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D958etukansi.kesken.fm Page 1 Tuesday, November 27, 2007 3:06 PM inen OULU 2008 UNIVERSITY OF OULU P.O. Box 7500 FI-90014 UNIVERSITY OF OULU FINLAND A C TA U N I V E R S I TAT I S S E R I E S A B C D E F G E D I T O R S SCIENTIAE RERUM NATURALIUM Professor Mikko Siponen HUMANIORA TECHNICA Professor Harri Mantila Professor Juha Kostamovaara MEDICA O U L U E N S I S D 958 ACTA Jouni Heikkinen OUTCOME AFTER MITRAL VALVE SURGERY FOR MITRAL VALVE REGURGITATION Professor Olli Vuolteenaho SCIENTIAE RERUM SOCIALIUM Senior Assistant Timo Latomaa SCRIPTA ACADEMICA Communications Officer Elna Stjerna OECONOMICA Senior Lecturer Seppo Eriksson EDITOR IN CHIEF Professor Olli Vuolteenaho EDITORIAL SECRETARY Publications Editor Kirsti Nurkkala ISBN 978-951-42-8680-3 (Paperback) ISBN 978-951-42-8681-0 (PDF) ISSN 0355-3221 (Print) ISSN 1796-2234 (Online) U N I V E R S I T AT I S O U L U E N S I S FACULTY OF MEDICINE, DEPARTMENT OF SURGERY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF OULU D MEDICA ACTA UNIVERSITATIS OULUENSIS D Medica 958 JOUNI HEIKKINEN OUTCOME AFTER MITRAL VALVE SURGERY FOR MITRAL VALVE REGURGITATION Academic Dissertation to be presented, with the assent of the Faculty of Medicine of the University of Oulu, for public defence in Auditorium 1 of Oulu University Hospital, on January 18th, 2008, at 12 noon O U L U N Y L I O P I S TO, O U L U 2 0 0 8 Copyright © 2008 Acta Univ. Oul. D 958, 2008 Supervised by Docent Martti Lepojärvi Docent Fausto Biancari Professor Tatu Juvonen Reviewed by Docent Jari Laurikka Professor Keijo Peuhkurinen ISBN 978-951-42-8680-3 (Paperback) ISBN 978-951-42-8681-0 (PDF) http://herkules.oulu.fi/isbn9789514286810/ ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online) http://herkules.oulu.fi/issn03553221/ Cover design Raimo Ahonen OULU UNIVERSITY PRESS OULU 2008 Heikkinen, Jouni, Outcome after mitral valve surgery for mitral valve regurgitation Faculty of Medicine, Department of Surgery, Department of Internal Medicine, University of Oulu, P.O.Box 5000, FI-90014 University of Oulu, Finland Acta Univ. Oul. D 958, 2008 Oulu, Finland Abstract The repair of degenerative mitral valve regurgitation has been shown to be an effective procedure with durable results. The techniques for mitral valve repair are not completely risk-free for late failure, and the identification of factors associated with this increased risk is of clinical relevance as it permits an appropriate selection of patients for whom mitral valve surgery should be offered and by which technique. The European system for cardiac operative risk evaluation score (EuroSCORE) has been used and demonstrated worldwide to be a valid tool for the prediction of immediate postoperative outcome after coronary artery bypass surgery. There are only a few studies which examine its value in heart valve surgery. Mitral valve repair has been shown to be associated with significant improvement in terms of functional capacity, but the late quality of life in these patients has not been adequately assessed, and there is no data on the quality of life of long-term survivors. The study population consisted of two groups of patients operated on at our institution. The first group included 164 patients who underwent isolated or combined mitral valve repair for mitral valve regurgitation during the period 1993 to 2000, while the second group consisted of 207 patients who underwent mitral valve repair (164 patients) or replacement (43 patients) for isolated mitral valve regurgitation during the same time-period. The first study aimed to identify preoperative variables which may have impact on the 30-day postoperative outcome. In the second study, the long-term outcome after mitral valve repair was evaluated in order to identify the risk factors associated with late failures. The third study analyzed quality of life after valve repair and compared it to that of an age- and gender-adjusted Finnish general population. In the fourth study, the validity of EuroSCORE was tested in predicting the immediate and late outcome of patients who had undergone mitral valve repair or replacement for isolated valve regurgitation Patient age, a history of prior cardiac surgery and NYHA functional class were independent predictors of poor outcome. A residual regurgitation grade of more than one immediately after primary repair and chronic pulmonary disease were independent predictors of mitral valve reoperation. After valve repair, quality of life was similar to the age- and sex-adjusted general Finnish population. Both additive and logistic EuroSCOREs were predictors of the immediate and late outcomes of patients after surgery for mitral valve regurgitation. Keywords: EuroSCORE, mitral valve regurgitation, mitral valve repair, mitral valve replacement, quality of life, RAND-36 Health survey To Katri, Kreeta and Saara 5 6 Acknowledgements The present study was carried out in the Department of Surgery in co-operation with the Department of Medicine, of the Oulu University Hospital, during the years 2000–2007. I am deeply grateful to my supervisor, Docent Martti Lepojärvi, M.D., Ph.D., Head of Cardiothoracic Surgery, for giving me the idea and possibility to study this challenging aspect of cardiac surgery. I also express my thanks to Professor Tatu Juvonen, M.D., Ph.D., Head of the Department of Surgery. He provided me with valuable ideas, material, and financial support to aid in performing the research. I wish to express my deepest gratitude to my collegue Docent Fausto Biancari, M.D., Ph.D., for helping me during this study. It was his knowledge of research work, continuous support, never-failing optimism and guidance that made this work possible. I would like to thank Docent Kari Haukipuro, M.D., Ph.D., Head of Division of Anesthesiology, Surgery and Neurosurgery, for giving me the opportunity to practice my scientific and clinical work in my hometown clinic, and for aiding in organizing the financing for this. I wish to thank Docent Jari Satta, M.D., Ph.D. for his assistance with the study. I am grateful to Professor Keijo Peuhkurinen M.D., Ph.D. and Docent Jari Laurikka M.D., Ph.D. for reviewing the present manuscript. I would like to thank Docent Paavo Uusimaa, M.D., Ph.D., Jukka Juvonen, M.D., Ph.D., Docent Matti Niemelä, M.D., Ph.D., Kari Ylitalo, M.D., Ph.D., for the echocardiography examinations. I would like to express my gratitude to Virpi Honkala, M.D., the Head of the Department of Surgery in the Raahe Central Hospital and Juhani Ottelin, M.D, former Head of the Department of Surgery in the Western Ostrobothnia Central Hospital (L-PKS), for introducing to the field of surgery and guiding me during my first years. I would also thank Professor Pentti Kärkölä, M.D., Ph.D., former Head of the Division of Cardiothoracic and Vascular Surgery, for his expert guidance in the field of cardiac surgery. My thanks go to my roommates Jarmo Lahtinen, M.D., Martti Mosorin, M.D. and Panu Taskinen, M.D., Ph.D. for their unfailing support in the clinical work. I also thank all of my colleagues in the Division of Cardiothoracic and Vascular surgery for their cooperation: Docent Risto Pokela, M.D., Ph.D., Kari Ylönen, 7 M.D., Esa Salmela, M.D., Docent Pekka Rainio, M.D., Ph.D., Docent Vesa Anttila M.D. Ph.D., Docent Jussi Rimpiläinen, M.D., Ph.D., Pekka Romsi, M.D., Ph.D., and Arjaleena Ilo, M.D.. I am grateful to my brother-in-law Michael Spalding, M.D., Ph.D., for revising the English language of this thesis. I deeply thank my mother Aili Hannuniemi, his husband Aarne (”Ari”) Hannuniemi and my sister Heli Spalding, M.D., Ph.D., for their love, support, and encouragement throughout my life. I also thank my mother-in-law Liisa Junnikkala and my father-in-law Juho (”Jussi”) Junnikkala for their trust and love. Finally I express my loving thanks to my dear wife Katri, for her love and support, and to my lovely little girls Kreeta and Saara, the true stars of my life. You are the most precious thing in my life. This work was supported financially by Oulu University Hospital and the Finnish Foundation for Cardiovascular Research. Oulu, October, 2007 8 Jouni Heikkinen Abbreviations ACE Angiotensin converting enzyme AF Atrial fibrillation AMI Acute myocardial infarction ASD Atrial septal defect BMI Body mass index BSA Body surface area CABG Coronary artery bypass grafting CI Confidence interval COPD Chronic obstructive pulmonary disease CPB Cardiopulmonary bypass LVEF Left ventricular ejection fraction EuroSCORE The European system for cardiac operative risk evaluation score IMR Ischemic mitral regurgitation INR International normalized ratio IQR Interquartile range LV Left ventricle MOF Multiorgan failure MR Mitral regurgitation MRI Magnetic resonance imaging MV Mitral valve MVA Mitral valve annuloplasty MVR Mitral valve repair NYHA New York Heart Association OR Odds ratio PAP Pulmonary artery pressure PISA Proximal isovelocity surface area PTFE polytetrafluoroethylene ROC Receiver operating characteristics RR Relative risk SAM Systolic anterior motion SE Standard error TEE Transesophageal echocardiography TIA Transient ischemic attack TVP Tricuspid valve plasty 9 10 List of original publications This thesis is based on the following articles, which are referred to in the text by their Roman numerals: I Heikkinen J, Biancari F, Satta J, Salmela E, Juvonen T & Lepojärvi M (2005) Predictors of postoperative mortality after mitral valve repair: Analysis of a series of 164 patients. Scand Cardiovasc J 39: 71–77. II Heikkinen J, Biancari F, Uusimaa P, Satta J, Juvonen J, Ylitalo K, Niemelä M, Salmela E, Juvonen T & Lepojärvi M (2005) Long-term outcome after mitral valve repair. Scand Cardiovasc J 39: 229–236. III Heikkinen J, Biancari F, Satta J, Salmela S, Juvonen T & Lepojärvi M (2005) Quality of life after mitral valve repair. J Heart Valve Dis 14: 722–726. IV Heikkinen J, Biancari F, Satta J, Salmela E, Mosorin M, Juvonen T & Lepojärvi M (2007) Predicting the immediate and late outcome after surgery for mitral valve regurgitation with EuroSCORE. J Heart Valve Dis 16: 116– 121. 11 12 Contents Abstract Acknowledgements Abbreviations List of original publications Contents 1 Introduction 15 2 Review of the literature 19 2.1 Surgical anatomy of the mitral valve ...................................................... 19 2.2 Mitral regurgitation ................................................................................. 23 2.2.1 Etiology......................................................................................... 23 2.2.2 Pathophysiology............................................................................ 26 2.2.3 Clinical manifestations.................................................................. 27 2.2.4 Diagnosis and assessment of mitral valve regurgitation............... 28 2.2.5 Treatment ...................................................................................... 31 2.2.6 Surgical procedures....................................................................... 34 2.2.7 Results of mitral valve surgery in mitral regurgitation ................. 38 3 Aims of the study 41 4 Materials and methods 43 4.1 Material ................................................................................................... 43 4.2 Methods................................................................................................... 48 4.3 Statistical analysis .................................................................................. 51 5 Results 53 5.1 Predictors of postoperative mortality after mitral valve repair ............... 53 5.1.1 Overall outcome............................................................................ 53 5.1.2 Immediate postoperative outcome after mitral valve repair as a lone procedure........................................................................ 56 5.1.3 Immediate postoperative outcome after mitral valve repair with concomitant procedures ........................................................ 56 5.2 Long-term outcome after mitral valve repair .......................................... 57 5.2.1 Long-term survival........................................................................ 57 5.2.2 Survival freedom from redo mitral valve surgery......................... 60 5.2.3 Survival freedom from stroke ....................................................... 62 5.2.4 Long-term outcome among patients with myxomatous degenerative disease...................................................................... 62 5.2.5 Long-term echocardiographic findings......................................... 64 13 5.3 Quality of life after mitral valve repair ................................................... 66 5.4 Predicting the immediate and late outcome after surgery for mitral valve regurgitation with EuroSCORE .......................................... 68 5.4.1 30-day postoperative outcome ...................................................... 68 5.4.2 Late outcome................................................................................. 71 6 Discussion 75 6.1 Predictors of postoperative mortality after mitral valve repair ............... 75 6.2 Long-term outcome of mitral valve repair .............................................. 76 6.3 Quality of life after mitral valve repair ................................................... 77 6.4 Predicting the immediate and late outcome after surgery for mitral valve regurgitation using the EuroSCORE................................... 