兽研摘要
背景
黏液瘤性二尖瓣疾病（MMVD）是小体型犬最常见的心脏病，其特征为瓣膜退行性变导致的二尖瓣反流（MR），可能进展为左侧心力衰竭。本报告描述了三例患有严重MMVD（美国兽医内科学院C期或D期）的犬，尽管瓣膜退行性变持续存在，却出现了意外的MR自发性减轻。
病例介绍
三只犬最初表现为心力衰竭症状及左心房和左心室增大。包括利尿剂在内的标准治疗改善了其病情；然而，进一步监测发现，由于二尖瓣增厚，对合间隙减小，导致MR减少。同时伴有心脏尺寸的显著缩小。因此，停用了利尿剂，所有犬仅用pimobendan即成功管理。
结论
据我们所知，这是首例报道MMVD中MR自发性减少的病例，其中对合间隙变窄在临床改善中发挥了作用。这些病例可能拓宽目前对MMVD进展的认识，提示在罕见情况下，心脏重构和临床状态可发生变化。需要进一步研究以更好地理解其潜在机制。
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引言
黏液瘤性二尖瓣疾病（MMVD）是犬最常见的心脏病，尤其在小体型犬中（Keene et al. 2019）。尽管MMVD的病因仍不明确，但某些品种中已涉及遗传因素。该疾病的特征是瓣膜细胞成分和细胞外基质的变化，尤其影响胶原含量和排列。海绵层扩张表现为蛋白聚糖含量的变化。细胞外基质失调起核心作用，活化的肌成纤维细胞通过增加蛋白水解酶释放而迅速分解胶原和弹性蛋白（Keene et al. 2019）。这些机制诱导二尖瓣装置畸形，最终导致二尖瓣反流（MR）（Fox 2012）。因此，发生心脏重构，伴左心房（LA）和左心室增大，最终因LA压力升高导致心力衰竭（Keene et al. 2019）。对合间隙是指二尖瓣前叶和后叶之间的“间隙”，代表二尖瓣叶对合缺失的区域。对合间隙越大，反流量越大（Adamo et al. 2016）。
为缓解临床症状，使用利尿剂至关重要。若未进行二尖瓣修复，大多数患者瓣膜状况会恶化，且由于耐药性和利尿剂的天花板效应，最终进展为美国兽医内科学院（ACVIM）D期，即难治期（Keene et al. 2019）。在人类中，呋塞米的天花板剂量可因患者病情严重程度和肾功能衰竭的存在而异。一般而言，在犬中，当呋塞米每日总剂量达到8 mg/kg或正在使用等效剂量的托拉塞米时，ACVIM D期即被认为难治（Keene et al. 2019; Oh and Han 2015）。
本报告记录了三只偏离典型进展的犬的病例。所有超声心动图检查均由同一位经验丰富的操作者使用同一超声系统（GE Vivid E90）完成。所有病例均一致采用标准成像切面和测量方案。所有病例均表现为与心力衰竭相关的临床症状，超声心动图显示二尖瓣腱索部分断裂，导致严重MR。观察到显著的LA和左心室增大。给予了左心衰竭的标准治疗，所有病例临床症状均得到缓解。连续超声心动图监测显示二尖瓣进一步退行性变，瓣膜增厚更为明显。然而，随着对合间隙减小，观察到MR显著减少。对于MR的评估，采用反流量（mL）和反流分数（%）评估作为定量方法（图1），而MR射流面积与LA面积之比（%）作为半定量方法（Muzzi et al. 2003）。结果，在所有三例中，利尿剂被停用，患者仅用pimobendan进行管理。据我们所知，我们的报告是首例记录ACVIM C期或D期MMVD伴心力衰竭病例中MR自发性减少的报告。
[图：病例2初次就诊后28个月拍摄的超声心动图图像。为定量评估二尖瓣反流]
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病例介绍
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病例1
一只14岁绝育雌性马尔济斯犬因睡眠呼吸频率增加和咳嗽就诊于我院。此前睡眠时呼吸频率维持在每分钟20次，但据报连续3天以上超过每分钟35次。胸部X线片上，椎体心脏大小（VHS）为12.8，椎体左心房大小（VLAS）为3.2，提示左心房增大。由于未发现明显的肺部浸润，随即进行了经胸超声心动图检查。超声心动图显示，二尖瓣前叶增厚为4.63 mm，对合间隙为4.18 mm，代表半定量二尖瓣反流的二尖瓣反流射流面积与左心房面积之比为72.16%。定量测量二尖瓣反流量的反流容积为98.8 mL，反流分数为95.4%。左心房与主动脉（LA:AO）比值为2.52，按体重归一化的舒张期左心室内径（LVIDDN）为2.01，E峰为1.56 m/s，提示左心房和左心室均增大。患者开始口服呋塞米治疗，未预先静脉给药。在开始由呋塞米2 mg/kg每日两次（bid）、贝那普利0.5 mg/kg bid、匹莫苯丹0.3 mg/kg bid和螺内酯1 mg/kg bid组成的标准治疗后，临床症状改善。