缺血性二尖瓣关闭不全(ischemic mitral regurgitation，IMR)指由于冠心病心肌梗死或广泛心肌缺血引起的二尖瓣关闭不全。由于IMR患者的二尖瓣瓣叶和瓣下结构本身并无典型病理病变，通常IMR被理解为功能性的二尖瓣关闭不全，是二尖瓣关闭不全中的一种特殊类型。心肌梗死患者中有高达50％的个案出现IMR，按病程划分可分为急性及慢性IMR，在慢性IMR患者中，最常见的起始病变是继发于局部心肌缺血的左心室重构、扩大，引起二尖瓣瓣环扩大变形、瓣下结构移位以及牵拉导致瓣叶运动受限。目前针对重度慢性IMR的手术适应证、手术方式的选择仍存有广泛争议。既往的心脏瓣膜病治疗指南指出，对于严重的缺血性二尖瓣关闭不全患者而言，如果接受了最佳的内科治疗（包括心脏再同步治疗）后仍存在明显的临床症状，可以考虑行二尖瓣手术。由于此类患者手术风险较高，手术所带来的益处与手术本身的风险相比，孰优孰劣尚不能完全确定，上述指南将手术治疗的推荐建议列为IIb级，且未对手术方式的选择给出建议。2016年美国胸外科学会(The American Association for Thoracic Surgery, AATS)和2017美国心脏协会(American Heart Association, AHA)对上述指南进行了更新，认为重度IMR患者会导致心力衰竭等不良事件，增加死亡率，应该考虑与其他心脏手术同期手术治疗(COR IIa, LOE C)，也可考虑单独针对重度二尖瓣关闭不全手术治疗(COR IIb, LOE C)；①二尖瓣置换术（mitral valve replacement, MVR）适用于接受了最佳的内科治疗（包括心脏再同步治疗）后仍存在明显的临床症状的患者，这类患者同时存在基底部室壁瘤/运动异常，瓣叶栓系明显，或者左心室明显扩张（左心室舒张末期直径，left ventricular end-diastolic dimension，LVEDD＞6.5cm）（COR IIa，LOE B）。② 二尖瓣成形术（mitral valve plasty, MVP）适用于接受了最佳的内科治疗（包括心脏再同步治疗）后仍存在明显的临床症状的患者，但是这些患者不应合并基底部室壁瘤/运动异常、瓣叶栓系明显、或者左心室明显扩张（LVEDD＞6.5cm）（COR IIb，LOE B）。然而，制定上述指南所依据的研究项目均存在不同的缺陷，最为突出的问题是随访时间较短，大多数研究中MVR未保留瓣下结构，且该研究结论未充分针对患者的具体特点提出个体化治疗的建议。

    因此，我们有必要开展研究进一步探讨重度IMR的治疗方案。我们回顾性分析2002年1月-2014年12月期间于本院住院接受外科手术治疗的慢性重度IMR患者的基本资料并随访术后中远期恢复状况，通过对比二尖瓣人工瓣环成形术（mitral valve annuloplasty, MVA）与MVR的治疗效果、比较MVR术中是否保留瓣下结构对治疗效果的影响，对重度IMR患者的外科治疗提出建议；由于目前MVA治疗重度IMR的效果仍需改善，一方面，我们探索预测及预防MVA术后功能性二尖瓣狭窄的方法；另外一方面，以目前主流的小瓣环成形技术治疗IMR效果欠佳、现行的成形环型号选择标准存在缺陷为切入点，提出了围术期根据二尖瓣功能状态调整成形环型号可能会改善IMR的治疗效果这一新观点。针对目前尚不能在围手术期方便、有效的调节成形环型号这一问题，研发了新型可调节二尖瓣成形环并申请了发明专利。