78 7 Conclusions 79 References Original publications 14 1 Introduction Mitral regurgitation (MR) is a common clinical condition in which there is an abnormal flow of blood from the left ventricle back to the left atrium across an incompetent mitral valve during ventricular systole. Mitral regurgitation was first identified by Corvisart in 1808 (Selzer et al. 1972). Treatment of the disorder consisted of diuretics and digitalis preparations for the next 150 years (Cooper & Gersh 1998). The earliest attempts at reconstruction of the mitral valve were for relief of mitral stenosis. Gibbon introduced the cardiopulmonary bypass in 1953 and this led to efforts to perform mitral valve repair for mitral insufficiency using direct access through the left atrium. The first clinically successful mitral valve prosthesis was implanted by Starr in 1960 (Starr & Edwards 1961). This was a major step in the treatment of mitral regurgitation and calcified mitral stenosis. The earliest techniques used for direct repair of mitral regurgitation involved attempts to correct dilatation of the posterior mitral annulus by suture plication (Kay et al. 1978). Modern mitral valve repair was initiated in the ‘70s by Carpentier (Carpentier et al. 1971) and Duran (Duran et al. 1978). Indeed, the single most important advance in valve repair was the description by Carpentier of a systematic approach to the classification of abnormalities of the mitral valve leaflets, annulus, and subvalvular apparatus of chordae and papillary muscles (please, see paragraph 2.2.1 Etiology) (Carpentier 1983). The true prevalence of chronic mitral regurgitation is still unknown. Mitral regurgitation is the second most common heart valve disease in Europe and North America after aortic valve stenosis (Cooper & Gersh 1998). In a review of all patients seen at the Mayo Clinic from 1980 to 1989 with isolated mitral regurgitation from flail mitral leaflet, the annual mortality rate was 6.3%, a rate significantly higher than that for age-matched controls. Cardiovascular events were the cause of death in 69% of cases, and the incidence of surgery or death was 90% at 10 years (Ling et al. 1996). A linear rate of 1–8% per year of sudden death has recently been reported in patients with MR due to flail leaflets followed conservatively (Grigoni et al. 1999, Lung et al. 2002). This figure ranges from 0 to 8% per year in patients with no or minimal symptoms (Grigoni et al. 1999, Lung et al. 2002). There are three different types of mitral operation currently used for the correction of mitral regurgitation. These are mitral valve repair, mitral valve replacement with preservation of part or all of the mitral apparatus, and mitral valve replacement with removal of the mitral apparatus. Each procedure has its 15 advantages and disadvantages, and therefore the indications for each of them are somewhat different. In most cases, mitral valve repair is the operation of choice when the valve is suitable for repair and the appropriate surgical skill and expertise are available (Bonow et al. 2006, Gillinov et al. 1998, Gillinov et al. 2001, Gillinov et al. 2003a–b, Gillinov & Cosgrove 2003). Valve repair is currently a feasible surgical option in 70% to 90% of cases of pure or predominant mitral regurgitation at experienced centres and it should be possible in nearly all instances of degenerative mitral valve disease (Barlow et al. 1996). Repair of degenerative mitral valve regurgitation has been shown to be an effective procedure with durable results. This has led to an increasing use of techniques of repair over replacement (Nowicki et al. 2003, Savage et al. 2003). Mitral valve repair for regurgitation is associated, however, with a significant immediate postoperative mortality. In 1997, Muehrcke and Cosgrove (Muehrcke& Cosgrove 1997) estimated a mortality of 3.4% by combining data from nine series of mitral valve repair. A more recent series reported 30-day mortality rates which vary from nil (Greelish et al. 2003) to 10% (Grossi et al. 2001), an observation suggesting that, along with surgical expertise, patient selection and indication for mitral valve repair may significantly influence the immediate outcome. Immediate postoperative mortality rates seem to be significantly higher after mitral valve replacement compared with mitral valve repair (Roques et al. 2003a, Thourani et al. 2003, Gillinov et al. 2001, Edwards et al. 2001). In particular, early postoperative mortality after mitral valve replacement may approach 15% (Roques et al. 2003a, Gillinov et al. 2001, Edwards et al. 2001). A ten-year survival freedom from fatal cardiac event after mitral valve repair has been reported to range from 92% (Braunberger et al. 2001) to 94% (Yau et al. 2000) and 10-year survival freedom from redo mitral valve surgery from 72% (Yau et al. 2000 ) to about 90% (Braunberger et al. 2001, Gillinov et al. 1998, Mohty et al. 2001). Gillinov et al ( Gillinov et al. 2003a) reported that unadjusted survival at 30 days and 1, 5 and 10 years was 97%, 92%, 79% and 59% after mitral valve repair and 94%, 88%, 70%, and 37% after replacement. The survival benefit of repair became evident after 2 years. Good results with mitral valve repair have also been reported in patients with end-stage cardiomyopathy (Gummert et al. 2003, Szalay et al. 2003, Bolling et al. 1998). Enriquez-Sarano et al. (1995) reported improved LV function and survival in patients undergoing valve repair compared to valve replacement with or without preservation of the subvalvular apparatus. In that study 195 patients underwent valve repair and were compared with 214 patients 16 who underwent valve replacement. Operative mortality was 2.6% and 10.3 % and ten-year survival was 68% and 52%, respectively. Mitral valve repair has also been shown to be associated with a significant improvement in terms of functional capacity (Goldsmith et al. 2001, Goldsmith et al. 1998). Goldsmith and colleagues (Goldsmith et al. 2001) reported on the improvement of quality of life, as assessed by the short form 36 questionnaire 3 months after mitral valve repair and replacement. Mitral valve repair was associated with a significant increase in 7 out of 8 parameters, whereas improvement was modest after mitral valve replacement. Mitral valve repair was found to be an independent predictor of early better quality of life (Goldsmith et al 2001). The same authors also observed an improvement of quality of life in patients aged 75 years or older who underwent mitral valve surgery (Goldsmith et al. 1998). There is no data to date, however, on the quality of life long after mitral valve repair. The European system for cardiac operative risk evaluation score (EuroSCORE) has been used and shown worldwide to be a valid tool for the prediction of immediate postoperative outcome after adult cardiac surgery (Nashef et al. 1999, Geissler et al. 2000, Nilsson et al. 2004). There is also some evidence that this risk scoring method is a good predictor of late outcome after coronary artery bypass surgery (Toumpoulis IK et al. 2004, De Maria et al. 2005, Biancari et al. 2006) and after heart valve surgery (Toumpoulis IK et al. 2005, Kasimir et al. 2004). 17 18 2 Review of the literature 2.1 Surgical anatomy of the mitral valve The mitral valve is situated between the left atrium and left ventricle. The mitral apparatus includes the leaflets, annulus, chordae tendinae, papillary muscles, and left ventricle. It has two leaflets, the anterior (aortic) and posterior (mural) leaflet. Both leaflets are attached directly to the mitral annulus and to the papillary muscles by primary and secondary chordae. The chordae tendinae arise from the papillary muscles and insert into the mural surface of the leaflets (Figure 1) (Lawrie 1998). Fig. 1. The relationships of the cardiac valves. Modified from Duran 1992. The anterior mitral leaflet roughly resembles a truncated triangle and is much more mobile than the posterior leaflet (Lawrie 1998). The anterior leaflet is in direct continuity with the fibrous skeleton of the heart. It occupies 35–45% of the annular circumference, but its leaflet area is almost identical to that of the posterior leaflet. The posterior leaflet is rectangular and has three scallops: a middle, a posteromedial and an anterolateral scallop (Gillinov & Cosgrove 2003). The two leaflets are connected at the annulus by the posteromedial and anterolateral commisures, which are usually distinctly developed (Fann et al. 2003). Motion of the posterior leaflet is more restricted than that of the anterior leaflet (Gillinov & 19 Cosgrove 2003). The posterior mitral leaflet is attached to thinner chordae tendinae than the anterior leaflet and its motion is restrained by chordae during both systole and diastole (Fann et al. 2003). In normal valves, posterior movement of the much more mobile anterior leaflet into apposition with the much less mobile posterior leaflet is responsible for the bulk of the systolic closure of the mitral orifice (Lawrie 1998). This is such as the posterior annulus is more flexible and it is not attached to rigid surrounding structures (Gillinov & Cosgrove 2003). The mitral annulus is a pliable junctional zone of fibrous and muscular tissue joining the left atrium and ventricle which anchors the hinge portion of the anterior and posterior mitral leaflets (Fann et al. 2003). The average area of the mitral orifice as defined by the mitral annulus is 6.5 cm2 in women and 8 cm2 in men. The effective orifice area through the level of the leaflets measured clinically is about 30% less than the above mentioned values (Lawrie 1998.) The area of the mitral orifice is reduced by 25–40 % during systole, mainly as a result of a dynamic reduction of the size of the posterior annulus which decreases the anteroposterior diameter of the valve orifice and increases the area of leaflet coaptation (De Oliveira et al. 2006). The mitral annulus is roughly elliptical (sometimes described as D- or kidneyshaped), with greater eccentricity in systole than in diastole, while in a threedimensional model the annulus is described as being “saddle-shaped” (Fann et al. 2003). During systole the height of the saddle is increased as the annular dimensions decrease (Lawrie 1998). The mitral annulus moves upward into the left atrium in diastole and toward the LV apex during systole. The annulus moves little during late diastole. The annulus moves a greater distance (3 to 16 mm toward the LV apex) during isovolumic contraction and ventricular ejection. The orifice of the mitral valve changes shape, from elliptical during systole to circular during late diastole. The annulus is flexible and decreases in diameter during each systolic contraction by approximately 26%. This flexibility increases leaflet coaptation during systole and maximizes the orifice area during diastole (Fann et al. 2003). The circumflex coronary artery courses laterally around the mitral annulus in the posterior atrioventricular groove. The coronary sinus runs more medially in the same groove. The aortic valve is situated between the anterior and posterior fibrous trigones. The bundle of His is located near the posterior trigone. The artery feeding the atrioventricular node, usually a branch of the right coronary artery, runs a course parallel and is located close to the annulus of the anterior and posterior fibrous trigones (Gillinov & Cosgrove 2003.) 20 Fig. 2. Surgical anatomy of the mitral valve. Note its important anatomic relationships with the aortic valve, the circumflex coronary artery, and the coronary sinus. Modified from Gillinow & Cosgrove 2003. The chordae tendinae arise from the papillary muscles or the left ventricular wall and are distributed to both leaflets. The papillary muscles typically consist of two prominent structures: an anterolateral and posteromedial papillary muscle. Papillary morphology may vary widely from this form. Flattened sheets of muscle can give rise to the chordae, and in some cases the chordae appear to arise from the wall of the ventricle itself (Lawrie 1998). The anterolateral papillary muscle receives blood from the septal branches of the left anterior descending artery, and from the branches of the circumflex artery. The posteromedial papillary muscle receives its blood supply from either the left circumflex artery or from a distal branch of the right coronary artery, depending on which is the dominant system. It is more prone to ischemia and rupture caused by coronary artery occlusion than is the anterior papillary muscle (De Oliveira et al. 2006). The chordae tendinae are classically and functionally divided into three groups. First-order or primary chordae originate near the papillary muscle tips and insert on the leading edge of the leaflets. These chordae prevent valve edge prolapse during systole. The second-order or secondary chordae originate in the same location and insert on the 21 ventricular surface of the leaflets at the junction of the rough and clear zones (Fann et al. 2003). These chordae contribute to ventricular function. Secondary chordae enable the ventricle to contract in an efficient cone-shaped fashion. In fact, when the secondary chordae are excised, the left ventricle assumes a globular shape (Gillinov & Cosgrove III 2003). The third-order, also termed the tertiary or basal chordae, originate directly from the trabeculae carnae of the ventricular wall, and attach to the posterior leaflet near the annulus (Fann et al. 2003). The chordae insertions into the posterior leaflet are formed in three layers: marginal attached to the edge, intermediate and mural. The chordae of the anterior leaflet insert primarily into the free margin of the leaflet and there are fewer chordae attached to other portions of the underside of the anterior leaflet (Lawrie 1998). The contribution of the papillary muscles to left ventricle chamber volume is 5% to 8% during diastole, and 15% to 30% during systole (Fann et al. 2003). The posterior left ventricular wall and papillary muscles play an important role in leaflet coaptation and valve competence (Gillinov & Cosgrove 2003). Papillary muscles help to maintain the optimal position of the subjacent ventricular wall during systole, which in turn preserves the conical shape of the ventricle during systole (Lawrie 1998). Ventricular dilatation may affect the alignment and tension on the papillary muscles and therefore valve competence (Gillinov & Cosgrove III 2003). Fig. 3. Anatomy of the mitral valve. Modified from Duran 1992. 22 2.2 Mitral regurgitation Mitral regurgitation (MR) is a common valvular disorder which can arise from abnormalities of any part of the mitral valve apparatus. There is an abnormal flow of blood from the left ventricle to the left atrium across an incompetent mitral valve during ventricular systole (Cooper & Gersh 1998) The widespread use of colour Doppler echocardiography, a sensitive technique for detecting valvular regurgitation, has increased the recognition of this condition in even healthy subjects. The true prevalence of chronic mitral regurgitation is unknown. A trivial amount of mitral regurgitation is detectable with sensitive Doppler techniques in up to 70% of normal adults. This is often called physiologic mitral regurgitation. In a review of 3486 subjects in the Strong Heart Study, the prevalence of moderate or severe mitral regurgitation was 0.2– 1.9% (Jones et al. 1999). In the Framingham study, a population-based cohort, mitral regurgitation of mild severity or worse on colour Doppler echocardiography was present in 19% of men and women (Singh et al. 1999). In the Coronary Artery Risk Development in Young Adults study, which consists of 4352 healthy men and women between 23 and 35 years of age, mitral regurgitation was noted as present in 10.9% of the cohort. Of these cases, 93 % were mild in severity (Reid et al.1994). The Cardiovascular Health Study assessed 5201 randomly selected people aged 65 and older with echocardiography. The prevalence of MR was 30.1%, with 26.6% of the cases meeting the criteria for moderate-to-severe regurgitation (Reid et al.1997.) Mitral regurgitation burdens the left ventricle with an excessive volume load which leads to a series of compensatory myocardial and circulatory adjustments. These adjustments vary over the prolonged course of the disorder, so that the changes that are operative in acute or subacute MR are eventually replaced by other compensatory mechanisms. Finally, the myocardium fails, the ventricle decompensates, and the patient exhibits signs of heart failure (Gaasch et al. 1985, Carabello 1993, Gaasch et al 1993). 2.2.1 Etiology Dysfunction of one or more components of the valvular-ventricular complex can lead to mitral regurgitation during ventricular systole. Diastolic regurgitation results from delayed ventricular contraction, but this phenomenon appears to have few clinical implications (Fann et al. 2003). 