Underlying this thesis is the McKenzie school of thought, a physiotherapy approach that teaches clinicians to recommend particular exercises to their clients in an attempt to accelerate recovery/ prevent recurrence of disc prolapse. The recommendations are based on an untested clinical theory that movements opposite to those that cause disc prolapse can achieve reversal of disc prolapse. Little consideration has been given scientifically to the reversal of the failure process of the lumbar discs. Three in vitro and one in vivo study were designed to attain a greater understanding of both disc failure and the mechanics of its clinical treatment responses and thereby provide a foundation for evidence-based practice. The first in vitro study in this thesis compared in vitro and in vivo herniated discs in an attempt to link the two and provide a more thorough understanding of the in vitro model proposed to test the mechanical theory underlying the McKenzie derangement approach. Ten C3/4 osteoligamentus porcine specimens were repeatedly flexed or flexed and side bent to result in posterior migration of the nucleus. Three of the 10 specimens had posterior migration of the nucleus. Statistically significant (p < 0.01) and clinically significant (>33%) disc height loss occurred in all 10 specimens. The results provide a sub-classification of in vitro herniated discs that is similar to the spectrum of herniated discs that occurs in vivo. Continuing from the disc height loss sub-classification of post-herniated in vitro discs, the second in vitro study in this thesis pursues alternate methods of creating herniation with the goal of creating herniation without causing more than thirty three percent disc height loss of the specimens. Repeated flexion of porcine cervical specimens under a lower compression level (1kN) resulted in disc herniation but with loss of 50% of the pre-test disc height (p < 0.001). Re-hydrating specimens by injecting the disc after a period of failure testing with a barium sulphate nucleus mix (n = 5) or by placing the specimen in a saline bath for an extended period of time (n = 4) resulted in a significant increase of the disc height of the specimens. Further flexion testing of the specimens significantly reduced the disc height again. Intermittent saline injection of specimens (n = 3) during the failure procedure did not prevent or reduce the disc height loss that occurred in the absence of saline injections. Using higher compression levels (2 and 2.596kN, n = 4), failure testing under torque control (n = 3), non-physiologically starting the annular rupture (n = 5) and using hypolordotic thoracic porcine spines (n = 9) instead of porcine cervical spines were unsuccessful attempts at creating herniations. This study indicated that the in vitro model used in the first in vitro study displayed features from one end of the spectrum of damage seen clinically but was then the best-available. Combined these two studies provide a framework for interpretation of the results of the subsequent and third in vitro study in this thesis. The focus of the third study is the mechanical investigation of the McKenzie clinical theory of the treatment response seen in vivo in prolapsed discs, which is that movements or positioning can alter the location of a displaced portion of nucleus in a prolapsed disc. This study is a proof of the principle on which this aspect of the McKenzie approach is based and provides, to the author’s knowledge, the first scientific evidence supporting the theory that repeating movements opposite to those that caused posterior migration of the nucleus can centralize the prolapsed material. The results indicate that the McKenzie approach works on some prolapsed discs and not on others. Consideration of the changes in disc height of the specimens during the testing procedures offers some understanding of the varied success of this approach and exposes a vast area of future research that will refine the clinical approach and mechanical understanding of this specific disc pathology. The fourth study, an in vivo study, provides a first look at the kinematics and kinetics of the current in vivo application of this approach. Twenty asymptomatic subjects volunteered to participate in this study and performed frequently prescribed McKenzie exercises and a selection of activities of daily living during which a 3-SPACE Isotrak system measured their three dimensional lumbar kinemetics. One subject underwent a series of McKenzie exercises while electromyography and three-dimensional lumbar motion were measured. Mean peak extension of extension in standing and extension in lying exercises were within 3% (SD 22.33%) of each other. An additional 6.75% (SD 11.18%) of extension occurred when the extension in lying exercise was combined with a Grade 3 Maitland extension mobilization to L3, a passive physiotherapy technique that involves the therapist applying intermittent low amplitude oscillations to, in this case, the posterior aspect of the spinous process with the goal of subsequently increasing the range of active motion in the direction of the mobilization. The peak extension during the extension in lying exercise was increased after the mobilization relative to the pre-mobilization range. The mean peak right side bend in the right side glide exercise, normalized to the full right side bend range, was 61% (SD 17.4%). The L4-5 forces at the position of peak extension in extension