom LV function and dimensions are normal remains a difficult decision. This difficulty is mainly related to the belief that the operation bcannot make the patient better.Q
Cardiopulmonary functional testing In the present study, we quantified the changes in cardiopulmonary functional capacity and in exercise tolerance in candidates for minimally invasive videoassisted mitral valve repair for severe MR before and 4 months after operation. Before surgery, all patients were in sinus rhythm and had a normal EF, and 80% percent of patients claimed to be completely asymptomatic. Despite these very favorable baseline clinical characteristics, a significant improvement in peak oxygen uptake, maximal workload, and peak oxygen
pulse was observed in the group as a whole. These improvements were even more pronounced in completely asymptomatic patients. Moreover, there was no increase in anaerobic threshold after mitral valve repair, suggesting that the improvement was not due to training. In addition, patients’ rating of their overall quality of life was significantly better 4 months after than before the operation. Taken together, these results suggest that most patients with a severe MR are not truly asymptomatic, or, at least, that they tend to minimize their complaints, which appear and progress very slowly. This aspect also emphasizes the difficulty of the clinical follow-up of patients with a severe MR. Symptoms are masked by their insidious appearance and progression. The statistically significant increase in some indices of exercise tolerance indicates that patients with severe MR have an exercise tolerance that is abnormal, although they claim the contrary.
Predictors of cardiopulmonary functional status improvement Among the conventional echocardiographic preoperative measurements, only resting LVEF and the ERO
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184 Madaric et al
Figure 2
Figure 3
Correlation between the postoperative changes in Vo2max and preoperative LV EF (left panel) and preoperative LVCR (right panel). Individual values of preoperative (Pre OP) and postoperative (Post OP) Vo2max in overall group of patients (N = 26, left panel) and in subgroup with LV EF N60% and NYHA class I (n = 19, right panel).
were related—albeit modestly—to the improvement in o2max. In contrast, a strong relationship was found between LVCR during exercise and the improvement of o2max after minimally invasive mitral valve repair. Leung et al15,16 have previously shown that LVCR (ie, the ability of the LV to increase EF during exercise) predicts functional recovery after mitral valve repair in patients with MR. Hence, the latent LV dysfunction, often underestimated in patients with chronic MR, may be unmasked during exercise. The present data extend the findings of Leung et al15,16 because patients with a low LVCR did not improve their cardiopulmonary capacity nor their exercise tolerance. More generally, these results are in line with the concept that mitral valve repair performed at an early stage—when the damage to the LV is absent or minimal—provides the greatest benefit.
Exercise-induced changes in MR severity In patients with an MR secondary to an ischemic cardiomyopathy, the RV has been shown to increase during exercise regardless of the degree of MR at rest.17 In addition, these changes in RV are paralleled by changes in pulmonary pressure. They carry a poor prognosis18 and represent a major mechanism leading to acute pulmonary edema in these patients with depressed LV function.19 In contrast, the present data indicate that in patients with primary MR, exercise is not accompanied by an increase in RV or ERO. This emphasizes the difference in mechanisms underlying primary and secondary MR. Limitations Patients included in the present study represent a selected patient population with severe MR who underwent an uncomplicated minimally invasive video-
assisted mitral valve repair. The present result should indeed be considered as a proof of concept and cannot necessarily be extrapolated to all patients with severe MR in whom mitral repair is contemplated. Although not supported by any data so far, it might be speculated that the minimally invasive nature of the procedure contributes to the restoration of the cardiopulmonary function. Indeed, unlike a standard sternotomy, an endoscopic procedure totally preserves the integrity of the thoracic cavity. Moreover, the absence of active rib spreading (unlike a true thoracotomy procedure) markedly reduces postoperative pain.6 Second, the present study did not aim at comparing the different surgical approaches for mitral valve repair because all patients were operated by video-assisted surgery. Third, the absence of exercise-induced increase in RV and ERO might at least partially be explained by the fact that patients in the present study had very large RVs and ERO at baseline. Whether patients with moderate primary MR might exhibit exercise-induced increase in RV requires further studies.
Conclusion Minimally invasive video-assisted mitral valve repair improves exercise capacity of patients with severe MR but no or mild symptoms, especially in patients with preserved LV contractility.
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