Approximately 2% of the population have mitral regurgitation (MR) and many may be not tolerant for mitral valve surgery. The objective of this thesis was to investigate the comparative safety, effectiveness, and cost-effectiveness of percutaneous mitral valve repair using MitraClip System for patients with severe MR. Articles in MEDLINE, Embase, CNKI, and the Cochrane Library published from 1997 to February 2017 were searched for evidence of safety and effectiveness. A systematic review was conducted to address the uncertainty in the safety and effectiveness of MitraClip system in patients with MR. A cost-effectiveness analysis and cost-utility analysis in U.S. settings was conducted to address the uncertainty in health economic evaluation for the MitraClip system. One randomized trial and seven observational studies were included in the systematic review. The pooled data show that 30-day, one-year and two-year survival are similar in MitraClip arm and surgery arm. Residual MR occurs more frequently after MitraClip therapy than surgery, especially in younger patients, functional MR patients, and patients whose LVEF<50%. The risk of 30-day major adverse event from lower odds ratio appeared to be lower in older patients and patients whose LVEF≥50%.For economic evaluation, the base case incremental costs per LY and per QALY were $ 28,217.18 and $27,344.38 US dollars, respectively. Results were most sensitive to alternative assumptions regarding time horizon and long-term survival. Therefore, low quality of evidence due to lack of conclusive RCT data suggested that MitraClip system may provide improvements in MR, patients’ quality of life and survival advantage. It is cost-effective as threshold of $50,000 U.S. dollars per QALY gained for high surgical risk patients. Future RCT designed to reduce confounding and lessen participant attrition, which have adequate sample size, consistent reporting of outcomes, and adequate length of follow-up period will better evaluate the clinical benefits of the MitraClip System. / Thesis / Master of Health Sciences (MSc) / Mitral regurgitation is an abnormal leakage of blood back into the left heart chambers. About 2% of the population who have chronic mitral regurgitation are elderly and are at high risk for surgery. For such patients, a treatment has been proposed that involves a catheter puncturing the skin of the groin and travelling all the way to the affected valve to deploy a device that clips and repairs the valve leaflets (a mitral valve clip). This thesis sought to compare the safety, effectiveness and cost-effectiveness of mitral valve clips with current standards of care in patients at high risk for surgery. To address this question, we searched, critically appraised, and collated existing research evidence. We found that this new treatment was not harmful and may provide a survival advantage. In addition, the approach may be cost-effective when compared to current stand of care in patients at high risk for surgery.

Since living conditions have improved and antibiotics have entered routine use, valvular heart disease (VHD) in the developed world is mostly degenerative in origin, rather than rheumatic. Our population is increasing with age, and therefore the burden of VHD is likely to increase. Despite this, the epidemiology & prognostication in VHD remain poorly understood. A better understanding of the prevalence of VHD in our population, and improved methods of predicting outcomes, are essential if we are to be better equipped to meet the challenges of this new “epidemic”. This thesis aims to improve our knowledge of the prevalence of VHD in the elderly, and the potential benefits of cardiac magnetic resonance (CMR) assessment of patients with clinically significant mitral regurgitation. The prevalence of undiagnosed valvular heart disease in those aged 65 and over is examined in Chapters 2 and 3. Chapter 2 outlines a population-based screening study for VHD in primary care in Oxfordshire, which the author played a central role in establishing. The results show that VHD is extremely common in this cohort, and is strongly associated with increasing age. In chapter 4, the level of anxiety provoked by screening for VHD is looked at; this demonstrates that only a small number of patients have significant anxiety levels, but it is more likely in those with a new diagnosis of VHD, and in women. From Chapter 5 onwards, the thesis focuses on the use of CMR in patients with significant mitral regurgitation (MR). In Chapter 5, the clinical value of quantitative assessment of MR using CMR is examined, showing that it was able to predict progression to symptoms or surgery in these patients. In conclusion, this thesis offers insights into the prevalence of VHD in the elderly population, and looks at the anxiety associated with looking for VHD in this group. The potential clinical benefits of CMR in patients with MR are examined, and quantification of MR with this modality would appear to be of prognostic utility.