in lying and extension in standing were 828.97N and 1368.86N respectively. The peak flexion ranges of the activities of daily living investigated match those previously used to create disc prolapse when applied at high repetitions and under moderate axial compression. The lumbar spine ranges achieved in commonly prescribed McKenzie rehabilitative and preventative exercises and those that occur in seemingly non-problematic activities of daily living were quantified. The results of this study will enhance clinical practice by providing quantitative evidence of the relative peak motion of the McKenzie exercises as well as highlighting seemingly benign activities of daily living that involve levels of flexion, side bend and rotation sufficient to cause disc damage and even prolapse. The macroscopic goal of this thesis was to attain a greater understanding of the mechanics of both disc failure and its clinical treatment responses and thereby provide a foundation for evidence-based practice, a goal that was successfully achieved. This thesis ultimately challenged and increased our understanding of pathological discs while simultaneously adding information to assist clinical decision making. Several new contributions to the existing knowledge of lumbar spine biomechanics and clinical concepts of treating disc prolapse have been made.

Underlying this thesis is the McKenzie school of thought, a physiotherapy approach that teaches clinicians to recommend particular exercises to their clients in an attempt to accelerate recovery/ prevent recurrence of disc prolapse. The recommendations are based on an untested clinical theory that movements opposite to those that cause disc prolapse can achieve reversal of disc prolapse. Little consideration has been given scientifically to the reversal of the failure process of the lumbar discs. Three in vitro and one in vivo study were designed to attain a greater understanding of both disc failure and the mechanics of its clinical treatment responses and thereby provide a foundation for evidence-based practice. The first in vitro study in this thesis compared in vitro and in vivo herniated discs in an attempt to link the two and provide a more thorough understanding of the in vitro model proposed to test the mechanical theory underlying the McKenzie derangement approach. Ten C3/4 osteoligamentus porcine specimens were repeatedly flexed or flexed and side bent to result in posterior migration of the nucleus. Three of the 10 specimens had posterior migration of the nucleus. Statistically significant (p < 0.01) and clinically significant (>33%) disc height loss occurred in all 10 specimens. The results provide a sub-classification of in vitro herniated discs that is similar to the spectrum of herniated discs that occurs in vivo. Continuing from the disc height loss sub-classification of post-herniated in vitro discs, the second in vitro study in this thesis pursues alternate methods of creating herniation with the goal of creating herniation without causing more than thirty three percent disc height loss of the specimens. Repeated flexion of porcine cervical specimens under a lower compression level (1kN) resulted in disc herniation but with loss of 50% of the pre-test disc height (p < 0.001). Re-hydrating specimens by injecting the disc after a period of failure testing with a barium sulphate nucleus mix (n = 5) or by placing the specimen in a saline bath for an extended period of time (n = 4) resulted in a significant increase of the disc height of the specimens. Further flexion testing of the specimens significantly reduced the disc height again. Intermittent saline injection of specimens (n = 3) during the failure procedure did not prevent or reduce the disc height loss that occurred in the absence of saline injections. Using higher compression levels (2 and 2.596kN, n = 4), failure testing under torque control (n = 3), non-physiologically starting the annular rupture (n = 5) and using hypolordotic thoracic porcine spines (n = 9) instead of porcine cervical spines were unsuccessful attempts at creating herniations. This study indicated that the in vitro model used in the first in vitro study displayed features from one end of the spectrum of damage seen clinically but was then the best-available. Combined these two studies provide a framework for interpretation of the results of the subsequent and third in vitro study in this thesis. The focus of the third study is the mechanical investigation of the McKenzie clinical theory of the treatment response seen in vivo in prolapsed discs, which is that movements or positioning can alter the location of a displaced portion of nucleus in a prolapsed disc. This study is a proof of the principle on which this aspect of the McKenzie approach is based and provides, to the author’s knowledge, the first scientific evidence supporting the theory that repeating movements opposite to those that caused posterior migration of the nucleus can centralize the prolapsed material. The results indicate that the McKenzie approach works on some prolapsed discs and not on others. Consideration of the changes in disc height of the specimens during the testing procedures offers some understanding of the varied success of this approach and exposes a vast area of future research that will refine the clinical approach and mechanical understanding of this specific disc pathology. The fourth study, an in vivo study, provides a first look at