23 In the past, rheumatic fever was the predominant cause of mitral regurgitation. Nowadays, the most common etiology of systolic mitral regurgitation in patients undergoing surgery is myxomatous degeneration, also termed flail leaflet, floppy mitral valve or mitral valve prolapse (29–70% of cases) (Fann et al. 2003). Other causes include ischemic mitral regurgitation (IMR), dilated cardiomyopathy (also termed functional mitral regurgitation (FMR)), mitral annular calcification, infective endocarditis, idiopathic chordal rupture, congenital anomalies, endocardial fibrosis, collagen-vascular disorders and traumatic rupture (Fann et al. 2003). The use of appetite suppressants (phentermine, fenfluramine and dexfenfluramine) for weight loss has also been associated with an increased prevalence of cardiac valvular insufficiency (Khan et al. 1998). Degenerative mitral valve disease is the most common form of valvular heart disease and it is the most common indication for mitral valve surgery in North America and Europe. The estimated prevalence is 4–5% of the general population. Approximately 5% of the patients with mitral valve prolapse ultimately develop mitral regurgitation requiring surgery (Gillinov & Cosgrove 2003). Some degree of mitral valve prolapse is seen in echocardiography in 5% to 6% of the normal female population. It can be familial and associated with hypertension (Procacci et al. 1976). Although mitral valve prolapse appears to be more widespread in women, severe mitral valve regurgitation due to mitral valve prolapse is more common in men (Fann et al. 2003). The classic features of degenerative mitral valve disease include leaflet prolapse (the posterior leaflet more commonly) and annular dilatation (Gillinov & Cosgrove 2003). A prolapse is considered to be present when the free edge of one or both leaflets overrides the plane of the valve orifice (annulus) during systole (De Oliveira et al. 2006). Chordae may be elongated, thinned, ruptured or thickened (Gillinov & Cosgrove 2003). The prognosis for the mitral valve prolapse syndrome is benign. The age-adjusted survival rate of both men and women with mitral valve prolapse syndrome is similar to that of individuals without this common clinical entity (Bonow 2006). Ischemic mitral regurgitation (IMR) is a complication of coronary heart disease, particularly in the setting of a prior myocardial infarction. IMR caused by previous myocardial infarction can be the result of a ruptured papillary muscle, infarction of the papillary muscle without rupture, and functional regurgitation. Ruptured papillary muscle is most frequently caused by infarction in the circumflex and/ or right coronary artery distribution (Gillinov & Cosgrove 2003). This is a life-threatening complication which accounts for 5% of deaths after acute myocardial infarction. The complication usually occurs within two to seven days 24 after myocardial infarction (Gillinov et al. 2001, Miller 2001). Patients with myocardial infarction, but not ruptured papillary muscles suffer leaflet prolapse, while patients with isolated functional ischemic MR will have normal papillary muscles, chordae and leaflets, but the leaflets fail to coapt. Failure of coaptation can be caused by annular dilatation, leaflet tethering or both. Myocardial infarction produces ventricular dilatation and dysfunction, and the resulting geometric changes prevent leaflet coaptation (Gillinov & Cosgrove 2003). In patients with functional mitral regurgitation the papillary muscles, chordae and valve leaflets are normal. There are two major causes of this condition: ischemia as discussed above, as well as any cause of dilated left ventricle. MR may result from annular enlargement secondary to left ventricular dilatation or papillary muscle displacement due to left ventricular remodelling (Trichon & O`Connor 2002). Some degree of functional MR is almost always present in patients with severe dilated cardiomyopathy, regardless of the etiology of cardiomyopathy (Trichon & O`Connor 2002, Koelling et al. 2002, Strauss et al. 1987). Functional MR is also a common problem in patients with end-stage renal disease on maintenance dialysis. Volume expansion is primarily responsible for the cardiac enlargement (Cirit et al. 1998). A decrease in the prevalence of rheumatic valve disease has been witnessed in surgical practice in North America and Europe. Pathologic features of rheumatic mitral valve disease produce varying degrees of regurgitation, stenosis or mixed lesions. Acute rheumatic valvitis produces leaflet prolapse and mitral regurgitation (Gillinov & Cosgrove III 2003). Mitral annular calcification is a degenerative disease that is essentially limited to the elderly. Most patients are older than 60 years of age, and women are affected more often than men. Annular calcification causes mitral regurgitation by displacing the mitral leaflets, by immobilizing the peripheral portion of the mitral leaflets or by impairing the presystolic sphincteric action of the annulus (Fann et al. 2003). Native valve endocarditis is generally caused by streptococcal or staphylococcal species. Pathologic findings include chordal rupture (70%), vegetation (62%), leaflet perforation (53%) and abscess (7%) (Gillinov & Cosgrove 2003). Carpentier et al. classified mitral regurgitation into three pathoanatomic types based on leaflet prolapse or excessive motion: normal leaflet motion (type I), leaflet prolapse or excessive motion (type II) and restricted leaflet motion (type 25 III). Type III is further subdivided into two groups based on leaflet restriction during diastole (type IIIa) or during systole (type IIIb) (Carpentier 1983). Fig. 4. Carpentier`s segmental classification of the mitral valve and functional classification of the types of leaflets and chordal motion associated with mitral regurgitation. Modified from Carpentier 1983. Type I MR is present when there is annular dilatation, as in cardiomyopathy, or with leaflet perforation as in endocarditis. Type II MR is caused by elongation or rupture of the chordae tendineae, as often occurs in degenerative disease, or of the papillary muscles, as occurs in ischaemic disease. Type IIIa MR occurs when there is commissural fusion and leaflet or chordal thickening, as seen in rheumatic disease. In type IIIb MR there is chordal retraction (rheumatic) or papillary muscle retraction (ischaemic) or displacement (ischaemic or functional cardiomyopathy) (De Oliveira et al. 2006). 2.2.2 Pathophysiology The pathophysiology of acute MR differs markedly from that of chronic MR. The clinical impact of acute mitral incompetence is largely modulated by left atrium compliance. Acute MR results in high left atrial pressure, which can rapidly lead to pulmonary edema. In patients with chronic MR, compensatory changes increase left atrial and pulmonary venous compliance over time so that symptoms of pulmonary congestion may be negligible for several years. In mitral regurgitation, impedance to LV emptying is decreased because the mitral orifice is in parallel 26 with the LV outflow tract. Regurgitation into the left atrium increases left atrial pressure and reduces forward systemic flow. Left atrial pressure rises significantly during ventricular systole, followed by an abrupt decline in early diastole (Fann et al. 2003). The most significant change occurring during the evolution from acute to chronic MR is the enlargement of the left ventricle. Despite LV chamber enlargement, preload at the sarcomer level returns to a normal or near normal level (Ross et al. 1971). Systolic unloading is gradually replaced by normal systolic wall stresses as the end-systolic volume increases. LV contractility, loading conditions, and ejection fraction remain within the normal range while a large end-diastolic volume is responsible for an enhanced total stroke volume. An enlarged compliant atrium contributes to a decline in pulmonary venous pressures. A very important aspect of the pathophysiology of MR is the nature of the transition from a compensated to a decompensated state. Such a change may occur as a consequence of progressive increments in the regurgitant volume and/or chamber size. This decompensated state is characterized by substantial and progressive ventricular enlargement with increased LV diastolic pressures, increased systolic wall stress, and a decline in the ejection fraction. The fall in left ventricular ejection fraction is due to both a depressed contractile state and excessive afterload. These changes in LV size and function are often accompanied by progressive atrial enlargement, atrial arrhythmias, pulmonary hypertension, and, eventually, signs and symptoms of congestive heart failure (Gaasch & Zile 1991). 2.2.3 Clinical manifestations The nature and severity of symptoms associated with chronic MR are related to the severity of regurgitation, its rate of progression, the pulmonary artery pressure and associated cardiac disease. Patients with mild to moderate MR may remain asymptomatic with little or no hemodynamic compromise for many years, as there is little volume overload of the ventricle and cardiac hemodynamics and forward cardiac output remain normal. Even in patients with severe MR, most remain asymptomatic until the occurrence of left ventricular failure, pulmonary hypertension or the onset of atrial fibrillation (Otto 2001). The compensated phase of MR is variable and may last for many years, but the prolonged burden of volume overload may eventually result in LV dysfunction. Patients with chronic severe MR have a high likelihood of developing symptoms or LV dysfunction over the course of six to ten years (Ling et al. 1996). 27 The most common symptoms are exertional dyspnea and fatigue due to the combination of decreased forward cardiac output and an increase in left atrial pressure due to backflow across the mitral valve. Another common clinical presentation is paroxysmal, persistent or permanent atrial fibrillation. Patients with more severe disease and left ventricular enlargement eventually progress to symptomatic heart failure with pulmonary congestion and edema. Other symptoms such as thromboembolism, hemoptysis and right-sided failure do occur, but are less common than with mitral stenosis. There is a high risk for infective endocarditis in patients with an abnormal mitral valve and moderate to severe mitral regurgitation (Otto 2001). 2.2.4 Diagnosis and assessment of mitral valve regurgitation Cardiac auscultation Cardiac auscultation remains the most widely used method of screening for valvular heart disease. A heart murmur may have no pathological significance or may be an important clue to the presence of valvular, congenital, or other structural abnormalities of the heart (Bonow et al. 2006). The mitral regurgitation murmur is heard in the systolic phase, but its timing, duration, quality, intensity, location, and radiation are variable and depend upon the etiology and on which component of the mitral apparatus is diseased. In most cases, the murmur is holosystolic, commencing immediately after S1 and continuing up to and sometime beyond and obscuring A2, a result of the persistent pressure gradient between the left ventricle and atrium (Otto 2001). The murmur is heard best over the apex, radiating to the axilla, and when very loud, it may often radiate to the back. It is most often blowing and high pitched in quality. The loudness of the murmur does not necessarily correlate with the severity of functional or ischemic MR. In IMR, severe regurgitation may be present with a soft murmur. There is a better correlation between murmur grade and regurgitant severity with primary mitral valve disease (Otto 2001). A loud murmur associated with a thrill has a specificity of 91% for severe regurgitation, but a sensitivity of only 24%. Conversely, severe regurgitation is rarely present with a grade 1–2 murmur. There is, however, a wide range of regurgitant severity with a grade 3 murmur (Desjardins et al. 1996). Heart failure and the volume and geometry of the ventricle can affect the timing, intensity, and quality of the mitral regurgitation murmur. In patients with 28 MR due to dilatation of the valvular annulus, the murmur often diminishes in intensity or disappears as heart failure is treated and left ventricular function improves (Otto 2001). Chest radiograph Chest x-rays often yield qualitative information on cardiac chamber size, pulmonary blood flow, pulmonary and systemic venous pressure, and cardiac calcification in patients with cardiac murmurs (Bonow et al. 2006). The most common finding on the chest radiograph in patients with MR is cardiomegaly, which is a result of an enlargement of the left ventricle and left atrium. Left ventricular enlargement causes the cardiac silhouette to be displaced towards the left chest wall and the chamber becomes globular. Enlargement of the left atrium results in a straightening of the left heart border, with the appearance of a double density and an elevation of the left main stem bronchus. The right ventricle is usually normal in size, unless pulmonary hypertension is present. Similarly, the lung fields are usually clear unless congestive heart failure is present. Calcification of the mitral valve annulus may be seen (Otto 2001). Acute mitral regurgitation is often not associated with an enlarged heart shadow and may produce only mild left atrial enlargement. Interstitial edema is seen in patients with acute mitral regurgitation or in those with progressive LV failure secondary to chronic mitral regurgitation (Fann et al. 2003). When abnormal findings are present on chest Xray, an echocardiography should be performed (Bonow et al. 2006). Echocardiography Echocardiography with color flow and spectral Doppler evaluation is an important non-invasive method for assessing the significance of cardiac murmurs. Echocardiography is essential for establishing valve morphology and function, chamber size, wall thickness, and ventricular function, as well as pulmonary and hepatic vein flow. The initial transthoracic echocardiogram should disclose the anatomic cause of the MR. Multiple parameters from the Doppler examination should be used to diagnose severe MR, including the color flow jet width and area, the intensity of the continuous-wave Doppler signal, the pulmonary venous flow contour, the peak early mitral inflow velocity, and quantitative measures of the effective orifice area and regurgitation volume (Bonow et al. 2006). Threedimensional echocardiography in patients with mitral regurgitation has been 29 shown to be fairly accurate in elucidating the dynamic mechanism of mitral regurgitation leaks, but only offers qualitative information (Fann et al. 2003). The handgrip test can also be used during echocardiography in order to evaluate any increase of mitral valve regurgitation occurring during isometric exercise (Spain et al. 1990). Transthoracic imaging is diagnostic in most cases, but if image quality is suboptimal, transesophageal imaging is recommended (Enriquez-Sarano et al. 1999). Transesophageal echocardiography (TEE) is always indicated to establish the anatomic basis for severe MR in patients in whom surgery is recommended in order to assess the feasibility of repair as well as to guide repair. TEE is not indicated for routine follow-up or surveillance of asymptomatic patients with native valve MR (Bonow et al. 2006). Vena contracta is the point in a fluid stream where the diameter of the stream is at its minimum as was first observed and defined by Evangelista Torricelli in the seventeenth century. An echocardiographic measurement of the vena contracta has been shown to provide a good estimate of the severity of the regurgitant orifice area of the mitral valve (Hall et al. 1997). An echocardiographic estimation of the proximal isovelocity surface area (PISA) is also currently performed for assessement of the mitral valve regurgitant orifice area (Utsunomiya et al. 1991). Cardiac catheterization and angiography Cardiac catheterization can provide important information as to the presence and severity of valvular obstruction, valvular regurgitation, and intracardiac shunting. Preoperative coronary angiography is recommended in all patients with MR over 40 years of age and in any patient with a history or clinical presentation suggesting the presence of coronary artery disease (Gillinov & Cosgrove 2003). It is also necessary when there is any discrepancy between clinical and non-invasive findings. Hemodynamic measurements are indicated when pulmonary artery pressure is out of proportion to the severity of MR as assessed by non-invasive testing (Bonow et al. 2006). A left ventricular angiogram obtained during cardiac catheterization may establish the presence and severity of MR. The diagnostic finding is opacification of the left atrium during systole. The rapidity and density of opacification of the left atrium provides a semi-quantitive index of regurgitant severity. The angiogram can also provide a measurement of left atrial and ventricular dimensions and left ventricular function (Otto 2001). By measuring 30 rest and exercise pulmonary artery pressures and cardiac outputs, left- and rightsided heart catheterization can occasionally be useful to identify patients with primary myocardial disease who present with LV dilatation and relatively mild degrees of mitral regurgitation (Fann et al. 2003). Newer techniques Magnetic resonance imaging (MRI) is a non-invasive modality which can be employed to assess the cardiovascular system, including cardiac structure and function (Hundley et al. 1995, Nayak et al. 2000, Kozerke et al. 2001). MRI and newer advanced techniques, such as moving-slice velocity mapping, control volume method, and real-time colour-flow MRI have been used to evaluate and quantify the degree of mitral regurgitation. The presence of valvular regurgitation can be determined, LV volumes and mitral regurgitant fraction estimated, and information concerning mitral and coronary anatomy obtained (Fann et al. 2003). 