本研究共分四个章节进行论述：

第一部分  瓣膜成形术与置换术治疗重度缺血性二尖瓣关闭不全的对比研究

背景

尽管目前的指南建议手术治疗重度IMR，但是并没有明确二尖瓣成形术及置换术的适应证。

方法

连续纳入2002年1月-2014年12月期间于中国医学科学院阜外医院住院手术治疗的436例重度IMR患者，其中316例（72.5％）接受了二尖瓣瓣环成形术（MVA），120例（27.5％）接受了二尖瓣置换术（MVR）。使用Cox比例风险回归模型和倾向性评分匹配调整基线差异后比较长期结果。

结果

平均随访时间为59个月（四分位间距，37-85月）。随访期间MVA组左心室舒张末期内径明显大于MVR组（P = 0.019）、二尖瓣关闭不全复发的发生率明显高于MVR组（P＜0.001）；使用倾向性评分匹配后得到109对患者，两匹配组在总生存率、免于心源性死亡及免于严重心脑血管不良事件（major adverse cardiac or cerebrovascular events , MACCE）的发生率方面均无显著性差异。亚组分析显示：相对于MVR组，MVA组在年龄≥65岁或左心室射血分数（ejection fraction, EF）≥50％（P = 0.014，P = 0.016）的患者中能更好的避免心源性死亡；相对于MVA组，MVR组在年龄＜65岁、左心室EF＜50％或者左心室下壁基底室壁运动异常（basal wall motion abnormality, BWMA）（年龄：P=0.010; EF：P = 0.007，BWMA：P = 0.016）的患者中能更好的避免MACCE。

结论

MVR是治疗重度IMR的一种重要方法。相对于MVA，MVR更利于左心室重构。在临床实践中，我们应该依据相应的高危因素决定选择MVA还是MVR：当年龄≥65岁或左心室射血分数（EF）≥50％时，倾向于选择MVA；当年龄＜65岁，左心室EF＜50％或左心室下壁基底室壁运动异常时，倾向于选择MVR。

第二部分  二尖瓣置换术是否保留瓣下结构对重度缺血性二尖瓣关闭不全治疗效果的影响及其与人工瓣环成形术的对比

背景

尽管目前的指南推荐对重度IMR患者进行手术治疗，但是应该行二尖瓣成形术还是二尖瓣置换术尚存争议；二尖瓣置换术中保留瓣下结构与否对治疗效果的影响也尚未完全明确。本研究的目的：探讨MVR术中保留瓣下结构与否对治疗效果的影响；分别比较两种二尖瓣置换技术与MVA治疗重度IMR的临床结局。

方法

回顾性分析了2002年1月-2014年12月期间于阜外医院住院手术治疗的436例重度IMR患者资料，其中，316例（72.5％）接受了二尖瓣瓣环成形术（MVA），120例（27.5％）接受了二尖瓣置换术（MVR）。在120例MVR病例中，94（78.3%）例保留了瓣下结构，26（21.7%）例没有保留瓣下结构。使用倾向性评分匹配调整基线差异后比较术后早期并发症发生率及长期临床结局。

结果

平均术后随访时间为59个月（四分位间距，37-85月），分别使用倾向性评分匹配调整基线差异：⑴保留瓣下结构MVR与不保留瓣下结构MVR相比，两组患者在术后早期并发症发生率、MACCE发生率、心源性死亡率以及全因死亡发生率方面均没有明显差异（P＜0.05）；⑵保留瓣下结构MVR与MVA相比，两组患者在术后早期并发症发生率、MACCE发生率、心源性死亡率以及全因死亡发生率方面均没有明显差异（P＜0.05）；⑶不保留瓣下结构MVR与MVA相比，两组患者在术后早期并发症发生率、MACCE发生率、心源性死亡率以及全因死亡发生率方面均没有明显差异（P＜0.05）。

结论

本研究表明保留瓣下结构的MVR、不保留瓣下结构的MVR以及MVA三种手术方式均可用于治疗重度IMR。考虑到本研究为回顾性且样本量较小，今后需要开展前瞻性的大样本随机对照研究进一步探讨重度IMR的治疗方案。