Background: Accurate assessment of left ventricular (LV) systolic function in chronic severe primary mitral regurgitation (MR) is important as the aim is to consider surgical repair prior to the onset of irreversible LV dysfunction. However this can be difficult to judge as conventional measures of LV function (such as ejection fraction, EF) may remain normal despite impaired LV contractility due to the increased preload of the condition. Advanced echocardiographic techniques, including deformation imaging, appear promising as they are less load dependent. As the earliest symptoms in severe MR are usually exertional, this study aimed to assess markers of LV deformation on exercise in patients with normal resting EF in order to try and identify the earliest signs of LV decompensation.Methods: Transthoracic echocardiography was carried out at rest and on submaximal supine exercise in asymptomatic patients with moderate to severe chronic primary MR and matched controls. Conventional contractile reserve (CR) as measured by EF change on exercise was used to subdivide patients into those with preserved (CR+) and abnormal (CR-) LV function. Myocardial strain and twist were assessed using the speckle tracking technique.Results: MR patients failed to show the normal enhancement in systolic twist on exercise. The onset and peak of untwisting were delayed in MR at rest and normalised on exercise in CR+ but not in CR-. Abnormalities in twist on exercise worsened with increasing resting preload. Longitudinal strain tended to increase normally on exercise in CR+ but not in CR-. Systolic longitudinal strain rate correlated with twist at rest and on exercise, whereas diastolic strain rate correlated with the timing of untwisting on exercise.Conclusion: Abnormalities in myocardial deformation are seen at rest and on exercise in patients with severe MR, particularly in those with decompensated LV function. This may contribute to the development of functional impairment with progressive disease.

Vena contracta width (VCW) and effective regurgitant orifice area (EROA) are well established methods for evaluating mitral regurgitation using transesophageal echocardiography (TEE). For color-flow Doppler (CF) measurements Nyquist limit of 50–60 cm/s is recommended. Aim of the study was to investigate the effectiveness of a baseline shift of the Nyquist limit for these measurements. After a comprehensive 2-dimensional (2D) TEE examination, the mitral regurgitation jet was acquired with a Nyquist limit of 50 cm/s (NL50) along with a baseline shift to 37.5 cm/s (NL37.5) using CF. Moreover a real time 3-dimensional (RT 3D) color complete volume dataset was stored with a Nyquist limit of 50 cm/s (NL50) and 37.5 cm/s (NL37.5). Vena contracta width (VCW) as well as Proximal Isovelocity Surface Area (PISA) derived EROA were measured based on 2D TEE and compared to RT 3D echo measurements for vena contracta area (VCA) using planimetry method. Correlation between VCA 3D NL50 and VCW NL50 was 0.29 (p<0.05) compared to 0.6 (p<0.05) using NL37.5. Correlation between VCA 3D NL50 and EROA 2D NL50 was 0.46 (p<0.05) vs. 0.6 (p<0.05) EROA 2D NL37.5. Correlation between VCA 3D NL37.5 and VCW NL50 was 0.45 (p<0.05) compared to 0.65 (p<0.05) using VCW NL37.5. Correlation between VCA 3D NL37.5 and EROA 2D NL50 was 0.41 (p<0.05) vs. 0.53 (p<0.05) using EROA 2D NL37.5. Baseline shift of the NL to 37.5 cm/s improves the correlation for VCW and EROA when compared to RT 3D NL50 planimetry of the vena contracta area. Baseline shift in RT 3D to a NL of 37.5 cm/s shows similar results like NL50.