2.2.5 Treatment Medical treatment In earlier years, the treatment for chronic mitral regurgitation consisted essentially of the relief of symptoms of heart failure using diuretics and digitalis preparations (Levine & Gaasch 1996). More recently, it has become clear that medical therapy alone is not appropriate for the treatment of patients with mitral regurgitation with symptoms of heart failure unless surgery is contraindicated. Therefore, attention is at present focused on drugs which alter the hemodynamic abnormalities in patients with minimal or no symptoms in an attempt to prevent the sequelae of chronic volume overload (Cooper & Gersh 1998). There is no generally accepted medical therapy for the treatment of asymptomatic patients with chronic MR. No studies have been published which would support the hypothesis that vasodilator therapy is beneficial in such patients. In addition, the administration of vasodilators in patients with normal LV function might limit the development of symptoms due to increasing LV dysfunction, thereby masking symptoms indicating surgical treatment (Lung et al. 2002). Acute vasodilator therapy has a beneficial effect on patients with chronic mitral regurgitation. Intravenous nitroprusside decreases left ventricular enddiastolic pressure and volume while increasing forward stroke volume and cardiac 31 index. Hydralazine has similar salutary effects. Data regarding the chronic effect of vasodilators is less impressive. Chronic therapy provides the most benefit for patients with the largest hearts, the poorest systolic function, and the most disabling symptoms. When combined with digitalis and diuretics, for example, hydralazine can produce substantial symptomatic and hemodynamic improvement in patients who are in NYHA functional class II–IV (Greenberg et al. 1982). Angiotensin converting enzyme (ACE) inhibitors may also be beneficial in this setting (Schön et al. 1994). Chronic vasodilator therapy is only indicated in those who are not surgical candidates. ACE inhibitors in combination with nitrates are a reasonable choice in patients with coronary heart disease or idiopathic dilated cardiomyopathy. Beta-blockers lower systolic pressure without reducing left ventricular chamber size. Beta-blockers in combination with a diuretic can be used in hypertensive patients. If LV systolic dysfunction is present, biventricular pacing has been shown to reduce the severity of functional MR (Breithardt et al. 2003). The risk of an embolic event is increased when atrial fibrillation or mitral annular calcification is present. Long-term anticoagulation, with the INR maintained at 2.0 to 3.0, is recommended in patients who have atrial fibrillation or a history of systemic embolism and in patients with mitral annular calcification complicated by systemic embolism not documented to be calcific in origin or by atrial fibrillation (Salem et al. 2001). If atrial fibrillation occurs, the heart rate should be controlled with digitalis, rate-lowering calcium channel blockers, betablockers or, rarely, amiodarone (Bonow et al. 2006). Surgical treatment The most important predictors of postoperative outcome after surgery for mitral regurgitation are symptoms, age, atrial fibrillation, preoperative left ventricular function and the reparability of the valve. Older age increases the operative risks and negatively influences late outcome. It has been reported that the operative mortality for patients in NYHA class I–II was 0% below the age of 75 years and 3– 6% over this age (Tribouilloy et al. 1999, Lung et al. 2002). Survival was also reduced in patients older than 75 years, especially if mitral valve replacement was necessary or if the patient had concomitant coronary artery disease (EnriquezSarano et al. 1995). Pre-operative atrial fibrillation is a predictor of an excess late postoperative morbidity and mortality, while a duration of atrial fibrillation of over one year and a left atrial diameter of more than 50 mm are predictors of permanent postoperative atrial fibrillation. The most important predictors are left ventricular 32 ejection fraction and end-systolic diameter (Lung 2002.) A preoperative left ventricular ejection fraction less than 50 % is associated with an excess late mortality (Enriquez-Sarano et al. 1994a–b). The best results of surgery are observed in patients with a preoperative left ventricular ejection fraction more than 60%, a finding which is independent of the type of surgery (Lung et al. 2002). A preoperative left ventricle end-systolic diameter of more than 45 mm is closely correlated with a poor postoperative prognosis (Enriquez-Sarano et al. 1994a), while the progressive development of pulmonary hypertension is also a marker for a poor prognosis (Bonow et al. 2006). The probability of a successful outcome for valve repair is of crucial importance (Lung et al. 2002). In multiple studies comparing patients who were managed with medical therapy alone to those who had undergone surgery, the findings indicated that patients treated surgically have had a lower mortality rate. In a cohort with flail mitral leaflet, patients with severe MR treated surgically had 5-and 10-year survival rates no different than expected for age-matched controls, and surgery independently and beneficially influenced survival rate (Munoz et al. 1975, Braunwald 1997, Cooper & Gersh 1998). Indications for corrective surgery Patients with symptoms of severe (3–4/4) mitral regurgitation despite normal LV systolic function (ejection fraction greater than 60 % and end-systolic dimension less than 40 mm) require surgery. Surgery should be performed in patients with mild symptoms and severe mitral regurgitation especially if it appears that mitral valve repair can be performed. Mitral valve surgery should also be recommended for symptomatic patients with evidence of LV dysfunction (an ejection fraction equal to or less than 60% and an end-systolic diameter equal to or more than 40 mm) (Bonow et al. 2006). Surgical treatment is also recommended for asymptomatic patients with severe MR and with signs of left ventricular dysfunction (ejection fraction less than 60% and/or left ventricular end-systolic diameter more than 40 mm). Surgery in this group should be considered to prevent any further deterioration of left ventricular function. Atrial fibrillation and pulmonary hypertension (a pulmonary systolic pressure of more than 50 mmHg at rest or 60 mmHg on exercise) are also indications for mitral valve surgery in these patients (Lung et al. 2002). Surgery for asymptomatic patients with severe MR and normal LV function should be considered if there is a greater than 90 % likelihood of successful valve repair in a center experienced in this procedure (Bonow et al. 2006). 33 Preoperative atrial fibrillation is an independent predictor of reduced longterm survival after mitral valve surgery for chronic mitral regurgitation (EnriquezSarano et al. 1994). Predictors of the persistence of atrial fibrillation after successful valve surgery are the presence of atrial fibrillation for more than one year and a left atrial size more than 50 mm. Many clinicians consider the recent onset of atrial fibrillation to be an indication in and of itself for surgery, if there is a high likelihood of valve repair (Bonow et al. 2006). In patients presenting for mitral valve operation with chronic atrial fibrillation, a concomitant Maze procedure may prevent future thromboembolic events by restoring normal sinus rhythm (Cox JL 2000). In severe mitral regurgitation secondary to acute myocardial infarction, hypotension and pulmonary edema often occur. Treatment is aimed at hemodynamic stabilization. Revascularization of the coronary artery supplying an ischemic papillary muscle may improve the degree of mitral valve regurgitation. Such an improvement is unlikely on most cases, however, and severe MR requires mitral valve repair with an annuloplasty ring or replacement (Bonow et al. 2006). Surgical indications in cases with ischemic mitral regurgitation are controversial. The indication for mitral valve operation in the patient who undergoes CABG with mild to moderate MR is still unclear, but data does exist to indicate a benefit of mitral valve repair in such patients. (Prifti et al. 2001). In patients undergoing coronary artery bypass grafting, grade 3 to 4 MR should be addressed (Gillinov & Cosgrove 2003). Mitral valve repair could be offered to selected patients with ischemic cardiomyopathy and functional mitral regurgitation. These patients should be offered surgery only if they have grade 3+ or 4 mitral regurgitation (Bolling et al. 1998, Chen et al. 1998, Bishay et al. 2000). Surgical indication in cases of endocarditis is well established. This includes heart failure unresponsive to medical therapy, multiple embolic events, uncontrolled sepsis, and an extension of the infection into surrounding structures. In addition, early operation is indicated for fungal and staphylococcal infections (Gillinov & Cosgrove 2003). 2.2.6 Surgical procedures Three different mitral operations are currently used for the correction of mitral regurgitation: mitral valve repair, mitral valve replacement with preservation of part or all the mitral apparatus, and mitral valve replacement with removal of the mitral apparatus. In most cases, mitral valve repair is the operation of choice when 34 the valve is suitable for repair and the appropriate surgical skill and expertise are available. This procedure preserves the patient`s native valve without a prosthesis and therefore avoids the risk of chronic anticoagulation or prosthetic valve failure late after surgery. Preservation of the mitral apparatus leads to better postoperative LV function and survival than in cases in which the apparatus is disrupted (Bonow et al. 2006). The choice of procedure depends upon the cause of the mitral regurgitation, the anatomy of the mitral valve, and the degree of left ventricle dysfunction. The advantages of mitral valve repair over mitral valve replacement include improved long-term survival, a better preservation of left ventricular function, and greater freedom from endocarditis, thromboembolism and anticoagulant-related hemorrhage (Gillinov & Cosgrove 2003). With the introduction of standardized surgical techniques (Carpentier et al. 1971, Duran et al. 1978, David et al. 1993, Gillinov et al. 1998), mitral valve repair has become reproducible and worldwide performed. In experienced centres, valve repair is currently a feasible surgical option in 70% to 90% of cases of pure or predominant mitral regurgitation and should be feasible in nearly all instances of degenerative mitral valve disease (Cooper & Gersh 1998, Barlow JB 1996). For proper identification of the location of lesions in the leaflets, a segmental classification has been created. The three scallops of the posterior leaflet are designated as P1 (close to the anterolateral commisure), P2 (the middle scallop), and P3 (close to the posteromedial commisure). The corresponding segments of the anterior leaflet are called A1, A2 and A3 (Figure 4). The aim of mitral valve repair is to obtain a valve that no longer leaks, and also to achieve anatomical restoration of all components of the mitral apparatus. Mechanical stress on the valve should be reduced to a minimum. Standard mitral valve repair is based on two main groups of technical steps: to correct any abnormal motion of the leaflets and chordal apparatus and to remodel and stabilise the annulus by implantation of the supporting ring (De Oliveira et al. 2006). Isolated prolapse of the posterior leaflet is the most frequent lesion leading to mitral regurgitation and accounts for up to 60% of the cases in most surgical series (De Oliveira et al. 2006). Prolapse of the posterior leaflet, whether the result of ruptured chordae or elongated chordae, is treated by quadrangular resection of the prolapsing segment, annular plication in the corresponding area, and a subsequent suture of the free edges of the leaflets (Carpentier 1983). The sliding repair of the posterior leaflet, an alternative for posterior annular plication, was devised by Carpentier to prevent left ventricular outflow tract obstruction caused by systolic 35 anterior motion (SAM) of the anterior leaflet of the mitral valve (Carpentier 1988). SAM only occurs in patients undergoing a quadrangular resection for degenerative disease and, before the development of the sliding leaflet repair. SAM could compromise the repair in 5% to 10% of cases (Gillinov & Cosgrove III 2003). Quadrangular resection of the prolapsing segment may include up to 50% of the length of the posterior leaflet if necessary (De Oliveira et al. 2006). Fig. 5. Surgical technique used to repair a flail segment of the middle scallop of the posterior leaflet. (a) Redundant area is isolated. (b) Flail or redundant areas are excised. (c) Annuloplasty is performed with a pledgeted suture and the leaflets are reapproximated using 5–0 suture. (d) Posterior annuloplasty device is inserted. Modified from Duran 1992. Prolapse of the anterior leaflet requires a different technique for repair (Gillinov & Cosgrove 2003). This situation is usually the result of elongation or rupture of the anterior leaflet chordae. Anterior leaflet resection is rarely indicated, because there may not be enough tissue for reconstruction of the leaflet (De Oliveira et al. 2006). Carpentier described two techniques effective for restoring normal motion in the leaflet. The first is chordal or papillary muscle shortening and the second technique is chordal transfer (Carpentier 1983). David was one of the pioneers who used polytetrafluoroethylene (PTFE) sutures as neochordae (David 1989). Annular enlargement is quite common in patients with degenerative disease. This usually only occurs along the posterior annulus. Annuloplasty is performed to 36 correct annular dilatation, increase leaflet coaptation, reinforce suture lines, and prevent further dilatation. Annuloplasty rings may be flexible or rigid, complete or incomplete (Gillinov & Cosgrove III 2003). In 1995, Alfieri et al. described the edge-to-edge repair which is also called double orifice repair (Fucci et al. 1995). When employed to correct anterior leaflet prolapse, a suture affixes the free edge of a segment of the normal posterior leaflet to the free edge of a prolapsing portion of the anterior leaflet. The normal posterior leaflet with its chordae serves to anchor the anterior leaflet, restricting its excessive motion (Fucci et al. 1995, Alfieri et al. 2001). Satisfactory mid-term results with this technique have been reported (Kuduvalli et al. 2006, Oc et al. 2005). This technique is currently also being performed percutaneously with encouraging results (Feldman et al. 2006). Patient with ischemic MR, CABG alone is usually insufficient and leaves many suffering a significant residual MR. These patients would benefit from concomitant mitral valve repair at the time of the CABG. Mitral annuloplasty alone with a downsized annuloplasty ring is often effective for relieving MR (Gillinov et al. 2001). Functional MR is generally manageable with annuloplasty alone. Functional MR may be corrected by placement of an annuloplasty ring which decreases the annular circumference, shortens the intertrigonal distance, reduces the septallateral (anterior-posterior) annular diameter, and restores the geometry of the annulus, thereby allowing the mitral valve leaflets to coapt (Prifti et al. 2001). The precise choice of the type of annuloplasty (flexible vs. rigid, complete vs. incomplete) is still controversial (Gillinov et al. 1998, Bolling et al. 1998). Resection of the secondary chordae of the posterior leaflet may permit some additional mobility of this structure and better coaptation. The issue of leaflet tethering by malalignment of the papillary muscles, which results from progressive left ventricle dilatation, can not yet be solved by surgery. New solutions have been proposed, such as the Coapsys annuloplasty system (called Myocor), in which artificial chords are implanted across the left ventricular cavity and supported by synthetic buttons over the epicardium. A new annuloplasty ring, geoForm, has been launched. It has a much narrower anteroposterior diameter and a camel hump shape that suspends the postero-basal portion of the annulus and ventricular wall (De Oliveira et al. 2006.) If leaflet tethering is extensive and annuloplasty fails, mitral valve replacement and preservation of the subvalvular apparatus is indicated (David & Ho 1986). 