 第三部分  人工瓣环成形术治疗缺血性二尖瓣关闭不全术后二尖瓣功能性狭窄的预测与预防

背景

目前尚无预测、预防MVA治疗IMR术后功能性狭窄的方法。本研究拟探索MVA术后二尖瓣功能性狭窄的危险因素及应对措施。

方法

纳入阜外医院2008年11月-2015年10月间114例接受二尖瓣人工瓣环成形术治疗的慢性缺血性二尖瓣关闭不全患者，中位随访时间为8（四分位间距，6-12）个月。采用单因素、多因素logistic回归分析二尖瓣功能性狭窄的危险因素，进一步使用ROC曲线分析进入模型的危险因素的阈值及价值。分析慢性缺血性二尖瓣关闭不全患者人工瓣环植入术后舒张期二尖瓣跨瓣峰值压差变化规律，对比不同型号成形环对舒张期二尖瓣跨瓣峰值压差的影响。

结果

全组病例术后6-12个月舒张期二尖瓣跨瓣峰值压差有明显的上升趋势，且与术后早期舒张期二尖瓣跨瓣峰值压差密切相关（r=0.398，P＜0.001）。使用较小型号的二尖瓣成形环（AUC=0.68，P=0.005）及术后早期较高的舒张期二尖瓣跨瓣峰值压差（AUC=0.75，P＜0.001）是术后6-12个月二尖瓣功能性狭窄的两个有意义的预测因素。当患者体表面积≥1.90 m²时使用≤27mm的人工成形环及术后早期二尖瓣跨瓣峰值压差≥7.4mmHg将明显增加术后6-12个月二尖瓣功能性狭窄的风险。

结论

慢性缺血性二尖瓣关闭不全患者人工瓣环成形术后二尖瓣跨瓣压差有明显的上升趋势，在保证成形效果的基础上应考虑选择较大的二尖瓣人工成形环。为了避免术后6-12个月可能出现的二尖瓣功能性狭窄，当体表面积≥1.90 m²时应慎用≤27mm的成形环；术后早期二尖瓣跨瓣峰值压差≥7.4 mmHg会显著增加术后6-12个月二尖瓣功能性狭窄的风险。

第四部分  新型可调节二尖瓣成形环的研制

目前IMR已经成为常见疾病，二尖瓣成形术是治疗此类疾病的重要手段。在二尖瓣成形术的众多技术中，使用人工成形环行瓣环成形术已经成为基石，得到了普遍的认可。本研究团队以目前瓣环成形术治疗IMR的效果仍需改善、现行的成形环型号选择标准存在缺陷为切入点，提出了围术期根据二尖瓣功能状态调整成形环型号可能会改善IMR的治疗效果这一新观点。针对目前尚不能在围手术期方便、有效的调节成形环型号这一问题，本团队成功研发出了新型可调节二尖瓣成形环并申请了发明专利。今后尚需通过开展动物实验考察成形环型号的变化对IMR治疗效果的影响，验证新型可调节二尖瓣成形环治疗IMR的有效性并探索其机制，同时探明目前主流的小瓣环成形术是否不宜应用于治疗IMR，为术前选择成形环型号提出新的建议，也为IMR的个体化治疗提供崭新的思路。

  Ischemic mitral regurgitation(IMR), which results from functional valve incompetence due to myocardial injury and adverse left ventricular remodeling, develops in approximately 50% of patients after an infarction. The leaflets themselves are normal, and the disease occurs in the myocardium rather than in the valve itself. IMR is a consequence of adverse left ventricular remodeling after myocardial injury with reduced closing forces, enlargement of the left ventricular chamber and mitral annulus, apical and lateral migration of the papillary muscles, and leaflet tethering. These processes lead to malcoaptation of the leaflets and variable degrees of mitral regurgitation that can fluctuate dynamically as a function of volume status. Practice guidelines recommend consideration of chordal-sparing replacement or mitral-valve repair for patients with severe IMR that is causing symptoms despite the best available medical therapy and, possibly cardiac resynchronization. Because of lacking conclusive evidence to indicate which of these interventions is superior, these guidelines do not specify whether to repair or replace the mitral valve. 2016 update to the american association for thoracic surgery consensus guidelines on IMR indicated that：MV surgery is reasonable at time of other cardiac surgery (e.g., CABG, AVR)(COR IIa, LOE C), MV surgery may be considered as an isolated procedure for treatment of patients with severe symptoms (NYHA III/IV) despite GDMT(COR IIb, LOE C). ①Mitral valve replacement(MVR) is reasonable in patients with severe IMR who remain symptomatic despite Guidelinedirected medial and cardiac device therapy, and who have a basal aneurysm/dyskinesis, significant leaflet tethering, and/or severe left ventricle dilation (LVEDD>6.5 cm) (COR IIa, LOE B). ②Mitral valve repair with an undersized complete rigid annuloplasty ring may be considered in patients with severe IMR who remain symptomatic despite Guideline-directed medical and cardiac device therapy and who do not have a basal aneurysm/dyskinesis, significant leaflet tethering, or severe left ventricle enlargement (COR IIb, LOE B).