Introdução: A Insuficiência Mitral (IM) crônica orgânica tem fisiopatologia complexa. Os sintomas de insuficiência cardíaca e piora da capacidade funcional, podem aparecer apenas tardiamente, quando já existe disfunção contrátil do ventrículo esquerdo (VE). O teste cardiopulmonar de exercício (TCPE) pode avaliar objetivamente a capacidade funcional e auxiliar a conduta médica nos pacientes com IM, mas, pouco se conhece sobre o efeito da cirurgia em suas variáveis. Objetivos: Avaliar os efeitos da correção cirúrgica da IM nas variáveis do TCPE realizados em bicicleta e em esteira rolante. Métodos: Foram selecionados 72 pacientes com IM grave e submetidos à cirurgia corretiva da valvopatia, sendo nestes realizados ecocardiograma (ECO) e TCPE ± 30 dias antes da cirurgia, e de seis a 12 meses após a cirurgia. Resultados: A média das idades foi de 49,9 ± 16,9 anos. Houve predominância do sexo masculino, da etiologia degenerativa e da classe funcional I ou II pela NYHA em 41 pacientes (56,9%), 50 pacientes (69,4%) e 51 pacientes (70,8%), respectivamente. O reparo mitral foi realizado em 47 pacientes (65,3%) e a troca valvar em 25 pacientes. Após a cirurgia houve redução do volume atrial esquerdo (VAE), de 124,4 ± 58,9 ml para 76,4 ± 34,0 ml (p<0,001), do volume diastólico final do VE (VDFVE), de 151,7 ± 35,7ml para 109,6 ± 42,8 ml (p<0,001), do volume sistólico final do VE (VSFVE), de 47,6 ± 18,0 para 43,9 ± 27,1ml (p<0,001), da fração de ejeção (FE), de 69,1 ± 6,3 para 61,30 ± 8,2% (p<0,001) e da pressão sistólica em artéria pulmonar (PSAP), de 46,7 ± 15,9 para 35,4 ± 12,5 mm Hg (p<0,001). Também foi observado uma diminuição do consumo de oxigênio (VO2) pico em ambas as modalidades de exercício após a cirurgia (bicicleta: de 1356 ± 506 para 1269 ± 408 mL.min-1, p=0,015; esteira: de 1618 ± 579 para 1536 ± 447 mL.min-1, p=0,06), assim como a variável OUES (bicicleta: de 1530 ± 516 para 1414 ± 415, p=0,001; esteira: de 1761 ± 585 para 1691 ± 508, p=0,050). O pulso de oxigênio (O2) aumentou após a cirurgia apenas no TCPE realizado em esteira, de 10,7 ± 4,0 para 11,5 ± 3,2 mL.bat-1 (p=0,023). No TCPE realizado em esteira, a diferença percentual do OUES apresentou significativa correlação negativa com a diferença percentual do VDFVE (r=-0,277; p=0,034), do VAE (r=-0,275; p=0,035) e da PSAP (r=-0,282; p=0,041), respectivamente. No TCPE realizado na bicicleta, a diferença percentual do OUES revelou correlação negativa apenas com a diferença percentual da PSAP (r=-0,359; p=0,010). Conclusão: A cirurgia valvar mitral, não determinou aumento do VO2 pico e do OUES apesar da melhora sintomática avaliada pela classe funcional (NYHA). Entretanto, a variável OUES apresentou correlação negativa com parâmetros ecocardiográficos de remodelação cardíaca. O TCPE é uma ferramenta útil e promissora, podendo auxiliar na conduta médica em pacientes com IM. / Introduction: Chronic organic Mitral Regurgitation (MR) has a complex physiopathology. The symptoms of heart failure and functional capacity worsening may appear too late, when a left ventricle (LV) contractile dysfunction already exists. The cardiopulmonary exercise testing (CPET) may objectively assess the functional capacity and helps in the medical conduct concerning patients with MR, but little is known about the surgery effect on its variables. Objectives: To evaluate the effects of the MR surgical correction on the variables related to the CPET performed on stationary bicycle and treadmill. Methods: A total of 72 patients with severe MR were selected and underwent a surgery for valvulopathy correction and an echocardiogram (ECHO) and CPET were performed around 30 days before the surgery and then from six to 12 months after the surgery. Results: The patients were aged an average 