the kinematics and kinetics of the current in vivo application of this approach. Twenty asymptomatic subjects volunteered to participate in this study and performed frequently prescribed McKenzie exercises and a selection of activities of daily living during which a 3-SPACE Isotrak system measured their three dimensional lumbar kinemetics. One subject underwent a series of McKenzie exercises while electromyography and three-dimensional lumbar motion were measured. Mean peak extension of extension in standing and extension in lying exercises were within 3% (SD 22.33%) of each other. An additional 6.75% (SD 11.18%) of extension occurred when the extension in lying exercise was combined with a Grade 3 Maitland extension mobilization to L3, a passive physiotherapy technique that involves the therapist applying intermittent low amplitude oscillations to, in this case, the posterior aspect of the spinous process with the goal of subsequently increasing the range of active motion in the direction of the mobilization. The peak extension during the extension in lying exercise was increased after the mobilization relative to the pre-mobilization range. The mean peak right side bend in the right side glide exercise, normalized to the full right side bend range, was 61% (SD 17.4%). The L4-5 forces at the position of peak extension in extension in lying and extension in standing were 828.97N and 1368.86N respectively. The peak flexion ranges of the activities of daily living investigated match those previously used to create disc prolapse when applied at high repetitions and under moderate axial compression. The lumbar spine ranges achieved in commonly prescribed McKenzie rehabilitative and preventative exercises and those that occur in seemingly non-problematic activities of daily living were quantified. The results of this study will enhance clinical practice by providing quantitative evidence of the relative peak motion of the McKenzie exercises as well as highlighting seemingly benign activities of daily living that involve levels of flexion, side bend and rotation sufficient to cause disc damage and even prolapse. The macroscopic goal of this thesis was to attain a greater understanding of the mechanics of both disc failure and its clinical treatment responses and thereby provide a foundation for evidence-based practice, a goal that was successfully achieved. This thesis ultimately challenged and increased our understanding of pathological discs while simultaneously adding information to assist clinical decision making. Several new contributions to the existing knowledge of lumbar spine biomechanics and clinical concepts of treating disc prolapse have been made.

archives@tulane.edu / Pelvic organ prolapse (POP) is a pelvic floor disorder characterized by the descent of the female pelvic organs. 11% of women will require surgical intervention for POP at some point in their lifetime. While it is evident that POP results from a weakening of the tissues that support the pelvic organs, little has been done to identify associations between this loss of mechanical integrity and the risk factors for POP. The objective of this study was to determine correlations between POP risk factors and the structure-function relationships of the uterosacral ligament (USL), a supportive structure of the upper vagina and cervix that weakens in cases of POP. To achieve this, USL samples and pertinent clinical information were collected from consented female patients at Ochsner Medical Center receiving routine gynecological procedures under IRB approval. Clinical factors were compared between POP and non-POP groups. Post-menopausal USL tissue samples were analyzed through biaxial mechanical testing and histology, and the results were correlated to quantify USL structure-function relationships. Statistical associations were then determined between risk factors and changes in USL structure and mechanics. The post-menopausal POP group had a significantly higher proportion of Caucasian women, vaginal atrophy, instrumented delivery, and episiotomy compared to non-POP controls. Non-POP and POP stage I/II USLs were significantly less extensible than POP stage III/IV USLs, and higher collagen content was associated with decreased tissue extensibility. Smoking was the primary risk factor associated with both structural and mechanical changes in the USL; it was associated with both lower collagen content and higher tissue extensibility. The findings of this study are essential to understand POP etiology, and they have the potential to impact clinical care for POP by allowing for the development of predictive models to determine patient-specific treatment strategies. / 1 / Isabella Johnson