随后，根据临床症状复发情况向上滴定利尿剂剂量，最终在呋塞米8 mg/kg/日和多巴胺0.4 mg/kg/日给药时观察到临床改善。随后进行持续监测，初次就诊26个月后，观察到患者心脏大小减小。初次诊断26个月后获得的X线片显示，患者VHS降至11.6，VLAS降至2.4。超声心动图显示，二尖瓣前叶增厚增加至9.55 mm，但先前观察到的对合间隙减小至难以测量的程度。因此，二尖瓣反流射流面积与左心房面积之比（%）降至37.5%。与先前测量相比，反流容积降至5.67 mL，反流分数降至34.5%。LA:AO比值为1.56，LVIDDN为1.16，E峰为0.85 m/s，显示较先前测量值减小。患者在最后6个月内仅使用匹莫苯丹治疗，未使用利尿剂（图2）。
[图：病例1的胸部X线片和超声心动图图像。标记为A、B、C和D的图像为初始]
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病例2
一只9岁去势雄性马尔济斯犬因呼吸困难和咳嗽就诊于我院。胸部X线片上，VHS为11.3，VLAS测得为3.1，与左心房增大一致。右后肺叶可见轻度浸润性病变。静脉给予呋塞米0.5 mg/kg/h持续8小时并补充氧气后，呼吸频率稳定。在随后的住院期间，呋塞米以2 mg/kg每日两次的剂量静脉给药，并持续补充氧气。住院第三天，由于呼吸频率保持稳定，进行了经胸超声心动图检查。超声心动图显示，二尖瓣前叶增厚为2.78 mm，对合间隙为3.61 mm，代表半定量二尖瓣反流的二尖瓣反流射流面积与左心房面积之比为88.5%。定量测量二尖瓣反流量的反流容积为28.33 mL，反流分数为96%。LA:AO比值为2.13，LVIDDN为1.55，E峰为1.43 m/s，提示左心房和左心室均增大。由于超声心动图检查在住院和治疗约2天后进行，超声心动图参数可能被低估。与第一例的治疗方案相似，开始由呋塞米2 mg/kg bid、依那普利0.5 mg/kg bid、匹莫苯丹0.3 mg/kg bid和螺内酯1 mg/kg bid组成的标准治疗，患者临床状况保持稳定。初次诊断28个月后获得的X线片显示，患者VHS降至10.0，VLAS降至2.2。超声心动图显示，二尖瓣前叶增厚增加至5.36 mm，但先前观察到的对合间隙减小至难以测量的程度。因此，二尖瓣反流射流面积与左心房面积之比（%）降至11.1%。与先前测量相比，反流容积降至3.46 mL，反流分数降至55.04%。LA:AO比值为1.39，LVIDDN为1.25，E峰为0.7 m/s，显示较先前测量值减小。该患者在最后22个月内仅使用匹莫苯丹治疗，未使用任何利尿剂（图3）。
[图：病例2的胸部X线片和超声心动图图像。标记为A、B、C和D的图像为初始]
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病例3
一只12岁去势雄性马尔济斯犬因呼吸困难和咳嗽就诊于我院。胸部X线片显示VHS为11.4，VLAS为3，提示左心房增大。右后肺叶可见轻度浸润性病变。经两次间隔2小时静脉给予呋塞米2 mg/kg并辅以吸氧治疗后，临床症状改善。临床改善后行经胸超声心动图检查。超声心动图显示二尖瓣前叶增厚为2.63 mm，对合间隙为2.49 mm，二尖瓣反流射流面积与左心房面积之比（代表半定量二尖瓣反流）为69%。反流体积（定量测定二尖瓣反流量）为82.8 mL，反流分数为96.36%。LA:AO比值为2.53，LVIDDN为1.96，E峰为1.91 m/s，提示左心房和左心室均增大。开始标准治疗，包括呋塞米1.5 mg/kg每日两次、依那普利0.5 mg/kg每日两次、匹莫苯丹0.3 mg/kg每日两次和螺内酯1 mg/kg每日两次，患者临床状况保持稳定。初次诊断后12个月拍摄的X线片显示患者VHS降至10.8，VLAS降至2。超声心动图显示二尖瓣前叶增厚增至5.37 mm，但先前观察到的对合间隙已减小至难以测量的程度。因此，二尖瓣反流射流面积与左心房面积之比（%）降至27.1%。与先前测量相比，反流体积降至8.91 mL，反流分数降至62.61%。LA:AO比值为1.55，LVIDDN为1.08，E峰为0.63 m/s，较先前测量值降低。该患者在过去9个月仅使用匹莫苯丹治疗，未使用任何利尿剂（图4）。各病例的总体心脏测量值列于表1。
[图：病例3的胸部X线片和超声心动图图像。标记为A、B、C和D的图像为初始]
TABLE 1. Changes in heart indexes for Cases 1, 2 and 3.
| Case 1 | Case 2 | Case 3 | ||
|---|---|---|---|---|