49.9 ± 16.9 years. There was a predominance of male patients [41 patients (56.9%)], degenerative etiology [50 patients (69.4%)] and NYHA I or II functional class [51 patients (70.8%)]. Forty-seven (47) patients (65.3%) had their mitral valves repaired and 25 patients had them replaced. After the surgery, there was a reduction in the left atrial volume (LAV) from 124.4 ± 58.9 ml to 76.4 ± 34.0 ml (p<0.001), in the LV end-diastolic volume (LVEDV) from 151.7 ± 35.7ml to 109.6 ± 42.8 ml (p<0.001), in the LV end-systolic volume (LVESV) from 47.6 ± 18.0 to 43.9 ± 27.1ml (p<0.001), in the ejection fraction (EF) from 69.1 ± 6.3 to 61.30 ± 8.2% (p<0.001) and in the pulmonary artery systolic pressure (PASP) from 46.7 ± 15.9 to 35.4 ± 12.5 mm Hg (p<0.001). A reduction in the peak consumption of oxygen (VO2) was also observed in both types of exercise testing after the surgery (stationary bicycle: from 1356 ± 506 to 1269 ± 408 mL.min-1, p=0.015; treadmill: from 1618 ± 579 to 1536 ± 447 mL.min-1, p=0.06), as well as in the variable Oxygen Uptake Efficiency Slope (OUES) (stationary bicycle: from 1530 ± 516 to 1414 ± 415, p=0.001; treadmill: from 1761 ± 585 to 1691 ± 508, p=0.050). Pulse oxymetry readings (O2) increased after the surgery only for the CPET performed on the treadmill from 10.7 ± 4.0 to 11.5 ± 3.2 mL. heartbeat -1 (p=0.023). For the CPET performed on the treadmill, the OUES percent difference showed significant negative correlation with the percent difference of LVEDV (r=-0.277; p=0.034), LAV (r=-0.275; p=0.035) and PASP (r=-0.282; p=0.041), respectively. For the CPET performed on the stationary bicycle, the percent difference of the OUES showed a negative correlation only with the percent difference of PSAP (r=-0.359; p=0.010). Conclusion: The mitral valve surgery caused no increase in the peak VO2 or OUES despite the symptomatic improvement as assessed through the functional class (NYHA). However, the variable OUES showed negative correlation with the echocardiographic parameters of cardiac remodeling. The CPET is a useful and promising tool, and may help in the medical conduct concerning patients with MR.

Introdução: A Insuficiência Mitral (IM) crônica orgânica tem fisiopatologia complexa. Os sintomas de insuficiência cardíaca e piora da capacidade funcional, podem aparecer apenas tardiamente, quando já existe disfunção contrátil do ventrículo esquerdo (VE). O teste cardiopulmonar de exercício (TCPE) pode avaliar objetivamente a capacidade funcional e auxiliar a conduta médica nos pacientes com IM, mas, pouco se conhece sobre o efeito da cirurgia em suas variáveis. Objetivos: Avaliar os efeitos da correção cirúrgica da IM nas variáveis do TCPE realizados em bicicleta e em esteira rolante. Métodos: Foram selecionados 72 pacientes com IM grave e submetidos à cirurgia corretiva da valvopatia, sendo nestes realizados ecocardiograma (ECO) e TCPE ± 30 dias antes da cirurgia, e de seis a 12 meses após a cirurgia. Resultados: A média das idades foi de 49,9 ± 16,9 anos. Houve predominância do sexo masculino, da etiologia degenerativa e da classe funcional I ou II pela NYHA em 41 pacientes (56,9%), 50 pacientes (69,4%) e 51 pacientes (70,8%), respectivamente. O reparo mitral foi realizado em 47 pacientes (65,3%) e a troca valvar em 25 pacientes. Após a cirurgia houve redução do volume atrial esquerdo (VAE), de 124,4 ± 58,9 ml para 76,4 ± 34,0 ml (p<0,001), do volume diastólico final do VE (VDFVE), de 151,7 ± 35,7ml para 109,6 ± 42,8 ml (p<0,001), do volume sistólico final do VE (VSFVE), de 47,6 ± 18,0 para 43,9 ± 27,1ml (p<0,001), da fração de ejeção (FE), de 69,1 ± 6,3 para 61,30 ± 8,2% (p<0,001) e da pressão sistólica em artéria pulmonar (PSAP), de 46,7 ± 15,9 para 35,4 ± 12,5 mm Hg (p<0,001). Também foi