37 Eighty percent of infected mitral valves are amenable to repair. Radical debridement is a cornerstone of the operative treatment of endocarditis. All infected material must be removed. Leaflet perforations are repaired with autologous patches, while abscess cavities are debrided and excluded with a pericardial patch (Gillinov & Cosgrove III 2003). 2.2.7 Results of mitral valve surgery in mitral regurgitation The outcome of patients who have undergone mitral valve repair is excellent. In a review of 1072 patients who underwent primary isolated mitral valve repair for mitral regurgitation due to degenerative disease in the Cleveland Clinic, the inhospital mortality was 0.3% (Gillinov et al. 1998). The long-term outcome was addressed in another series of 242 patients followed for eight years after valve repair, the survival rate being 91% (Flameng et al. 2003). Mitral valve replacement, previously the only surgical option, is associated with an operative mortality rate of 2% to 7%, as well as the long-term risks associated with a prosthetic valve. No randomized trials have been published comparing these two operations. A number of retrospective studies have demonstrated improved LV function and survival in patients undergoing valve repair as compared to valve replacement with or without preservation of the subvalvular apparatus. EnriquezSarano et al. performed a comparative analysis of patients undergoing mitral valve repair (195 patients) or mitral valve replacement (214 patients) at the Mayo clinic between 1980 and 1990 (Enriquez-Sarano et al 1995). Patients undergoing valve repair were less symptomatic and had better LV function. Valve repair remained an independent favourable predictor of operative mortality rate, late survival at 5 and 19 years, and postoperative ejection fraction. Survival was 100% of the expected survival in the valve repair group at 10 years, whereas in the valve replacement group it was only 83% of that expected (Enriquez-Sarano et al. 1995). Thromboembolism is uncommon after mitral valve repair in contrast with prosthetic mitral valve replacement. Warfarin is usually only used for three months after mitral valve repair unless chronic atrial fibrillation is present, and anticoagulant-related hemorrhage is therefore almost nonexistent. Furthermore, repaired mitral valves suffer bacterial endocarditis much less frequently than prosthetic valves (Lawrie 1998). Braunberger et al. (Braunberger et al. 2001) reported very long-term results (more than 20 years) of 162 patients who underwent mitral valve repair performed by Carpentier`s group between 1970 and 1984. The valves were repaired using the 38 techniques of Carpentier. The 20-year Kaplan-Meier survival rate was 48%, which is similar to the survival rate for a normal population with the same age structure. During the 20 years of follow-up, 7 patients underwent reoperation. Valve replacement was carried out in 5 patients, and repeat repair was carried out in 2 patients (Braunberger et al. 2001). Carpentier reported on a comparison of 100 mitral valve repairs with 100 porcine valves, 100 Starr valves and 100 Björk valves. The clinical characteristics of the patients were similar. Hospital mortality was 2% for repair and 12% to 13% for prosthesis. Survival at 7 years was 82% after mitral valve repair and 56% to 61% after mitral valve replacement. Freedom from thromboembolism was 96% after mitral valve repair, 94% after mitral valve replacement with porcine valves, and 70% and 68% after mitral valve replacement with mechanical valves. No fatal thromboembolism occurred in the mitral valve repair group compared with a 20% to 28% fatal thromboembolism rate in the prosthetic groups. The risk for reoperation at 7 years was 13% after mitral valve repair, 8.5% after mitral valve replacement with a bioprosthesis, 8% after replacement with a Starr prosthesis, and 18% after replacement with Björk valves (Carpentier et al. 1983). Chauvaud et al. (2001) reported excellent long-term results of reconstructive surgery in rheumatic mitral valve insufficiency. The surgical techniques used were implantation of a prosthetic ring in 95%, shortening of the chords and leaflet enlargement with autologous pericardium, and commisurotomy. Hospital mortality rate was 2% and the mean follow-up was 12 years. Freedom from reoperation was 82±19% at 10 years and 55±25% at 20 years. The main cause (83%) of reoperation was progressive fibrosis of the mitral valve. Goldsmith and colleagues reported on improvement in the quality of life, as assessed by a short form 36 questionnaire, 3 months after mitral valve repair and replacement (Goldsmith et al. 2001). Mitral valve repair was associated with a significant increase in 7 out of 8 parameters, whereas after mitral valve replacement the improvement was modest. Mitral valve repair was found to be an independent predictor of early better quality of life (Goldsmith et al. 2001). The same authors also observed an improvement of quality of life in patients aged 75 years or older who underwent mitral valve surgery (Goldsmith et al. 1999). Functional ischaemic mitral regurgitation is difficult to repair due to the complex mechanism involved in the development of this condition. Surgical treatment of functional ischemic mitral regurgitation is associated with poor longterm survival. Operative mortality ranges from 5 to 10%, and 5-year survival was only about 50%, while 30% of the patients have significant recurrent mitral 39 regurgitation, as shown by McGee from Cleveland Clinic in a series of 585 patients (McGee et al. 2004). Bolling and others reported excellent freedom from recurrent mitral regurgitation in patients with ischemic cardiomyopathy (Bolling et al. 1998, Bishay et al. 2000). Calafiore reported a higher five year survival with mitral valve repair (75%) than with mitral valve replacement (66%) (Calafiore et al. 2004). In patients operated on for endocarditis, hospital mortality is 0% to 7% (Gillinov & Cosgrove 2003). When compared to replacement, repair of the infected mitral valve results in greater freedom from recurrent infection and better early and late survival (Muehrcke et al. 1997). These results demonstrated the low operative risk associated with the procedure and the durability of mitral valve repair in the long run, which makes this operation the gold standard in surgical treatment of degenerative mitral valve regurgitation The results in other types of pathology are less favourable, but generally superior to those observed with valve replacement (De Oliveira et al. 2006). Patient selection, accurate evaluation of the cause or causes of mitral regurgitation, and a well-executed operation using the appropriate repair technique are all critical factors in the early and late success of mitral valve repair. 40 3 Aims of the study The aims of the present study were: 1. To identify those variables which were associated with an increased risk of immediate postoperative mortality after mitral valve repair. 2. To evaluate the long-term results and to identify the risk factors associated with late adverse events after mitral valve repair. 3. To compare the quality of life of patients who had undergone mitral valve repair with that of an age- and gender-adjusted Finnish general population using the RAND-36 Health Survey. 4. To investigate the value of the European system for cardiac operative risk evaluation score (EuroSCORE) for prediction of the immediate and late outcome after mitral valve repair and replacement for mitral valve regurgitation. 41 42 4 Materials and methods 4.1 Material In studies I–III, one-hundred and sixty-four consecutive patients (mean age 60.7, median 63.0, interquartile range 53.1–68.6) underwent mitral valve repair either isolated or in combination with other procedures at our institution from January, 1993 to December, 2000. Any mitral valve repair performed as a lone procedure or associated with any other cardiac procedure was included in these studies. Figure 6 depicts the number of mitral valve repairs done annually since 1993 and shows an increase in the number of mitral valve repairs performed during the last years of the series. 40 Overall no. of M VRs No. of MVRs associated with other procedures 11.4% 35 10.3% No. of M VRs/year 30 25 4.8% 10.5% 20 5.9% 15 0% 0% 0% 10 5 0 1993 1994 1995 1996 1997 1998 1999 2000 Fig. 6. Number of mitral valve repairs (MVRs) performed each year. Percentages represent the 30-day mortality rate for each year. No significant association was observed between the year of operation and postoperative mortality (p=0.64). Data on pre-, intra- and postoperative variables were collected retrospectively from patients’ records. Data on postoperative outcome after discharge from the cardiac surgery ward were obtained by reviewing the hospital records inclusive of data from all wards in our hospital. If the patient was discharged to another hospital for medical treatment or rehabilitation, outcome data were retrieved from 43 discharge records of these institutions. Furthermore, patients were contacted by mail and causes of late death obtained from a national registry. In the second study, seventy-two long term survivors residing in the area close to our Institution were evaluated using transthoracic echocardiography a median of 5.6 years (25 and 75 interquartile range, 3.8–7.5) after mitral valve repair. The echocardiographic examination was carried out in our institution or in those central hospitals where resources were available for long-term follow-up. Survival outcome has been evaluated as secondary to all causes of death, cardiovascular causes (cardiac causes and stroke) or cardiac causes (including immediate postoperative deaths). In the third study, the validated Finnish version of the RAND-36 Health Survey questionnaire (Hays et al. 1993, Aalto et al. 1999) has been sent by surface mail to all long-term survivors. Among 130 late survivors after mitral valve repair, 109 (83.8%) answered the RAND-36 Health Survey questionnaire and form the basis for that study. The quality of life as assessed by the RAND-36 Health Survey in these patients was compared to that of an age- and gender-adjusted Finnish general population as previously assessed by Aalto and collaborators (Aalto et al. 1999). Preoperative risk factors of studies I and II are summarized in Table 1, respectively. Table 2 summarizes the clinical data of the patients included in study III. 44 Table 1. Preoperative demographics (Study I and II). Variables No. (%) Age 63.0 (53.1–68.6) Females/males 42 (25.6) / 122 (74.4) 1.9 (1.8–2.0) Body surface area (m2) 25.6 (23.0–28.0) Body mass index (kg/m2) Asthma / chronic obstructive pulmonary disease 12 (7.3) Lower limb ischemia 7 (4.3) Hypertension 26 (15.9) Hyperlipidemia 14 (8.5) Diabetes 16 (9.8) Transient ischemic attack / stroke () Active endocarditis 0 Coronary artery disease 61 (37.2) Previous myocardial infarction 21 (12.8) Recent myocardial infarction 7 (4.3) Unstable angina pectoris 4 (2.4) Left main disease 11 (6.7) NYHA functional class I 4 (2.4) II 69 (42.1) III 59 (36.0) IV 32 (19.5) Atrial fibrillation 37 (22.6) Mitral valve pathology Annulus dilatation 4 (2.4) Anterior leaflet disease 31 (18.9) Posterior leaflet disease 88 (53.7) Both anterior and posterior leaflet involved 11 (6.7) Ruptured chordae 59 (36.0) Ruptured papillary muscle 1 (0.6) Calcified annulus 12 (7.3) Etiology Myxomatous degeneration 139 (84.8) Rheumatic 3 (1.8) Ischemic 6 (3.7) Endocarditis 4 (2.4) Penetrating trauma 2 (1.2) No evident cause 10 (6.1) Type Mitral regurgitation 162 (98.8) Mitral regurgitation and stenosis 2 (1.2) Prior cardiac operation 11 (6.7) Coronary artery bypass surgery 4 (2.4) Atrial septal defect repair 4 (2.4) Mitral valve repair 1 (0.6) Aortic coartaction 1 (0.6) Penthalogy of Fallot 1 (0.6) Left ventricular ejection fraction (158 pts) 65 (57–71) Left atrium diameter (mm) (137 pts) 50 (46–56) Mitral valve regurgitation grade II 11(6.7) III 104(63.4) IV 44(26.8) Mean pulmonary artery pressure (mmHg) (147 pts) 26 (20–34) 2.33 (2.02–2.90) Cardiac index (L/min/m2) (155 pts) Continuous variables are reported as the median plus 25th and 75th interquartile range. NYHA: New York Heart Association. 45 Table 2. Preoperative characteristics of mitral valve repair patients (Study III). Variables Mean age (years) Gender ratio (F:M) Mean body surface area (m2) Mean body mass index (kg/m2) Asthma / chronic obstructive pulmonary disease Lower limb ischemia Hypertension Hyperlipidemia Diabetes Transient ischemic attack / stroke Active endocarditis Coronary artery disease Previous myocardial infarction Recent myocardial infarction Unstable angina pectoris Left main disease NYHA functional class I II III IV Atrial fibrillation Mitral valve regurgitation grade II III IV Etiology Myxomatous degeneration Rheumatic Ischemic Endocarditis Penetrating trauma No evident cause Prior cardiac operation Atrial septal defect repair Mean left ventricular ejection fraction (%) NYHA: New York Heart Association. No. (%) 60.4 (median 63.0, IQR 52.9–68.1) 28(25.7)/81 (74.3) 1.9 (median 1.9, IQR 1.8–2.0) 25.8 (median 25.4, IQR 22.8–27.7) 7 (6.4) 6 (5.5) 13 (11.9) 11 (10.1) 7 (6.4) 6 (5.5) 0 (0) 7 (6.4) 3 (2.8) 2 (1.8) 9 (8.3) 4 (3.7) 58 (53.2) 33 (30.3) 14 (12.8) 21 (19.3) 9 (8.3) 71 (65.1) 28 (25.7) 94 (86.2) 3 (2.8) 5 (4.6) 3 (2.8) 2 (1.8) 2 (1.8) 2 (1.8) 63 (median 65, IQR 57–70) In study IV, two-hundred and seven patients underwent mitral valve repair or replacement for mitral valve regurgitation at our institution from 1993 to 2000. Data on 180 patients were available for the retrospective calculation of additive and logistic EuroSCORE (Nashef et al. 1999, Roques et al. 2003b). Postoperative outcome after discharge from the cardiac surgery ward was obtained by reviewing the hospital records inclusive of data from all wards of our hospital. If the patient was discharged to another hospital for medical treatment or rehabilitation, outcome data was retrieved from discharge records of the latter institutions. Preoperative risk factors in the overall series as well as in the mitral valve replacement and mitral valve repair group are summarized in Table 3. 