The study was undertaken to assess the results of the sacrospinous colpopexy procedure for the treatment of vault prolapse following hysterectomy. It was also to assess the results of the procedure in the treatment of marked uterovaginal prolapse and to compare its role in a group undergoing hysterectomy with a group in whom the uterus was conserved. A prospective study was undertaken between December 1991 and December 1992. Forty women with vm1lt prolapse following hysterectomy were included in one group. All these patients underwent posterior vaginal repair, enterocele sac obliteration and sacrospinous colpopexy. In 25 patients an anterior vaginal repair with sub urethral buttressing sutures was also perfom1ed. A long-needle bladder neck suspension operation was included for three women with coexistent stress incontinence. The mean follow-up period was six months. The success rate was 92%. Of the three failures one underwent a successful repeat sacrospinous colpopexy and repair. The main long-term complication was cystocele formation. A further 24 women with marked uterovaginal prolapse were also included. All women underwent anterior and posterior vaginal repairs, enterocele sac obliteration and sacrospinous ligament fixation. In 13 patients a vaginal hysterectomy was performed and in 11 the uterus was conserved. In the hysterectomy group the follow-up was four months. Although there have been no failures, one woman had developed a small asymptomatic cystocele. Follow-up in the group with uterine preservation was three and a half months. A gain, no failures were seen but three women had developed small asymptomatic cystoceles. There were no differences between the groups apart from a significantly shorter operating time in the patients who did not undergo hysterectomy. The sacrospinous colpopexy is effective in the treatment of vault prolapse. It avoids major abdominal surgery: and allows the surgeon to correct coexistent cystocele and rectocele. The procedure is a useful adjuvent to vaginal repair for marked degrees of uterovaginal prolapse, resulting in a well-supported vagina in the correct anatomical position.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

archives@tulane.edu / Pelvic organ prolapse (POP) is characterized by the descent of the pelvic organs due to the loss of pelvic support. The underlying mechanism leading to POP is unknown. However, age is a known risk factor for POP, and location and microstructural composition are both associated with prolapse. How the passive biaxial mechanical properties of the vagina change with age as well as between the anterior and posterior vaginal wall are not well-established. Additionally, the extent to which elastic fiber content disruption contributes to prolapse is unknown. The objective of this study was to elucidate the mechanical properties of the murine vagina as a function of age, location, and elastic fiber composition. A planar biaxial mechanical testing protocol evaluated mechanical properties of vaginal tissue from three age groups and the anterior and posterior vaginal walls. Additionally, histological analysis and opening angle measurements were performed on normal and elastase-treated tissues to determine the effect of elastic fiber disruption on mechanical function. Evaluation of mechanical changes within individual age groups showed that material stiffness was higher in the axial direction compared to the circumferential direction within the youngest age group but not in the older age groups. This may suggest that microstructural remodeling occurred that resulted in a comparable stiffness in both directions, thus, reducing the physiologic anisotropy of the tissue. As anisotropy is important for vaginal mechanohomeostasis, a disruption of this homeostasis may contribute to the increased prevalence of prolapse with age. Further, the posterior vaginal wall demonstrated a greater material stiffness compared to the anterior wall. However, prior worked suggests that increased stiffness is associated with prolapse and that anterior prolapse is more prevalent than posterior prolapse. Regional microstructural differences may be responsible for this disparity in material stiffness and may explain the increased susceptibility of the anterior vaginal wall to prolapse. Finally, elastin area fraction and mechanical function displayed a positive correlation suggesting that elastic fiber disruption directly affects mechanical properties. The data presented may improve clinical efficacy in POP treatment by elucidating relationships between POP risk factors and mechanical properties of the vagina. / 1 / Rachel Russell

Indiana University-Purdue University Indianapolis (IUPUI) / Women describe pelvic organ prolapse (POP) surgery as difficult to recover from. Expectancy is related to recovery in other surgeries but has not been examined in POP. There is no established measure of surgery expectancy or utility in women with POP. This research had four aims: 1) to establish the factor structure of a new measure of POP surgery expectancy; 2) to establish predictive validity of the expectancy measure by examining its ability to predict self-rated recovery over time; 3) to establish concurrent validity of the expectancy measure; and 4) to examine the ability of utility to predict additional variance in recovery. Exploratory factor analysis revealed a three-factor solution. Factors are conceptualized as: 1) Bladder/Bowel Function; 2) Sexual Function; and 3) Physical Function. Bladder/Bowel Function correlated with optimism and self-efficacy (r = .17, p = .03 and r = .27, p = .00, respectively). Physical Function was predictive of recovery at 42 days (standardized coefficient = .25; p < .05). However, these factors were generally poor and inconsistent predictors of recovery. Utility did not predict additional variance in recovery. Potential explanations for the poor predictive ability of the measure are discussed. The development of a measure that amends these limitations may still be beneficial. Further, exploring and establishing the relationship between surgery expectancy, utility, and recovery may guide physician-patient discussions and lead to improved surgical outcomes.