observado uma diminuição do consumo de oxigênio (VO2) pico em ambas as modalidades de exercício após a cirurgia (bicicleta: de 1356 ± 506 para 1269 ± 408 mL.min-1, p=0,015; esteira: de 1618 ± 579 para 1536 ± 447 mL.min-1, p=0,06), assim como a variável OUES (bicicleta: de 1530 ± 516 para 1414 ± 415, p=0,001; esteira: de 1761 ± 585 para 1691 ± 508, p=0,050). O pulso de oxigênio (O2) aumentou após a cirurgia apenas no TCPE realizado em esteira, de 10,7 ± 4,0 para 11,5 ± 3,2 mL.bat-1 (p=0,023). No TCPE realizado em esteira, a diferença percentual do OUES apresentou significativa correlação negativa com a diferença percentual do VDFVE (r=-0,277; p=0,034), do VAE (r=-0,275; p=0,035) e da PSAP (r=-0,282; p=0,041), respectivamente. No TCPE realizado na bicicleta, a diferença percentual do OUES revelou correlação negativa apenas com a diferença percentual da PSAP (r=-0,359; p=0,010). Conclusão: A cirurgia valvar mitral, não determinou aumento do VO2 pico e do OUES apesar da melhora sintomática avaliada pela classe funcional (NYHA). Entretanto, a variável OUES apresentou correlação negativa com parâmetros ecocardiográficos de remodelação cardíaca. O TCPE é uma ferramenta útil e promissora, podendo auxiliar na conduta médica em pacientes com IM. / Introduction: Chronic organic Mitral Regurgitation (MR) has a complex physiopathology. The symptoms of heart failure and functional capacity worsening may appear too late, when a left ventricle (LV) contractile dysfunction already exists. The cardiopulmonary exercise testing (CPET) may objectively assess the functional capacity and helps in the medical conduct concerning patients with MR, but little is known about the surgery effect on its variables. Objectives: To evaluate the effects of the MR surgical correction on the variables related to the CPET performed on stationary bicycle and treadmill. Methods: A total of 72 patients with severe MR were selected and underwent a surgery for valvulopathy correction and an echocardiogram (ECHO) and CPET were performed around 30 days before the surgery and then from six to 12 months after the surgery. Results: The patients were aged an average 49.9 ± 16.9 years. There was a predominance of male patients [41 patients (56.9%)], degenerative etiology [50 patients (69.4%)] and NYHA I or II functional class [51 patients (70.8%)]. Forty-seven (47) patients (65.3%) had their mitral valves repaired and 25 patients had them replaced. After the surgery, there was a reduction in the left atrial volume (LAV) from 124.4 ± 58.9 ml to 76.4 ± 34.0 ml (p<0.001), in the LV end-diastolic volume (LVEDV) from 151.7 ± 35.7ml to 109.6 ± 42.8 ml (p<0.001), in the LV end-systolic volume (LVESV) from 47.6 ± 18.0 to 43.9 ± 27.1ml (p<0.001), in the ejection fraction (EF) from 69.1 ± 6.3 to 61.30 ± 8.2% (p<0.001) and in the pulmonary artery systolic pressure (PASP) from 46.7 ± 15.9 to 35.4 ± 12.5 mm Hg (p<0.001). A reduction in the peak consumption of oxygen (VO2) was also observed in both types of exercise testing after the surgery (stationary bicycle: from 1356 ± 506 to 1269 ± 408 mL.min-1, p=0.015; treadmill: from 1618 ± 579 to 1536 ± 447 mL.min-1, p=0.06), as well as in the variable Oxygen Uptake Efficiency Slope (OUES) (stationary bicycle: from 1530 ± 516 to 1414 ± 415, p=0.001; treadmill: from 1761 ± 585 to 1691 ± 508, p=0.050). Pulse oxymetry readings (O2) increased after the surgery only for the CPET performed on the treadmill from 10.7 ± 4.0 to 11.5 ± 3.2 mL. heartbeat -1 (p=0.023). For the CPET performed on the treadmill, the OUES percent difference showed significant negative correlation with the percent difference of LVEDV (r=-0.277; p=0.034), LAV (r=-0.275; p=0.035) and PASP (r=-0.282; p=0.041), respectively. For the CPET performed on the stationary bicycle, the percent difference of the OUES showed a negative correlation only with the percent difference of PSAP (r=-0.359; p=0.010). Conclusion: The mitral valve surgery caused no increase in the peak VO2 or OUES despite the symptomatic improvement as assessed through the functional class (NYHA). However, the variable OUES showed negative correlation with the echocardiographic parameters of cardiac remodeling. The CPET is a useful and promising tool, and may help in the medical conduct concerning patients with MR.