46 Table 3. Preoperative characteristics (Study IV) Variables Age (years) Overall (%) Mitral valve repair (%) Mitral valve replacement (%) p-value 63.3 (53.8–69.2) 63.1 (53.3–68.8) 65.2 (56.6–73.1) 0.22 Females 56 (31.1) 38 (27.0) 18 (46.2) 0.022 Asthma / COPD 14 (7.8) 10 (7.1) 4 (10.3) 0.51 Extracardiac arteriopathy 7 (3.9) 5 (3.5) 2 (5.1) 0.64 Neurological dysfunction 9 (5.0) 6 (4.3) 3 (7.7) 0.41 Prior cardiac operation 14 (7.8) 11 (7.8) 3 (7.7) 1.00 4 (2.2) 1 ((0.6) 4 (2.2) 3 (1.7) 1 (0.6) 4 (2.8) 0 4 (2.8) 1 (0.7) 1 (0.7) 1 (0.7) 0 1 (2.6) 0 2 (5.1) 0 0 – – – – – – Serum creatinine>200 µmol/L 3 (1.7) 1 (0.7) 2 (5.1) 0.12 Active endocarditis 3 (1.7) 0 3 (7.7) 0.010 Coronary artery bypass surgery Aortic valve replacement Atrial septal defect repair Mitral valve repair Aortic coartaction Penthalogy of Fallot Congestive heart failure 16 (8.9) 9 (6.4) 7 (17.9) 0.025 Critical pre-operative state 10 (5.6) 2 (1.4) 8 (20.5) <0.0001 Diabetes 17 (9.4) 12 (8.5) 5 (12.8) 0.53 Coronary artery disease 68 (37.8) 52 (36.9) 16 (41.0) 0.64 28 (15.6) 14 (7.8) 9 (5.0) 17 (12.1) 4 (2.8) 4 (2.8) 11 (28.2) 10 (25.6) 5 (12.8) 0.014 <0.0001 0.024 1 (0.6) 13 (7.2) 106 (58.9) 53 (29.4) 0 8 (5.8) 92 (67.2) 37 (27.0) 1 (2.8) 5 (13.9) 14 (38.9) 16 (44.4) – – – – <0.0001 Previous myocardial infarction Myocardial infarction<3 months Unstable angina pectoris Regurgitation grade (173 patients) 1 2 3 4 0.005 NYHA functional class III–IV 112 (62.6) 77 (54.6) 35 (92.1) Atrial fibrillation (174 patients) 39 (21.7) 32 (23.0) 7 (20.0) 0.018 Systolic pulmonary artery pressure>60 mmHg 46 (25.6) 26 (18.4) 20 (51.3) <0.0001 126 (70.0) 39 (21.7) 15 (8.3) 114 (80.9) 23 (16.3) 4 (2.8) 12 (30.8) 16 (41.0) 11 (28.2) 149 (82.8) 4 (2.2) 10 (5.6) 7 (3.9) 2 (1.1) 8 (4.4) 119 (84.4) 3 (2.1) 5 (3.5) 4 (2.8) 2 (1.4) 8 (5.7) 30 (76.9) 1 (2.6) 5 (12.8) 3 (7.7) 0 0 – – – – – – 32 (17.8) 20 (14.2) 12 (30.8) 0.017 Type of operation Elective operation Urgent operation Emergent operation <0.0001 Etiology Myxomatous degeneration Rheumatic Ischemic Endocarditis Trauma No evident cause Left ventricular ejection fraction<50% Additive EuroSCORE Logistic EuroSCORE (%) – – – 0.09 5 (3–7) 4 (3–6) 8 (5–11) <0.0001 3.7 (2.1–7.6) 3.2 (1.9–5.8) 10.0 (4.0–26.8) <0.0001 Continuous variables are reported as the median plus 25th and 75th interquartile range. P-value is for difference between mitral valve repair and replacement groups. COPD: chronic obstructive pulmonary disease. NYHA: New York Heart Association functional class. 47 4.2 Methods A coronary angiography was routinely performed to assess the status of the coronary arteries and, in patients previously having undergone coronary artery bypass surgery, of the bypass grafts. The operation was performed through a median sternotomy employing moderate systemic hypothermia and antegrade/ retrograde cold blood cardioplegia. A transesophageal echocardiographic examination was carried out intraoperatively immediately before and after repair in all patients. Transthoracic echocardiography was performed before discharge in 152 patients. Low molecular weight heparin was administered postoperatively during the hospital stay and was followed by warfarin for three months, unless the patients had a prosthetic valve or chronic atrial fibrillation which was an indication for permanent anticoagulation treatment. The operative details for studies I and II are summarized in Table 4, while those for study III are summarized in table 5. 48 Table 4. Operative details (Study I and II). Variables No. (%) Type of operation Elective 131 (79.9) Urgent 26 (15.9) Emergent 7 (4.3) Atrial incision Superior 98 (59.8) Transseptal 31 (18.9) Lateral 28 (17.1) Other 7 (4.2) Findings at operation Annulus dilatation 23 (14.0) Anterior leaflet disease 28 (17.1) Posterior leaflet disease 77 (47.0) Both anterior and posterior leaflet involved 31 (18.9) Ruptured chordae 87 (53.0) Ruptured papillary muscle 5 (3.0) Calcified valve 2 (1.2) Annuloplasty 155 (94.5) Ring annuloplasty 101 (65.1) Other 54 (34.8) Leaflet resection and reconstruction 118 (72.0) Shortening of the chordae 12 (7.3) Chordae reconstruction with PTFE thread 34 (20.7) Associated procedures 84 (51.2) Coronary artery bypass surgery 58 (35.4) Tricuspid valve repair 20 (12.2) Atrial septal defect closure 10 (6.1) Maze 8 (4.9) Aortic valve replacement 1 (0.6) Aortic clamping time (min) 135 (113–177) Cardiopulmonary bypass duration (min) 183 (154–233) Length of operation (min) 275 (240–339) Intraoperative bleeding (mL) 800 (500–1275) PTFE: polytetrafluoroethylene 49 Table 5. Operative details (Study III). Variables No. (%) Type of operation Elective Urgent Emergent 93 (85.3) 12 (11.0) 4 (3.7) Findings at operation Annulus dilatation Anterior leaflet disease Posterior leaflet disease Both anterior and posterior leaflet involved Ruptured chordae Ruptured papillary muscle Calcified valve 12 (11.0) 15 (13.8) 55 (50.5) 25 (22.9) 61 (56.0) 2 (1.8) 0 (0) Ring annuloplasty 62 (56.9) Other annuloplasties 42 (38.5) Leaflet resection and reconstruction 86 (78.9) Shortening of the chordae Chordae reconstruction with PTFE thread 8 (7.3) 25 (22.9) Associated procedures Coronary artery bypass surgery Tricuspid valve repair Atrial septal defect closure Maze Aortic valve replacement 32 (29.4) 6 (5.5) 4 (3.7) 5 (4.6) 1 (0.9) Mean aortic clamping time (min) 142 (median 134, IQR 112–177) Mean cardiopulmonary bypass duration (min) 189 (median 179, IQR 153–216) Length of operation (min) 285 (median 270, IQR 240–310) Intraoperative bleeding (mL) 957 (median 700, IQR 500–1025) PTFE: polytetrafluoroethylene. In study IV, a St Jude Medical mechanical prosthesis (median size: 29 mm. IQR 27–31 mm) was used in all patients undergoing mitral valve replacement. The operative details for this study are summarized in Table 6. 50 Table 6. Operative details (Study IV). Variables Overall (%) Mitral valve repair (%) Mitral valve replacement (%) p-value 24 (13.3) 34 (18.9) 77 (42.8) 30 (16.7) 89 (49.4) 5 (2.8) 7 (48.9) 19 (13.5) 25 (17.7) 67 (47.5) 27 (19.1) 75 (53.2) 4 (2.8) 1 (0.7) 5 (12.8) 9 (23.1) 10 (25.6) 3 (7.7) 14 (35.9) 1 (2.6) 6 (15.4) 0.91 0.49 0.015 0.14 0.056 1.00 <0.0001 88 (48.9) 44 (24.4) – – – – - Findings at operation Annulus dilatation Anterior leaflet disease Posterior leaflet disease Both anterior and posterior leaflet involved Ruptured chordae Ruptured papillary muscle Calcified valve Annuloplasty Ring annuloplasty Other 101 (56.1) – – - Shortening of the chordae Leaflet resection and reconstruction 12 (6.7) – – - Chordae reconstruction with PTFE thread 31 (17.2) – – – 67 (37.2) 10 (5.6) 18 (10.0) 10 (5.6) 7 (3.9) 50 (35.5) 1 (0.7) 16 (11.3) 8 (5.7) 7 (5.0) 22 (56.4) 9 (23.1) 2 (5.1) 2 (5.1) 0 0.35 <0.0001 0.37 1.00 0.15 Aortic clamping time (min) 139 (114–182) 134 (113– 179) 156 (118–203) 0.090 Cardiopulmonary bypass duration (min) 189 (155–242) 183 (154– 234) 224 (170–260) 0.049 Length of operation (min) 285 (240–360) 275 (240– 349) 345 (265–380) 0.018 Associated procedures Coronary artery bypass surgery Aortic valve replacement Tricuspid valve repair Atrial septal defect closure Maze PTFE: polytetrafluoroethylene. P-value is for difference between mitral valve repair and replacement groups. 4.3 Statistical analysis Statistical analysis was performed using SPSS statistical software (SPSS v. 10.0.5 SPSS Inc., Chicago, IL, USA). Continuous variables were reported as the mean and median with 25th and 75th interquartile range (IQR). In study I, the Chi-square test and the Fisher`s exact test, with or without the Monte Carlo method, were used for univariate analysis of categorical data. The Mann-Whitney test was used to assess the distribution of continuous variables in different subgroups. The receiver operating characteristics (ROC) curve was used for identification of the best cutoff value of age in predicting postoperative adverse outcome. Logistic regression with the help of backward selection was used for multivariable analysis. In study II, the Kaplan-Meier method and Cox regression was used to evaluate the impact of variables on the long-term outcome. Only preoperative variables with p51 values<0.05 at univariate analysis were considered for inclusion in the regression model in both studies. In study III, the Wilcoxon test was used to assess any difference in terms of quality of life-related variables between the present patients and an age- and gender-adjusted general Finnish population. The Kaplan-Meier method was used to estimate survival. In study IV, a receiver operating characteristics (ROC) curve was used to evaluate the impact of additive and logistic EuroSCOREs on immediate postoperative mortality. The Kaplan-Meier method was used to estimate the long-term outcome. The Kaplan-Meier method and Cox regression were used to evaluate the impact of EuroSCOREs on longterm survival. Cox regression was used for multivariable analysis. In all studies, a p-value less than 0.05 was considered to be statistically significant. 52 5 Results 5.1 Predictors of postoperative mortality after mitral valve repair 5.1.1 Overall outcome Eleven (6.7%) out of 164 patients died during the immediate postoperative period, a median of 14 days after surgery (range 1–29 days). Data on the main preoperative variables and cause of death in these patients are reported in Table 7. The overall postoperative complications encountered in this series are listed in Table 8. 53 54 Female 11 67.7 51.3 73.0 77.2 79.4 65.7 69.5 82.6 63.3 74.2 65.2 Age (years) IV III III IV IV IV III III III III IV NYHA functional class 60 68 – 60 72 30 65 73 67 65 32 2.12 1.87 2.77 2.59 1.37 1.89 1.57 1.77 1.99 2.02 – 3 4 3 4 3 3 4 3 3 4 3 sinus FA FA Sinus FA Sinus FA Sinus FA Sinus FA Cardiac LVEF (%) Cardiac index Preop. MV regurgitation rythm (L/min/m2) grade CABG TVP CABG CABG CABG TVP No TVP Associated procedures 2 0 – 0 0 0 0 1 No No CABG Cox-Maze 2 1 29 7 21 8 23 1 21 25 13 14 4 Postop. MV Postop. regurgitatio day of n grade death CABG, ASD CABG, TVP, – ASD No No CABG MVA No No No CABG Prior cardiac surgery LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; MV: mitral valve, MVA: mitral valve annuloplasty; CABG: coronary artery bypass grafting; ASD: repair of atrial septal defect, TVP: tricuspid valve plasty; AMI:acute myocardial infarction; MOF: multiorgan failure; – : unknown. Male 10 Male 6 Male Male 9 Male 4 5 Female Male 3 Male Male 8 Male 1 2 7 Gender Pts. Table 7. Details of the patients who died immediately after the operation. AMI Sepsis, pneumonia MOF AMI Sepsis AMI MOF AMI Bleeding from trachestomy Cardiac tamponade AMI Causes of death Table 8. Postoperative complications (Study I). Type of postoperative complications No. (%) Postoperative bleeding requiring reoperation 22 (13.4) Postpericardiotomy syndrome 20 (12.2) Respiratory complications 19 (11.6) Renal complications 6 (3.7) Myocardial infarction 5 (3.0) Stroke 5 (3.0) Multiorgan failure 2 (1.2) Transient ischemic attack 1 (0.6) Wound complications 1 (0.6) Mediastinitis 1 (0.6) When patient age, NYHA functional class, unstable angina pectoris, cardiac rhythm, baseline cardiac index, history of prior cardiac surgery and concomitant procedures were included in the regression model (154 patients included in the analysis), patient age (median age of deaths/survivors: 69.4/61.8 years; p=0.006, for an increase of 10 units: OR 4.33, 95% CI 1.53–12.27), history of prior cardiac surgery (mortality rates with and without risk factor: 36.4% vs. 4.6%, p=0.006, OR 118.56, 95% CI 4.03–3491.14) and NYHA functional class (mortality rates: NYHA I: 0%, NYHA II: 0%, NYHA III: 10.2%, NYHA IV: 15.6%; p=0.011, OR 5.66, 95% CI 1.49–21.49) were shown to be significantly associated with an increased risk of postoperative death. The ROC curve for the data showed that patients’ age had an area under the curve of 0.762 (95% CI 0.622–0.901, p=0.004), its best cut-off value being 65 years (mortality in higher vs. lower age category: 13.4% vs. 2.1%; p=0.008, sensitivity 81.8%, specificity 62.1%, accuracy 63.4%). Age significantly correlated with baseline cardiac index (p<0.0001) and preoperative serum level of creatinine (p=0.006). Atrial fibrillation was significantly associated with older age (median, 65.9 vs. 60.8 years, p=0.024). Figure 7 depicts the increased mortality risk of patients aged more than 65 years undergoing MVR with a history of prior cardiac surgery. 55 100% (4/4 pts) 80 40 7.9% (5/63 pts) 20 0% (0/7 pts) Po st op erat iv 60 e m or ta lit y ra te (% ) 1 00 0a c ≥6 5y ea i rd ca u s t io n o i e v ra Pr op e 2.2% (2/90 pts) rs <6 5y ea rs d ar sc ou on i e v ti p r e ra No op ia c Fig. 7. Increase of postoperative mortality after mitral valve repair by increasing age in patients with or without a history of prior cardiac surgery (p< 0.0001). 5.1.2 Immediate postoperative outcome after mitral valve repair as a lone procedure Among patients who underwent mitral valve repair as lone procedure, only three patients had a history of prior cardiac surgery. One patient (1.3%) died postoperatively. He was a 74-year-old man who underwent elective operation and died of cardiac tamponade 14 days after surgery (patient 2, table 7). 5.1.3 Immediate postoperative outcome after mitral valve repair with concomitant procedures Among 84 patients who underwent MVR associated with other procedures, 10 (11.9%) died postoperatively. The postoperative mortality was similar when the analysis was restricted to those patients who had concomitant procedures other than Maze (9 out of 77 patients, 11.7%). Univariate analysis showed that a history of prior cardiac operation (p=0.006), age (p=0.040), body mass index (p=0.017), NYHA functional class (p=0.024) and 56 mean pulmonary artery pressure (p=0.023) were associated with an increased risk of postoperative death. When these factors were included in the regression model, a history of prior cardiac operation (p=0.05, OR 115.50, 95% CI 1.01–13228.35), age (p=0.027, for an increase of 10 units: OR 3.80, 95% CI 1.12–12.76) and NYHA functional class (p=0.032, OR 5.89, 95% CI 1.17–29.80) were significantly associated with an increased risk of postoperative death. 5.2 Long-term outcome after mitral valve repair The median follow-up period was 4.9 years (IQR, 3.2–7.2). Among operative survivors, 12 patients died of cardiac causes (7.9%), two of stroke (1.3%), one of pneumonia (0.7%), three of cancer (2.0%), two of trauma (1.3%), one of postoperative multiorgan failure (0.7%), one of gastrointestinal bleeding (0.7%), and one of subdural haematoma (0.7%). Nine patients (5.5%) underwent repeat cardiac surgery after mitral valve repair, while eight patients (4.9%) underwent redo mitral valve surgery (6 patients underwent mitral valve replacement and 2 underwent repeat mitral valve repair) after a median of 2.0 years (IQR 1.3–4.7). Four of the nine patients underwent redo mitral valve surgery within one year of surgery. 5.2.1 Long-term survival The ten-year survival rate from any cause of death was 70.2% (Fig. 8), whereas survival freedom from any fatal cardiovascular event was 73.2% (Fig. 9). Survival freedom from any fatal cardiac event was 75.9% (Fig. 10). 57 Survival (%) Pts. at risk – 164 90.2 148 88.4 145 86.6 133 84.4 99 82.6 81 79.3 64 74.9 43 74.9 33 74.9 19 70.2 7 79.5 43 79.5 33 79.5 19 74.5 7 Fig. 8. Overall survival after mitral valve repair (SE<0.060). Survival (%) Pts. at risk – 164 91.5 149 90.8 145 90.2 133 88.6 99 87.6 81 84.7 64 Fig. 9. Survival freedom from any fatal cardiovascular event after mitral valve repair (SE<0.061). 