Liu Yuet Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 165-191). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.iii / Abbreviations --- p.vi / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Incidences and Prevalence --- p.2 / Chapter 1.2 --- Anatomy of Uterus and its Support Mechanism --- p.3 / Chapter 1.3 --- Pathophysiology of Uterine Prolapse --- p.5 / Chapter 1.4 --- Classification of Uterine Prolapse --- p.6 / Chapter 1.5 --- Etiology of Uterine Prolapse --- p.7 / Chapter 1.6 --- Treatment of Uterine Prolapse --- p.12 / Chapter 1.6.1 --- Conservative Treatment --- p.12 / Chapter 1.6.2 --- Surgical Treatment --- p.13 / Chapter 1.7 --- Molecular Basis of Uterine Prolapse --- p.14 / Chapter 1.7.1 --- Collagen Metabolism --- p.15 / Chapter 1.7.2 --- Extracellular Matrix Metabolism --- p.16 / Chapter 1.7.3 --- Advanced Glycation End-products --- p.18 / Chapter 1.7.4 --- Estrogen and Estrogen Receptors --- p.19 / Chapter 1.8 --- Gene Expression Profiling of Uterine Prolapse --- p.22 / Chapter 1.9 --- Microarray Gene Expression Profiling Analysis --- p.24 / Chapter 1.9.1 --- Types of Microarray --- p.26 / Chapter 1.9.2 --- Comparison of Oligonucleotide and cDNA Arrays --- p.31 / Chapter 1.10 --- Quantitative Real-time PCR --- p.32 / Chapter 1.10.1 --- Principle of TaqMan Real-time PCR --- p.32 / Chapter 1.10.2 --- Other Types of Real-time PCR --- p.33 / Chapter 1.11 --- Project Aims --- p.34 / Chapter 1.12 --- Significance of Study --- p.35 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.37 / Chapter 2.1 --- Materials --- p.37 / Chapter 2.1.1 --- Patients --- p.37 / Chapter 2.1.2 --- Cardinal Ligament Specimen --- p.38 / Chapter 2.2 --- Methods --- p.39 / Chapter 2.2.1 --- Homogenization of Cardinal Ligament Tissues --- p.39 / Chapter 2.2.2 --- Total RNA extraction --- p.39 / Chapter 2.2.3 --- Oligonucleotide Microarray --- p.41 / Chapter 2.2.3.1 --- Two-cycle cDNA Synthesis --- p.41 / Chapter 2.2.3.2 --- Cleanup of Double-stranded cDNA --- p.45 / Chapter 2.2.3.3 --- Synthesis of Biotin-labeled cRNA --- p.45 / Chapter 2.2.3.4 --- Cleanup and Quantification of Biotin-labeled cRNA --- p.46 / Chapter 2.2.3.5 --- Fragmenting the cRNA for Target Preparation --- p.47 / Chapter 2.2.3.6 --- Target Hybridization --- p.47 / Chapter 2.2.3.7 --- "Array Washing, Staining and Scanning" --- p.48 / Chapter 2.2.3.8 --- Statistical Analysis of Microarray Data --- p.49 / Chapter 2.2.4 --- Quantitative Real-time Polymerase Chain Reaction --- p.52 / Chapter 2.2.4.1 --- Primers and Probes --- p.52 / Chapter 2.2.4.2 --- Reverse Transcription --- p.53 / Chapter 2.2.4.3 --- Plate Setup --- p.53 / Chapter 2.2.4.4 --- Real-time PCR Reaction Mixture Setup --- p.54 / Chapter 2.2.4.5 --- Statistical Analysis of Real-time PCR Data --- p.54 / Chapter CHAPTER 3 --- RESULTS --- p.56 / Chapter 3.1 --- Microarray Gene Expression Data Analysis --- p.57 / Chapter 3.1.1 --- Unsupervised Gene Selection --- p.57 / Chapter 3.1.2 --- Supervised Gene Selection --- p.59 / Chapter 3.1.2.1 --- Gene Expression Profiles Distinguish Cardinal Ligament with Uterine Prolapse from Control and Identify Differentially Expressed Genes --- p.59 / Chapter 3.1.2.2 --- Gene Expression Profiles Distinguish Cardinal Ligament with Different Degrees of Uterine Prolapse from Control and Identify Differentially Expressed Genes --- p.72 / Chapter 3.1.2.3 --- Gene Expression Profiles Distinguish Cardinal Ligament with Third-degree Prolapse from First-degree Prolapse and Identify Differentially