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13420号 / 論医博第2228号 / 新制||医||1052(附属図書館) / (主査)教授 川上 浩司, 教授 湊谷 謙司, 教授 山下 潤 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DGAM

This study evaluates the impact of untreated preoperative severe mitral valve regurgitation (MR) on outcomes after left ventricular assist device (LVAD) implantation. Of the 234 patients who received LVAD therapy in the Heart Center Leipzig during a 6-year period, we selected those who had echocardiographic images of good quality and excluded those who underwent mitral valve replacement prior to or mitral valve repair during LVAD placement. The 128 patients selected were divided into 2 groups: Group A with severe MR (n = 65) and Group B with none to moderate MR (n = 63, 28 with moderate MR). We evaluated transthoracic echocardiography preoperatively [15 (7–28) days before LVAD implantation; median (interquartile range)] and postoperatively up to the last available follow-up [501 (283–848) days after LVAD]. We collected mortality, complications and clinical status indicators of the patient cohort. We observed a significant decrease in the severity of MR after LVAD implantation (severe MR 51% pre- vs 6% post-LVAD implantation, P < 0.001). There was no difference between groups in terms of right heart failure, rate of urgent heart transplantation, pump thrombosis or ventricular arrhythmias. There was no difference in 1-year survival and 3-year survival (87.7% vs 88.4% and 71.8% vs 66.6% for Groups A and B, respectively, P = 0.97). We concluded that preoperative severe MR resolves in the majority of patients early on after LVAD implantation and is not associated with worse clinical outcomes or intermediate-term survival.:Inhaltsverzeichnis Abkürzungsverzeichnis 3 1. Einführung 4 2. Formatierte Publikation 12 3. Zusammenfassung der Arbeit 19 4. Literaturverzeichnis 23 5. Anlagen 28 5.1. Statistical analysis of echocardiographic parameters in follow-up 28 5.2. Statistical Models Used 30 Darstellung des eignen wissenschaftlichen Beitrages 32 Erklärung über die eigenständige Abfassung der Arbeit 33 Lebenslauf 34 Publikationen 37 Danksagung 38

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The echocardiographic assessment of valvular heart diseases is the basic analysis of valvular defects next to clinical investigation and stethoscopy. Severity of mitral regurgitation (MR) is usually estimated by an integrated approach using semi quantitative parameters and is still one of the biggest challenges of echocardiography. Quantitative echocardiographic analysis of MR severity often fails to describe comprehensible hemodynamic conditions. However, comprehensive echocardiography based on standardized image acquisition and proper image quality is required to properly assess hemodynamic parameter comparable to cardiac magnetic resonance tomography. This review focuses on the uncertainty of MR severity assessed by echocardiography in recent trials of interventional MR treatment. In addition, the necessity to provide plausible echocardiographic data for individual decision making is highlighted. In conclusion, plausible functional diagnostics by rational echocardiography is a prerequisite in patients with valvular heart diseases.