However, there are various defects in the research projects on which the above guidelines are based. The most prominent problem is that the follow-up time is short, and the conclusions of the study do not fully address the specific characteristics of the patients to propose individualized treatment. Since there is currently no optimal treatment for severe IMR, we need to conduct studies to further investigate the treatment of severe IMR. Therefore, we retrospectively reviewed patients with severe chronic IMR admitted to our hospital who were undergoing surgical treatment between January 2002 and December 2014. We aimed to evaluate the long-term outcomes in patients with severe chronic IMR undergoing mitral valve annuloplasty (MVA) versus MVR, and then we assessed the long-term outcomes in patients with severe chronic IMR undergoing MVA , subvalvular sparing MVR, or non-subvalvular sparing MVR. Further more, we tried to predict and prevent functional mitral stenosis after MVA. In IMR, ring annuloplasty is associated with a significant rate of recurrent mitral regurgitation, and the selection of ring size is only based on intertrigonal distance which is defective. Based on those facts, we advance the notion that it is beneficial to adjust the size of ring in the perioperative period according to mitral valve function. As the size of current rings can not be adjusted perioperatively, we have successfully developed a novel adjustable annuloplasty ring which has been patented. In the present study, we aim to assess the impact of changes in the size of ring on IMR treatment to verify the effectiveness of the novel adjustable ring, as well as detect the mechanism. Furthermore, we will determine whether the current downsizing annuloplasty should not be applied to the treatment of IMR to provide suggestions for the selection of ring size. Finally, the study is expected to provides new ideas for the individualized treatment of IMR.

This study is divided into three chapters to discuss:

The first chapter  Mitral valve annuloplasty versus replacement for severe ischemic mitral regurgitation

BACKGROUND:

Although practice guidelines recommend surgery for patients with severe IMR, they do not specify whether to repair or replace the mitral valve.

METHODS:

436 consecutive patients with severe CIMR were eligible for inclusion in the study, of which 316 (72.5%) underwent MVA whereas 120 (27.5%) received MVR. After adjustment for baseline differences with Cox proportional hazard model and propensity score matching, the long-term outcomes were compared.

RESULTS:

At 59 months (interquartile range, 37–85 months) follow-up, though the left ventricle end-diastolic diameter was markedly larger (P=0.019), and the incidence of mitral regurgitation recurrence was significantly higher in the MVA group than in the MVR group (P<0.001), no significant difference was observed between the two propensity score-matched groups in overall survival, freedom from cardiac death, or avoidance of major adverse cardiac or cerebrovascular events (MACCE). MVA provides better results than MVR in freedom from cardiac death in subgroups of age≥65years and left ventricular ejection fraction (EF)≥50% (P=0.014 and P=0.016, respectively), whereas MVR was associated with a lower risk of MACCE than MVA in subgroups of age＜65 years, EF＜50% and left ventricular inferior basal wall motion abnormality (BWMA) (for age: P=0.010; for EF: P=0.007, and for BWMA: P=0.016).