58 Survival (%) – 91.5 90.8 90.2 90.2 89.2 85.8 80.9 80.9 80.9 75.9 Pts. at risk 164 148 145 133 99 81 64 43 33 19 7 Fig. 10. Survival freedom from any fatal cardiac event after mitral valve repair (SE<0.062). When the patients who died immediately after mitral valve repair were excluded from the survival analysis, the 10-year survival rate from any cause of death was 75.3% (SE 6.2%), survival freedom from any fatal cardiovascular event was 79.9% (SE 6.3%), and survival freedom from any fatal cardiac event was 81.3% (S.E 6.3%). Multivariable analysis showed that a history of previous cardiac surgery (p=0.009, RR 8.44, 95% CI 1.72–41.46), age (p=0.030, RR 1.08, 95% CI 1.01– 1.16), and atrial fibrillation (p=0.043, RR 3.27, 95% CI 1.04–10.29) were predictors of late cardiac death. At 10 years, survival freedom from fatal cardiac event was 36.3% in patients with a history of previous cardiac surgery and 78.6% in those who had not undergone any previous cardiac operation (p<0.0001). As previous cardiac surgery had a major impact especially on the immediate postoperative outcome, a subanalysis was done for prediction of late fatal cardiac event excluding operative deaths. Multivariable analysis showed that previous coronary artery bypass surgery (p=0.001, RR 155.26, 95% CI 7.74–3114.66) and concomitant coronary artery 59 bypass surgery (p=0.023, RR 4.81, 95% CI 1.24–18.65) were predictors of late cardiac death among operative survivors. 5.2.2 Survival freedom from redo mitral valve surgery The ten-year survival freedom from redo mitral valve surgery was 93.8% (Fig. 11). Survival (%) – 97.4 97.4 97.4 95.6 94.4 93.2 93.2 93.2 93.2 93.2 Pts. at risk 164 145 143 131 95 79 63 42 32 17 6 Fig. 11. Survival freedom from redo mitral valve surgery (SE<0.024). Table 9 summarizes the risk factors which the univariate analysis showed to be significantly associated with poor survival freedom after redo mitral valve surgery. Table 9. Preoperative risk factors predictive at univariate analysis of survival freedom after redo mitral valve surgery. Risk factors p-value RR (95% CI) Chronic obstructive pulmonary disease/asthma 0.004 8.17 (1.95–34.24) Calcified mitral valve 0.012 Immediate postoperative mitral valve regurgitation grade > 1 0.001 14.79 (1.80–121.33) 11.69 (2.60–52.56) Multivariable analysis showed that residual mitral valve regurgitation grade>1 as assessed during the immediate postoperative period (p=0.001, RR 21.64, 95% CI 3.60–130.20) and chronic obstructive pulmonary disease/asthma (p=0.013, RR 60 12.02, 95% CI 1.70–85.39) were predictors of late redo mitral valve surgery. Similar results were obtained when the variable use of bronchodilators/steroids (9 patients, p=0.006, RR 15.77, 95% CI 2.22–111.96) was included in the regression model instead of chronic obstructive pulmonary disease/asthma (12 patients). Multivariable analysis was restricted to 143 patients due to a lack of definitive immediate postoperative echocardiographic data in 12 patients, whereas 9 patients were censored due to a short follow-up. Ten-year survival freedom from redo mitral valve surgery was 95.7% in patients with an immediate postoperative mitral valve regurgitation 1 and 60.6% in those whose regurgitation grade was grade 2 (Fig. 12, p<0.0001). Fig. 12. Survival freedom from redo mitral valve surgery in 13 patients with a residual regurgitation grade 2 (--) (SE <19.7) versus 139 patients with a grade 0–1 (--) (SE < 0.021) as detected at echocardiography during the immediate postoperative period (log-rank test: p<0.0001). Ten-year survival freedom from redo mitral valve surgery was 66.8% in patients with chronic obstructive pulmonary disease/asthma and 95.2% in those without it (p=0.0006). 61 5.2.3 Survival freedom from stroke During the follow-up period, nine patients experienced stroke, four patients once and five patients twice. The ten-year survival freedom from stroke was 93.5% (Fig. 13). The linearized rate for stroke was 9.7%/patient-year. Survival (%) – 98.6 96.7 95.2 93.5 93.5 93.5 93.5 93.5 93.5 93.5 Pts. at risk 164 146 141 128 96 78 62 41 31 18 7 Fig. 13. Survival freedom from stroke (SE<0.021). 5.2.4 Long-term outcome among patients with myxomatous degenerative disease The immediate postoperative mortality was 6.5% (9 out of 139 patients). Among these patients with myxomatous degenerative mitral valve disease, the 10-year survival rate from any cause of death was 73.9%, whereas survival freedom from any fatal cardiovascular event was 83.7%. Survival freedom from any fatal cardiac event was 79.9%. These patients tended to have a better 10-year overall survival (73.9% vs. 53.9%, p=0.066) and a significantly better cardiovascular survival (83.7% vs. 62.8%, p=0.008) and cardiac survival (79.9% vs. 57.7%, p=0.015) than patients with other etiologies of mitral valve disease. When patients who died immediately after mitral valve repair were excluded from the survival analysis, the 10-year survival rate from any cause of death was 79.1%, survival freedom from any fatal cardiovascular event was 83.7%, and survival freedom from any fatal cardiac event was 85.5%. 62 When operative deaths were excluded from the analysis, a number of risk factors were shown to be associated with worse survival freedom from cardiac death (Table 10). Multivariable analysis showed that a low preoperative cardiac index was the only independent predictor of cardiac death (p=0.031, RR 0.10, 95% CI 0.014–0.81). At 10 years, survival freedom from fatal cardiac event was 89.1% in patients with a baseline cardiac index>2L/min/m2 and 73.7% in those with a baseline cardiac index<2L/min/m2 (log-rank, p=0.002). Table 10. Preoperative risk factors predictive at univariate analysis of survival freedom from fatal cardiac event after mitral valve repair for myxomatous degenerative mitral valve disease (operative deaths excluded). Risk factors p-value RR (95% CI) Age* 0.014 1.11 (1.02–1.22) Age > 65 years 0.0013 15.05 (1.76–128.99) Cerebrovascular disease 0.043 12.14 (1.08–137.03) Any previous or recent myocardial infarction 0.007 10.50 (1.88–58.62) Coronary artery disease 0.015 7.77 (1.49–40.53) Annulus dilatation 0.009 7.33 (1.63–32.99) Concomitant coronary artery bypass surgery* 0.014 7.93 (1.52–41.31) Only annuloplasty done as mitral valve repair* 0.011 6.94 (1.54–31.16) Baseline oxygen delivery 0.012 0.99 (0.98–0.99) Baseline oxygen delivery < 350 ml/min/m2 0.021 6.04 (1.31–27.88) Baseline cardiac index* 0.016 0.12 (0.02–0.67) RR: relative risk, C.I.: confidence interval. Asterisks indicate the variable included in the multivariable analysis. Disease other than isolated to the anterior leafleft (p=0.036, RR 9.40, 95% CI 1.15–76.75), rupture of a papillary muscle (p=0.023, RR 11.44, 95% CI 1.40– 93.77), calcified mitral valve (p=0.019, RR 12.44, 95% CI 1.51–102.18), only annuloplasty performed (p=0.020, RR 5.46, 95% CI 1.30–22.92), chronic obstructive pulmonary disease/asthma (p=0.004, RR 8.29, 95% CI 1.98–34.72) and residual mitral valve regurgitation grade>1 as assessed during the immediate postoperative period (p=0.001, RR 11.68, 95% CI 2.60–52.53) were predictors at univariate analysis of redo mitral valve surgery. Multivariable analysis showed that residual mitral valve regurgitation of a grade>1 as assessed during the immediate postoperative period (p=0.007, RR 15.87, 95% CI 2.16–116.67) and chronic obstructive pulmonary disease/asthma 63 (p=0.012, RR 14.75, 95% CI 1.80–121.09) were predictors of late redo mitral valve surgery also among patients with myxomatous degenerative disease. 5.2.5 Long-term echocardiographic findings After a median of 5.6 years (IQR, 3.8–7.5), no significant changes were detected in terms of left ventricular ejection fraction (Fig. 14), whilst mitral valve regurgitation grade (Fig. 15) along with New York Heart Association functional class (Fig. 16) were significantly lower than baseline values in these long-term survivors. Wilcoxon's test p=0.73 90 Left ventricular ejection fraction (%) 80 70 60 50 40 30 20 Baseline Last follow-up control Median length of follow-up: 5.6 years (IQR, 3.8-7.5) Fig. 14. Left ventricular ejection fraction before and a median of 5.6 years after mitral valve repair in 71 patients who underwent echocardiographic examination. 64 4 Wilcoxon's test p<0.0001 Mitral valve regurgitation grade 3 2 1 0 Baseline Last follow-up control Median length of follow-up: 5.6 years (IQR, 3.8-7.5) Fig. 15. Mitral valve regurgitation grade before and a median of 5.6 years after mitral valve repair in 70 patients who underwent echocardiographic examination. 65 New York Heart Association class 4 Wilcoxon's test p<0.0001 3 2 1 Baseline Last follow-up control Median length of follow-up: 5.6 years (IQR, 3.8-7.5) Fig. 16. New York Heart Association functional class before and a median of 5.6 years after mitral valve repair in 72 patients who underwent echocardiographic examination. The median left atrium diameter decreased from 50 mm (IQR, 46–57) to 44 mm (IQR, 40–49) (64 patients available for analysis, p<0.0001). 5.3 Quality of life after mitral valve repair The mean follow-up period was 5.1 years (median 4.9 years, IQR 3.2 to 7.2 years). Eleven patients (6.7%) died during the immediate postoperative period. Amongst operative survivors, 12 patients (7.9%) died later from cardiac causes, two of stroke (1.3%), one of pneumonia (0.7%), three of cancer (2.0%), two of trauma (1.3%), one of postoperative multiorgan failure (0.7%), one of gastrointestinal bleeding (0.7%), and one of subdural hematoma (0.7%). Nine patients (5.5%) underwent repeat cardiac surgery after mitral valve repair, eight patients (4.9%) having undergone redo mitral valve surgery (six patients underwent mitral valve replacement and two underwent repeat mitral 66 valve repair). Four patients underwent redo mitral valve surgery within the first year after surgery. At the 10-year follow-up, the overall survival rate in the study group was 70.2%, and it was 74.8% among the operative survivors. In the age- and genderadjusted general population, the expected 10-year survival is 93.9%. Of 130 late survivors, 109 (83.8%) answered the questionnaire and form the basis of the present study. The 21 non-responders were rather young at the time of mitral valve repair (mean 53.4 years; median 55.8, IQR 44.5–64.2) and also had a rather long survival after surgery (mean 7.5 years, median 7.8, IQR 5.8–9.7). Two of these patients had previously undergone surgery for atrial septal defect and for aortic coarctation, respectively. Six patients underwent concomitant coronary artery bypass surgery. An echocardiographic examination had been performed in all but three of these patients immediately after mitral valve repair. One patient was shown to have a grade 2 residual mitral valve regurgitation, whilst the others had from grade 0 to1 residual regurgitation. Immediately after surgery, 56 patients (51.4%) had no signs of mitral valve regurgitation at echocardiography, while 42 patients (38.5%) had grade 1 residual regurgitation and six patients (5.5%) grade 2. Echocardiographic examinations were not performed in five patients during their in-hospital stay. Figure 17 depicts the median quality of life scores in the study group compared with those of an age-and gender-adjusted general population. A Wilcoxon test indicated significantly higher mental health (p=0.04) and pain scores (p=0.015) and lower role functioning/physical score (p=0.008) in the study group. The mean total score for the study group was 512 (median 532; IQR: 360 to 678), but was 522 (median 538; IQR: 468 to 549) in the age- and gender-adjusted general population (p=0.72) (only 95 patients were included in the analysis due to isolated missing scores). Coronary artery disease, concomitant coronary artery bypass surgery and immediate postoperative residual mitral valve regurgitation of a grade more than 1 were not associated with a significantly poorer quality of life. 67 Fig. 17. RAND-36 Health Survey variable scores of long-term survivors after mitral valve repair (open bars) and of the age- and gender-adjusted general Finnish population (filled bars). *: p<0.05. 5.4 Predicting the immediate and late outcome after surgery for mitral valve regurgitation with EuroSCORE 5.4.1 30-day postoperative outcome The thirty-day postoperative mortality rate was 10.0% overall (18 patients) –7.1% (10 patients) in the mitral valve repair group and 20.5% (8 patients) in the mitral valve replacement group (p=0.013), respectively. Both the additive and the logistic EuroSCORE were significantly higher in the mitral valve replacement group compared with the mitral valve repair group. The additive EuroSCORE (p<0.0001, area under the ROC curve: 0.804, 95%CI 0.689–0.919, SE 0.059) as well as the logistic EuroSCORE (p<0.0001, area under the ROC curve: 0.806, 68 95%CI 0.695–0.918, SE 0.057) were significantly associated with 30-day postoperative death (Fig. 18). The thirty-day postoperative mortality rates are shown in Figure 19 according to the different quintiles of the additive and the logistic EuroSCORE. 1,0 Sensitivity 0,8 0,6 0,4 0,2 0,0 0,0 0,2 0,4 0,6 0,8 1,0 1 - Specificity Fig. 18. Area under the receiver operating characteristics curve of the additive EuroSCORE (__) and the logistic (--) EuroSCORE in predicting 30-day postoperative death after surgery for mitral valve regurgitation. 69 30-day postoperative mortality (%) 40 30 25 20 15 10 5 0 35 30-day postoperative mortality (%) p<0.0001 35 34 pts 44 pts 2 3-4 5-6 7-8 Additive EuroSCORE quintiles 45 pts 29 pts 28 pts 9-16 37 pts 36 pts p<0.0001 30 25 20 15 10 5 0 36 pts <1.85 35 pts 36 pts 1.85-3.07 3.08-4.99 5.00-9.23 9.24-60.6 Logistic EuroSCORE quintiles (%) Fig. 19. Thirty-day postoperative mortality rates according to different quintiles of the additive and the logistic EuroSCOREs. The number of patients per each quintile is reported below each column According to the ROC curve analysis, the best cutoff values for the additive and the logistic EuroSCOREs were 6 and 4.0%, respectively. Patients with an additive EuroSCORE of more than or equal to 6 had a 30-day postoperative mortality rate of 20.0%, whereas it was 2.9% in patients with an additive EuroSCORE of less than 6 (p<0.0001, sensitivity 83.3%, specificity 62.9%, accuracy 65.0%). Patients 70 with a logistic EuroSCORE of more than or equal to 4% had a 30-day postoperative mortality rate of 18.8%, whereas it was 2.1% in patients with an additive EuroSCORE of less than 4 (p<0.0001, sensitivity 88.8%, specificity 57.4%, accuracy 60.5%). 5.4.2 Late outcome Among operative survivors, 25 patients died during a median follow-up period of 5.1 years (IQR, 3.5–7.3 years). The ten-year overall survival rate from any cause of death was 74.7%. Patients who underwent mitral valve replacement had a significantly poorer long-term survival than those who had undergone mitral valve repair (p=0.01, Fig. 20). The additive EuroSCORE (median: 8 vs. 4, p<0.0001) and the logistic EuroSCORE (median: 9.6 vs. 3.1, p<0.0001) were significantly higher in the mitral valve replacement group compared with the mitral valve repair group also among operative survivors. Both the additive EuroSCORE (p<0.0001) and the logistic EuroSCORE (p=0.003) were predictors of late mortality of any cause. These scores remained significant predictors of late outcome, even when adjusted for type of surgery (mitral valve repair vs. replacement). Figures 21 and 22 shows the Kaplan-Meier estimates according to different quintiles of additive and logistic EuroSCOREs among operative survivors. Survival was particularly dismal in patients with an additive EuroSCORE of more than or equal to 6 (at 10 years, 54.4% vs. 86.6%, p<0.00001) or a logistic EuroSCORE of more than or equal to 4% (at 10 years, 58.7% vs. 86.6%, p<0.00001). 