Expressed Genes --- p.92 / Chapter 3.2 --- Validation of Microarray Data by Quantitative Real-time PCR --- p.96 / Chapter 3.2.1 --- Fold Change of Candidate Genes --- p.97 / Chapter 3.2.2 --- Correlation Between Microarray and Quantitative Real-time PCR Results --- p.102 / Chapter CHAPTER 4 --- DISCUSSIONS --- p.103 / Chapter 4.1 --- Global Gene Expression Profiling using Oligonucleotide Microarray --- p.103 / Chapter 4.1.1 --- Advantages of using Affymetrix GeneChipR Microarray for Gene Expression Profiling --- p.103 / Chapter 4.1.2 --- Microarray analysis software --- p.105 / Chapter 4.1.2.1 --- DNA-Chip Analyzer Software --- p.105 / Chapter 4.1.2.2 --- Comparison of Statistical Methods for Analysis of A ffymetrix GeneChipRMicroarray Data --- p.108 / Chapter 4.2 --- Validation of Microarray Data --- p.111 / Chapter 4.2.1 --- Advantages of using Quantitative Real-time PCR for mRNA Quantification --- p.111 / Chapter 4.3 --- Microarray Gene Expression Data Analysis --- p.115 / Chapter 4.3.1 --- Unsupervised Gene Selection --- p.115 / Chapter 4.3.2 --- Supervised Gene Selection --- p.115 / Chapter 4.3.2.1 --- Gene Expression Profiles Distinguish Cardinal Ligament with Uterine Prolapse from Control and Identify Differentially Expressed Genes --- p.115 / Chapter 4.3.2.2 --- Gene Expression Profiles Distinguish Cardinal Ligament with Different Degrees of Uterine Prolapse from Control and Identify Differentially Expressed Genes --- p.118 / Chapter 4.3.2.3 --- Gene Expression Profiles Distinguish Cardinal Ligament with Third-degree Prolapse from First-degree Prolapse and Identify Differentially Expressed Genes --- p.120 / Chapter 4.4 --- Potential Genes for Further Studies in Uterine Prolapse --- p.120 / Chapter 4.5 --- Implications of This Study --- p.157 / Chapter 4.6 --- Limitations of This Study --- p.160 / Chapter CHAPTER 5 --- CONCLUSIONS --- p.162 / Chapter CHAPTER 6 --- FUTURE PROSPECT --- p.164 / REFERENCES --- p.165

Women describe pelvic organ prolapse (POP) surgery as difficult to recover from. Expectancy is related to recovery in other surgeries but has not been examined in POP. There is no established measure of surgery expectancy or utility in women with POP. This research had four aims: 1) to establish the factor structure of a new measure of POP surgery expectancy; 2) to establish predictive validity of the expectancy measure by examining its ability to predict self-rated recovery over time; 3) to establish concurrent validity of the expectancy measure; and 4) to examine the ability of utility to predict additional variance in recovery. Exploratory factor analysis revealed a three-factor solution. Factors are conceptualized as: 1) Bladder/Bowel Function; 2) Sexual Function; and 3) Physical Function. Bladder/Bowel Function correlated with optimism and self-efficacy (<i>r</i> = .17, <i>p</i> = .03 and <i>r</i> = .27, <i>p</i> = .00, respectively). Physical Function was predictive of recovery at 42 days (standardized coefficient = .25; <i>p</i> < .05). However, these factors were generally poor and inconsistent predictors of recovery. Utility did not predict additional variance in recovery. Potential explanations for the poor predictive ability of the measure are discussed. The development of a measure that amends these limitations may still be beneficial. Further, exploring and establishing the relationship between surgery expectancy, utility, and recovery may guide physician-patient discussions and lead to improved surgical outcomes.