CONCLUSIONS:

MVR is a suitable management of patients with severe CIMR, and it is more favorable to ventricular remodeling. The choice of MVA or MVR should depend on major high-risk clinical factors.

The secend chapter  Long-Term outcomes of whether preserving subvalvular structure in MVR and thecomparison with MVA

BACKGROUND: 

Although practice guidelines recommend surgery for patients with severe IMR, they do not specify whether to repair or replace the mitral valve.The purpose of this study was to evaluate the long-term outcomes in patients with severe IMR undergoing MVA、 subvalvular sparing MVR、non-subvalvular sparing MVR.

METHODS:

436 consecutive patients with severe CIMR were eligible for inclusion in the study, of which 316 (72.5%) underwent MVA whereas 120 (27.5%) received MVR. Mitral leaflets were preservedwhenever possible (94/120, 78.3%), with posteriorleaflet preservation in 58(48.3%) patients, posterior and partial anterior leaflet preservation in 8(6.7%) patients, and both leaflets preservation in 28(23.3%) patients.After adjustment for baseline differences with propensity score matching, the long-term outcomes were compared.

RESULTS:

After adjustment for baseline differences with propensity score matching, at 53 months (interquartile range, 34–81 months) follow-up, there was no significant difference between MVA、subvalvular sparing MVR、non-subvalvular sparing MVR in risks of MACCE, cardiac death, or all-cause death (P＞0.05).

CONCLUSIONS:

MVA, subvalvular sparing MVR and non-subvalvular sparing MVR are suitable management of patients with severe IMR. Considering that this study is retrospective and with a small sample size, an appropriately powered, randomized, controlled trial evaluating the optimal management ofsevereIMR would be useful to confirm our results.

The third chapter  Predicting functional mitral stenosis after restrictive annuloplasty for ischemic mitral regurgitation

BACKGROUND:

Although we have realized that Restrictive mitral valve annuloplasty (MVA) may result in clinically significant functional mitral stenosis (MS), it still can’t be predicted. The purpose of this study was to identify the risk factors for clinically significant functional MS following restrictive MVA surgery for chronic ischemic mitral regurgitation (IMR).

METHODS:

We retrospectively reviewed 114 patients who underwent restrictive MVA with coronary artery bypass grafting (CABG) for treatment of chronic IMR. Clinically significant functional MS was defined as resting transmitral peak pressure gradient (PPG) ≥13 mm Hg.

RESULTS:

During the follow-up period (range 6-12 months), 28 patients (24.56%) developed clinically significant functional MS. The PPG at follow-up was significantly higher than that measured in the early postoperative stage (3-5 days after surgery). Moreover, there was linear correlation between the two measurements (r = 0.398; P<0.001). Annuloplasty size ≤27 mm and early postoperative PPG ≥7.4 mm Hg could predict clinically significant functional MS at 6-12 months postoperatively.

CONCLUSIONS:

Chronic IMR patients treated with restrictive MVA and CABG have significant increase in PPG postoperatively. Annuloplasty size ≤27 mm and early postoperative PPG ≥7.4 mm Hg can predict clinically significant functional MS at 6-12 months after surgery.

The forth chapter  The study on a novel adjustable mitral annuloplasty ring

At present, mitral annuloplasty has become an important way to treat IMR. Among the numerous techniques for mitral valve plasty, the use of annuloplasty ring has become more and more important, while ring annuloplasty is associated with a significant rate of recurrent mitral regurgitation, and the selection of ring size is only based on intertrigonal distance which is defective. Based on those facts, we advance the notion that it is beneficial to adjust the size of ring in the perioperative period according to mitral valve function. As the size of current rings can not be adjusted perioperatively, we have successfully developed a novel adjustable annuloplasty ring which has been patented. In the future, we will assess the impact of changes in the size of ring on IMR treatment to verify the effectiveness of the novel adjustable ring, as well as detect the mechanism. Furthermore, we will determine whether the current downsizing annuloplasty should not be applied to the treatment of IMR to provide suggestions for the selection of ring size. Finally, the study is expected to provides new ideas for the individualized treatment of IMR.