| LA:AO (< 1.70 = Score 1, 1.70–1.90 = Score 2, 1.91–2.5 = Score 3, > 2.50 = Score 4) | Before | 2.52 | 2.13 | 2.53 |
| After | 1.56 | 1.39 | 1.55 | |
| LVIDDN (< 1.70 = Score 1, 1.70–2.00 = Score 2, 2.10–2.30 = Score 3, > 2.30 = Score 4) | Before | 2.01 | 1.55 | 1.96 |
| After | 1.16 | 1.25 | 1.08 | |
| E peak (m/s) (< 1.20 = Score 1, 1.20–1.50 = Score 2, > 1.5 = Score 3) | Before | 1.56 | 1.43 | 1.91 |
| After | 0.85 | 0.7 | 0.63 | |
| Valve thickness (width; mm) (Normal width in 10 kg—1.44 [1.16–1.72]) | Before | 4.63 | 2.78 | 2.63 |
| After | 9.55 | 5.36 | 5.37 | |
| Coaptation gap (mm) | Before | 4.18 | 3.61 | 2.49 |
| After | 0 | 0 | 0 | |
| Regurgitant volume (mL) (mild = 5.39 ± 3.24, moderate = 15.21 ± 10.05, severe = 32.92 ± 20.28) | Before | 98.8 | 28.33 | 82.8 |
| After | 5.67 | 3.46 | 8.91 | |
| Regurgitant fraction (%) (mild = 33 ± 11.74, moderate = 57 ± 14.32, severe = 75 ± 8.08) | Before | 95.4 | 96 | 96.36 |
| After | 34.5 | 55.04 | 62.61 | |
| Ratio of MR jet area to LA area (%) (< 30% = mild MR, 30%–70% = moderate MR, > 70% = severe MR) | Before | 72.16 | 88.5 | 69 |
| After | 37.5 | 11.1 | 27.1 | |
| VHS (No heart enlargement < 10.5) | Before | 12.8 | 11.3 | 11.4 |
| After | 11.6 | 10 | 10.8 | |
| VLAS (Left atrial enlargement > 3) | Before | 3.2 | 3.1 | 3 |
| After | 2.4 | 2.2 | 2 |
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讨论
这些病例表明，患有重度MMVD的犬可能出现意外的临床结局。特别是，ACVIM C期和D期的犬由于疾病进展，通常需要持续药物治疗，包括利尿剂和其他标准治疗。然而，在本组病例中，尽管处于晚期阶段，二尖瓣反流却意外减轻。这种反流减少甚至发生在瓣膜退行性变持续进行的情况下，导致左心房和左心室尺寸缩小，从而促使停用利尿剂治疗。尽管此类病例罕见，但它们提示二尖瓣反流可能自发改善，为重度MMVD的管理带来了希望。尽管在人类医学文献中也很罕见，但已有由连枷状二尖瓣所致重度二尖瓣反流自发改善的类似病例报告。连枷状二尖瓣如不治疗，常导致重度反流和潜在左心室功能障碍。该病例突出了二尖瓣的适应性改变，即前叶增大减少了反流并促进了心室逆重构，而无需手术。有研究提示该过程涉及胚胎发育通路的重新激活，包括内皮–间充质转化，导致瓣叶面积和厚度增加。此类变化可能改善瓣叶对合并减少反流（Asmer et al. 2010）。然而，本组病例中这些结构变化的确切机制仍不清楚，所提出的解释应谨慎解读。