Mitral valve (MV) prolapse (MVP) is the most common cause of surgical mitral regurgitation (MR) in developed countries. The normal mitral annulus is saddle in shape, connecting the left atrium (LA) and left ventricle (LV) into a functional entity, and is susceptible to distortion by LA and LV remodeling. Annular nonplanarity is important for alleviating mechanical stress on mitral leaflets and chordae tendinae. Recently, loss of annular saddle shape has been demonstrated as a novel mechanism in the pathogenesis of degenerative MR. Hitherto, the prevalence and features of annular flattening have not been well assessed in MVP patients, as well as potential factors related to annular flattening. / Current guidelines recommend MV repair as the preferred treatment for clinically significant MR. Annuloplasty are routinely used to restore the annular structure and function. Recent long-term studies showed that anterior leaflet or bileaflet prolpase was associated with suboptimal outcomes. However, the relation between mitral leaflets and annular geometry in MVP is not completely understood. / The application of two-dimensional (2D) echocardiography (ECHO) has been limited since mitral annulus has a nonplanar configuration. Three-dimensional (3D) ECHO was shown to be superior to 2D in defining the anatomy of MVP. In this thesis, MVP was identified as systolic displacement (≥2 mm) of any segment of mitral leaflets into the LA passing the mitral annular plane, as indicated in a long axis view (parasternal or apical three-chamber). Finally, 117 MVP patients consecutively referred to our echo laboratory for transesophageal echocardiography (TEE) were retrospectively studied. Twenty-nine patients referred for TEE for suboptimal transthoracic images, exclusion of endocarditis, or evaluation of cardiac source of embolic event and found to have no underlying structural cardiac disease or arrhythmia were included as the normal reference. Standard 2D transthoracic ECHO and 2D/3D TEE were performed in all the subjects. Custom software was used for quantification of 3D MV morphology and key geometric parameters, including mitral annulus, leaflets and chordae, were automatically measured. / The main findings were as follows: / 1. Annular saddle shape flattening (annular height to commisural width ratio <15%) was a common abnormality in MVP patients. More than 50% MVP patients had annular flattening. / 2. Atrial fibrillation (AF) and mitral annular disjunction (MAD) were found to be independent factors associated with annular flattening. MAD was associated with more severe myxomatous MV changes with excessive traction on papillary muscle. The potential roles of MAD in the development of myxomatous MV disease may be