71 Patients at risk MV repair MV replacement 131 31 127 25 85 20 54 9 28 6 6 2 Fig. 20. Overall long-term outcome of operative survivors after mitral valve repair compared with mitral valve replacement. Additive EuroSCORE 2 5 3-4 8-16 6-7 Fig. 21. Kaplan-Meier estimate of overall long-term survival after surgery for mitral valve regurgitation according to different additive EuroSCORE quintiles among operative survivors (p<0.0001). 72 Logistic EuroSCORE 1.5% 2.8-3.9% 1.6-2.7% 4.0-8.0% 8.1-55.3% Fig. 22. Kaplan-Meier estimate of overall long-term survival after surgery for mitral valve regurgitation according to different logistic EuroSCORE quintiles among operative survivors (p<0.0001). 73 74 6 Discussion 6.1 Predictors of postoperative mortality after mitral valve repair Mitral valve repair has been established as the method of choice in the treatment of mitral valve regurgitation. Apart from the satisfactory long-term results, some authors have reported markedly lower immediate postoperative mortality in patients undergoing repair as compared with replacement (Gillinov et al. 2003, Grossi et al. 2001, Reece et al. 2004, Yau et al. 2000, Muehrcke et al. 1997, Roques et al. 2001). Such lower immediate mortality rates are, however, often likely to be due to selection bias (Gillinov et al. 2003, Grossi et al. 2001, Yau et al. 2000) as was confirmed in study IV. We can therefore conclude that when technically feasible, mitral valve repair is associated with a favourable operative outcome. The present studies represent an attempt to identify those risk factors associated with poor immediate outcome. The small size of this series and the rather broad heterogeneity of this patient population made the analysis somewhat complex, but the results are sound and reflect the current knowledge of risk factors in heart valve surgery (Roques et al. 2001). Repeat cardiac procedure is a well known risk factor in cardiac surgery. In our experience this condition was invariably lethal in the mitral valve repair patients older than 65 with a history of previous cardiac surgery. This observation calls for possible contraindication to mitral valve repair in patients with both these risk factors. Some recent studies (Bolotin et al. 2004, Burfeind et al. 2002, Byrne et al. 2001, Omnasch et al. 2002, Schroeyers et al. 2001), however, have shown that patients undergoing mitral valve surgery in the setting of prior cardiac surgery can benefit from avoiding a repeat median sternotomy. Right thoracotomy, videoassisted minithoracotomy or port-access surgery have been shown to be feasible in this setting and operative mortality rates range from nil to 5.7%. These results are remarkably better than our operative mortality after mitral valve repair in a prior cardiac surgery setting (36.4%). This approach is not feasible, however, in patients requiring concomitant procedures other than those involving the atrioventricular valves. Among patients who died postoperatively, were older than 65 and had a history of prior cardiac surgery, only one patient who in the present series underwent mitral valve repair and tricuspid valve annuloplasty would have potentially benefited from such minimally invasive approaches. Study I showed that in about half of patients undergoing mitral valve repair, concomitant procedures are required, the latter having been associated with a relevant increase 75 of mortality. In those patients not requiring any associated procedure, mortality is very low. This condition was not shown, however, to be an independent predictor of adverse outcome. 6.2 Long-term outcome of mitral valve repair Study II confirmed that mitral valve repair for regurgitation is associated with a favourable long-term outcome and a low risk of late reoperation, which is similar to previously reported figures (Braunberger et al. 2001, Gillinov et al. 1998; Mohty et al. 2001). A number of variables have been found to be associated with a less satisfactory outcome, however, while a history of prior cardiac surgery was the only independent predictor of cardiac death. Residual regurgitation at intraoperative echocardiography has been identified as an important factor associated with a significantly increased risk of reoperation (Mohty et al. 2001). In the present study, a residual regurgitation larger than grade 1 was an independent predictor of late redo mitral valve surgery, and it can therefore be considered an important measure of technical success beyond the progressive nature of mitral valve disease. This study showed a strong association between chronic obstructive pulmonary disease/asthma and the risk of redo mitral valve surgery. Although this may be coincidental, chronic obstructive pulmonary disease is frequently associated with the development of degenerative vascular disease such as aneurysms and pseudoaneuysms (Sakamaki et al. 2002; Ylönen et al. 2004). This suggests that chronic obstructive pulmonary disease and degenerative mitral valve disease may represent the results of an underlying connective tissue metabolic disorder. This risk factor has not been considered in previous studies and deserves further evaluation as it may be also a marker of accelerated progression of degenerative mitral valve disease. Long-term echocardiographic findings confirm the other clinical end-points, but the lack of serial echocardiographic evaluation involving all of these patients prevents any definitive conclusion as to whether mitral valve repair is effective and durable in patients who died before any possible need for mitral valve reoperation. In fact, it is possible that a few patients in this study deteriorated before an adequate cardiologic evaluation was performed. A recent study by Flameng and colleagues (Flameng et al. 2003) reminds us that continuous echocardiographic follow-up may disclose much poorer results than that depicted by late cardiac death or the need for repeat mitral valve surgery. These 76 observations suggest that, despite excellent clinical results, a number of patients experience significant mitral valve incompetence after mitral valve surgery, but do not undergo redo mitral valve surgery. In order to better identify the risk factors associated with late failure after mitral valve repair, it would therefore be more appropriate to evaluate actuarial estimates of echocardiographically verified recurrent severe mitral valve regurgitation. This follow-up method is not feasible, however, either in our hospital district or in many others due to a lack of resources. 6.3 Quality of life after mitral valve repair The survey showed that long-term survivors of a major surgical procedure such as mitral valve repair can experience a good quality of life which in, overall terms, is similar to that of the general population. Thus, the well-demonstrated durability of mitral valve repair is associated with improvement/preservation of the patient’s physical and psychological conditions. This finding is of particular relevance as this patient population is likely to be in rather poor general condition and to have a variety of comorbidities. In fact, the long-term survival of these patients is much lower than would be expected in an age- and gender-adjusted general population. Nonetheless, it is possible that any small improvement in terms of physical and psychological conditions following mitral valve repair is perceived by the patient as a major, positive change in their quality of life. This is suggested by significantly higher mental health and pain scores, despite a significantly lower physical role limitation score among these patients. Indeed, there is evidence that such a good quality of life is experienced by only some of the patients undergoing mitral valve repair due to considerable immediate and late cardiac-related mortality. Furthermore, the wide range of scores in the RAND-36 Health Survey variables suggests that any beneficial effect of mitral valve repair on the patient’s physical and psychological conditions is not shared equally by these patients. The present results might have been biased by the retrospective nature of this study and by the quite high number of non-responders.. Although the proportion of non-responders was relatively high (16.1%), this group of patients was rather young at the time of operation and survived long after surgery. Nonetheless, these observations suggest that they are likely to be alive and in good condition. 77 6.4 Predicting the immediate and late outcome after surgery for mitral valve regurgitation using the EuroSCORE Study IV showed that The EuroSCORE can act as an important tool in predicting both the immediate and late outcome after mitral valve surgery. This observation confirms the validity of the EuroSCORE and previous observations as to its value in predicting late outcome after isolated coronary artery bypass surgery as well as adult heart valve surgery. To the best of our knowledge, however, this is the first series dealing exclusively with patients who have undergone surgery for mitral valve regurgitation. This finding has major relevance as this risk scoring method is simple and, nowadays, used widely, thus making it an optimal tool for risk stratification and a valid means for a comparison of results. From the clinical point of view, it is worth noting that an additive EuroSCORE of more than or equal to 9 was associated in our experience with a prohibitive operative risk which, along with the observed poor late survival in operative survivors within the subgroup of patients with an additive EuroSCORE of more than or equal to 6, clearly distinguishes high-risk patients from low-risk patients. This provides a good estimate of operative risk and life expectancy after mitral valve surgery which can also be useful in the decision-making process. Furthemore, according to the present findings, mitral valve replacement is associated with rather poor immediate postoperative and late survival as compared with mitral valve repair. These considerations should be viewed along with the limitations of the small size of the present series. However, these findings seem to indicate that, nowadays, mitral valve replacement is only indicated in patients with mitral valve regurgitation not amenable for repair and that their operative risk is significantly higher than those in whom valve repair is technically feasible. Thus, in this study, the EuroSCORE indicated that the results of mitral valve repair are not comparable to those of mitral valve replacement, and further comparative analyses between these two procedures may benefit from including this risk scoring method. Finally, the present results indicate that prompt referral for mitral valve surgery can be of utmost benefit for these patients as conservative management may, in some case, dramatically increase the operative risk as well as shorten their life-expectancy. This is especially true in the case of patients who underwent mitral valve replacement in whom the prevalence of critical preoperative state and raised pulmonary artery pressure along with grade 4 mitral valve regurgitation were extremely high. 78 7 Conclusions 1. Multivariable analysis identified that advanced age, NYHA functional classes and history of prior cardiac surgery were independent predictors of 30-day postoperative death. In patients older than 65 years and with prior cardiac surgery, operative risk is very high. 2. Mitral valve repair has an excellent clinical long-term outcome. 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Am J Surg 187:83–87. 88 Original publications This thesis is based on the following articles, which are referred to in the text by their Roman numerals: I Heikkinen J, Biancari F, Satta J, Salmela E, Juvonen T & Lepojärvi M (2005) Predictors of postoperative mortality after mitral valve repair: Analysis of a series of 164 patients. Scand Cardiovasc J 39: 71–77. II Heikkinen J, Biancari F, Uusimaa P, Satta J, Juvonen J, Ylitalo K, Niemelä M, Salmela E, Juvonen T & Lepojärvi M (2005) Long-term outcome after mitral valve repair. Scand Cardiovasc J 39: 229–236. III Heikkinen J, Biancari F, Satta J, Salmela S, Juvonen T & Lepojärvi M (2005) Quality of life after mitral valve repair. J Heart Valve Dis 14: 722–726. IV Heikkinen J, Biancari F, Satta J, Salmela E, Mosorin M, Juvonen T & Lepojärvi M (2007) Predicting the immediate and late outcome after surgery for mitral valve regurgitation with EuroSCORE. J Heart Valve Dis 16: 116– 121. Reprinted with permission from Taylor and Francis (I, II) and ICR publisher Ltd. (III, IV). Original publications are not included in the electronic version of the dissertation 89 90 D958etukansi.kesken.fm Page 2 Tuesday, November 27, 2007 3:06 PM ACTA UNIVERSITATIS OULUENSIS SERIES D MEDICA 945. Tiainen, Johanna (2007) Bioresorbable plain and ciprofloxacin-releasing selfreinforced PLGA 80/20 implants' suitability for craniofacial surgery. Histological and mechanical assessment 946. Aaltonen, Vesa (2007) PKC and neurofibromin in the molecular pathology of urinary bladder carcinoma. The effect of PKC inhibitors on carcinoma cell junctions, movement and death 947. Kuvaja, Paula (2007) The prognostic role of matrix metalloproteinases MMP-2 and -9 and their tissue inhibitors TIMP-1 and -2 in primary breast carcinoma 948. Siira, Virva (2007) Vulnerability signs of mental disorders in adoptees with genetic liability to schizophrenia and their controls measured with Minnesota Multiphasic Personality Inventory 949. Komulainen, Silja (2007) Effect of antihypertensive drugs on blood pressure during exposure to cold. Experimental study in normotensive and hypertensive subjects 950. Anttonen, Vuokko (2007) Laser fluorescence in detecting and monitoring the progression of occlusal dental caries lesions and for screening persons with unfavourable dietary habits 951. Torppa, Kaarina (2007) Managerialismi suomalaisen julkisen erikoissairaanhoidon johtamisessa. Tutkimus yksityissektorin johtamisoppien soveltamisesta neljässä yliopistollisessa sairaanhoitopiirissä ja arvio managerialismin soveltuvuudesta julkisen erikoissairaanhoidon uudistamiseen 952. Hokkanen, Eero (2007) Neurologian kehitysvaiheita Oulussa ja Pohjois-Suomessa 953. Lahtinen, Jarmo (2007) Predictors of immediate outcome after coronary artery bypass surgery 954. Železnik, Danica (2007) Self-care of the home-dwelling elderly people living in Slovenia 955. Löfgren, Eeva (2007) Effects of epilepsy and antiepileptic medication on reproductive function 956. Jäälinoja, Juha (2007) The structure and function of normal and mutated collagen IX 957. Fonsén, Päivi (2007) Prolyl hydroxylases. Cloning and characterization of novel human and plant prolyl 4-hydroxylases, and three human prolyl 3-hydroxylases 958. Heikkinen, Jouni (2008) Outcome after mitral valve surgery for mitral valve regurgitation Book orders: OULU UNIVERSITY PRESS P.O. Box 8200, FI-90014 University of Oulu, Finland Distributed by OULU UNIVERSITY LIBRARY P.O. Box 7500, FI-90014 University of Oulu, Finland D958etukansi.kesken.fm Page 1 Tuesday, November 27, 2007 3:06 PM inen OULU 2008 UNIVERSITY OF OULU P.O. Box 7500 FI-90014 UNIVERSITY OF OULU FINLAND A C TA U N I V E R S I TAT I S S E R I E S A B C D E F G E D I T O R S SCIENTIAE RERUM NATURALIUM Professor Mikko Siponen HUMANIORA TECHNICA Professor Harri Mantila Professor Juha Kostamovaara MEDICA O U L U E N S I S D 958 ACTA Jouni Heikkinen OUTCOME AFTER MITRAL VALVE SURGERY FOR MITRAL VALVE REGURGITATION Professor Olli Vuolteenaho SCIENTIAE RERUM SOCIALIUM Senior Assistant Timo Latomaa SCRIPTA ACADEMICA Communications Officer Elna Stjerna OECONOMICA Senior Lecturer Seppo Eriksson EDITOR IN CHIEF Professor Olli Vuolteenaho EDITORIAL SECRETARY Publications Editor Kirsti Nurkkala ISBN 978-951-42-8680-3 (Paperback) ISBN 978-951-42-8681-0 (PDF) ISSN 0355-3221 (Print) ISSN 1796-2234 (Online) U N I V E R S I T AT I S O U L U E N S I S FACULTY OF MEDICINE, DEPARTMENT OF SURGERY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF OULU D MEDICA