当二尖瓣结构的复杂相互作用被破坏时，可发生MR。在人类中，由Alain Carpentier于20世纪70年代初引入的外科二尖瓣修复术可减轻MR，从而使重度MR患者的预后和管理发生显著变化（Lancellotti et al. 2010）。二尖瓣修复术后对合长度的重要性已有文献记载（Wei et al. 2017）。这一重要性在近年来的兽医研究中也被日益强调（Mihara et al. 2024）。根据已记载的证据，对合间隙增大可导致反流量增加，若不进行外科干预，药物治疗的局限性必将显现。此外，通过三维超声心动图评估了解剖反流口面积，重度MR患者的该面积大于轻度MR患者（Müller et al. 2017）。尽管该变量对诊断和预后的影响尚需进一步研究，但可以推断反流口本身的大小可能影响这一病理状态。这些发现与本报告中的病例一致，即对合间隙缩小与MR严重程度降低相关。值得注意的是，在本报告病例中，对合间隙的缩小是在没有任何外科干预的情况下发生的。这一观察可能具有重要的临床意义，因为它提示，在晚期MMVD犬中，二尖瓣对合的功能性改善在罕见情况下可通过非外科机制出现。
此外，在重度MR犬中，较近期提出的二尖瓣关闭不全超声心动图（MINE）评分使预测MMVD的严重程度和中位生存时间变得更加容易（Vezzosi et al. 2021）。本报告描述的三例均显示严重的瓣膜退行性变和部分腱索断裂，形成明显的对合间隙，并伴有显著反流。此外，使用MINE评分确认这些病例处于严重阶段；预期中位生存时间约为623天（95%置信区间，432–710天）。若不进行二尖瓣修复，所有这些病例均被假定具有通常预测的生存时间。然而，在所描述的三例中，尽管瓣膜退行性变进一步进展，对合间隙却缩小了，就好像患者接受了二尖瓣修复术一样。这伴有左侧心腔尺寸的减小。目前，这些犬仅使用pimobendan治疗，未使用任何利尿剂，并且存活，没有明显的呼吸困难、咳嗽或晕厥临床症状。
这一特殊结局为目前对MMVD自然进展的认识提供了新的见解。第一是自发性愈合的可能性。值得注意的是，在所有三例中，尽管二尖瓣持续存在退行性改变，但MR减轻，同时LA和左心室尺寸减小。这提示患者仅通过药物治疗即达到了临床稳定。疾病进展可能已停止甚至逆转。这一现象难以用现有知识解释，并凸显了探索瓣膜反流自然减轻从而缓解疾病进展的潜在机制的必要性。第二是逆转心脏重构的可能性。近期证据支持晚期MMVD犬心脏重构的可逆性（Mihara et al. 2024），该研究表明外科二尖瓣修复术显著恢复了对合长度、减少了反流量、改善了血流动力学并降低了用药需求，为即使在疾病晚期重构也可被改变提供了机制基础。然而，本报告病例尤其值得注意，因为它们显示了无需外科干预的自发性逆重构，强调了晚期MMVD中自然结构恢复的可能性。本研究的一个重要局限性是药物治疗的潜在混杂效应。尽管停用了利尿剂且观察到的改善持续存在，但不能完全排除pimobendan的作用。虽然已知pimobendan可改善血流动力学，但目前临床证据有限，尚不能证明其能够在晚期MMVD中诱导MR严重程度和心脏重构的显著且持续减轻。因此，治疗与内在结构变化各自的相对贡献仍不确定。第三是与长期生存的关联。同样重要的是，所有三例在心脏重构改善后均观察到长期生存。通常，对于由MMVD引起左心衰竭的患者，预期仅能短期生存。然而，这三例患者甚至在停用利尿剂后仍存活数月至数年。这可能与心脏功能的改善有关，并为探索更准确预测MMVD患者预后所需的新指标提供了重要线索。需要进一步研究以了解这一现象的潜在机制，并确定有助于预测此类结局的因素。
据我们所知，这是首例严重MMVD患者出现MR自发性减轻的报道。重要的是要认识到，伴有腱索断裂的MMVD预后仍然较差。然而，在极少数情况下，也可能出现良好的结局。
作者贡献
Hyo‐Seung Nam：概念化、研究、写作——初稿、方法学、可视化、数据管理。Yein Oh：概念化、研究、写作——审阅与编辑、方法学、监督。
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作者确认已遵守期刊作者指南页面所述的期刊伦理政策。由于本文为病例报告，无需伦理批准。
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ABSTRACT
Background
Myxomatous mitral valve disease (MMVD), the most common heart disease in small‐breed dogs, is characterized by mitral regurgitation (MR) resulting from valvular degeneration, which may progress to left‐sided heart failure. This report describes the cases of three dogs with severe MMVD (American College of Veterinary Internal Medicine Stages C or D) who exhibited an unexpected spontaneous reduction in MR despite continued valve degeneration.