through excessive mobility of the mitral apparatus or disturbing 3D annular configuration with reduced annular height and loss of the saddle shape. / 3. Annular flattening was associated with advanced myxomatous MV changes and a higher prevalence of complex prolapse (anterior leaflet and/or bileaflet prolapse). Complex prolapse was associated with more severe annular flattening and dilation, leaflets elongation, increased billow volume and impaired mitral-aortic coupling. / In summary, this thesis provided new data of the 3D MV geometry in MVP patients with new insights into the mechanisms of disease progression and strategies to improve surgical outcomes. Using new techniques in 3D TEE, the thesis demonstrated that annular flattening is a common abnormality, associated with AF, MAD, and more advanced, complex lesions, with implication in the complexity and timing of MV repair. The results suggested that annuloplasty with saddle-shaped rings may be important to restore the structure and function of MV and to improve the durability of repair, particularly important for complex lesions. These data also implied that maintenance of sinus rhythm may help to prevent annular flattening and progression of MVP-related MR. Finally, MAD may be an echocardiographic marker of annular flattening and may require specific surgical correction. / 在發達國家，需要外科治療二尖瓣反流(MR)最常見的原因是二尖瓣脫垂（MVP）。正常二尖瓣瓣環是一個非平面的馬鞍型結構，連接左心房和左心室使之成為一個功能性整體，其結構和功能易受到心房和心室重構的影響。馬鞍型瓣環有助於降低瓣葉和腱索的機械性壓力。最新研究表明瓣環馬鞍型結構缺失是MVP患者出現退行性MR的發病機制。但沒有研究評估瓣環扁平在MVP患者中的患病率，相關特征性改變及引起瓣環扁平的因素。 / 目前，指南推薦二尖瓣修复術作為伴有嚴重MR的脫垂病人的首選治療方法。二尖瓣修复術中常規使用瓣環成形術有助於恢復瓣環的結構和功能。臨床研究顯示脱垂累及前葉或雙葉的手术预后不理想。目前尚不清楚瓣葉和瓣環幾何結構之間存在的相互關係。 / 由於瓣環的非平面結構，三維超聲評估二尖瓣脫垂的價值優於二維超聲。在本研究中，二尖瓣脫垂被定義為長軸水平（胸骨旁長軸或者心尖三腔切面）二尖瓣瓣葉的任何部分發生收縮期向左房面移位，并超過瓣環水平2毫米以上。最後，我們回顧性地研究了117名被轉診到我們心臟超聲實驗室進行經食道超聲檢查的MVP病人。本研究同時入組了29名无其他潛在結構性心臟病或心律不齊的正常對照。他們由於欠佳的經胸超聲圖質量，或者為了排除心內膜炎，或者為了評價血栓是否來自心臟接受了经食道超聲檢查。所有研究對象均接受了標準的二維經胸超聲及二維/三維經食道超聲檢查。研究採用專業軟件對受試者二尖瓣的三維形態進行定量分析。該軟件可自動測量二尖瓣的重要幾何學參數，包括瓣環，瓣葉和鍵索。 / 研究的主要發現包括： / 1.瓣環扁平（瓣環高度與連合線長度之比不超過15%）是一種常見的解剖學異常，超過50%MVP的患者罹患該種畸形。 / 2. 房顫和二尖瓣瓣環分離是引起瓣環扁平的獨立影響因素。瓣環分離與較嚴重的黏液樣改變以及過多的乳頭肌牽拉相關，其在黏液樣二尖瓣疾病中的作用可能是通過引起二尖瓣裝置的過度移動，或通過降低瓣環的高度導致馬鞍形結構缺失從而破壞二尖瓣裝置正常三維幾何學結構。 / 3. 瓣環扁平與嚴重的黏液樣改變有關，同時合併高比例的複雜脫垂（前葉和/或雙葉脫垂）。複雜脫垂與嚴重瓣環扁平和擴大，瓣葉冗長及隆起容積增加相關，同時破壞了二尖瓣-主動脈瓣耦合。 / 總之，本文對MVP疾病進展的機制提出了新的見解，并為手術治療提供有效的策略。本文採用三維經食道超聲領域中最新的成像和圖像分析技術并發現在MVP患者中瓣環扁平是一種常見解剖學發現，其發病與房顫，瓣環分離及嚴重和複雜病變有明確的相關性。這些發現有助於病變複雜程度分級和確定手術時間。採用馬鞍形瓣環成形術既可以修復二尖瓣的結構和功能又能提高修复的持久性。其重要性在複雜MVP患者中尤為明顯。盡早復律可預防瓣環馬鞍形結構缺失和防止反流的加重。最後瓣環分離可作為检测瓣環扁平的超聲學指標，可能需要特殊的外科矯正。 / Jin, Chunna. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 152-165). / Abstracts also in Chinese. / Title from PDF title page (viewed on 12, September, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.