Case Presentation
Three dogs initially presented with symptoms of heart failure and left atrial and ventricular enlargement. Standard treatment, including diuretics, improved their conditions; however, further monitoring revealed that the coaptation gap decreased due to mitral valve thickening, leading to a reduction in MR. This was accompanied by a significant decrease in heart size. As a result, diuretics were discontinued, and all dogs were successfully managed with pimobendan alone.
Conclusions
To our knowledge, this is the first report of spontaneous MR reduction in MMVD, where coaptation gap narrowing played a role in clinical improvement. These cases may broaden the current understanding of MMVD progression, suggesting that, in rare instances, changes in cardiac remodelling and clinical status can occur. Further research is warranted to better understand the underlying mechanisms.
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Introduction
Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs, especially in small‐breed dogs (Keene et al. 2019). Although the cause of MMVD remains unclear, a genetic component has been implicated in some breeds. This disease is characterized by changes in the cellular components and extracellular matrix of the valve, particularly affecting collagen content and alignment. Expansion of the spongiosa layer is manifested as changes in proteoglycan content. Dysregulation of the extracellular matrix plays a central role, with activated myofibroblasts rapidly breaking down collagen and elastin through increased proteolytic enzyme release (Keene et al. 2019). These mechanisms induce malformation of the mitral apparatus, ultimately leading to mitral regurgitation (MR) (Fox 2012). As a result, cardiac remodelling occurs with left atrial (LA) and left ventricular enlargement, eventually leading to heart failure due to increased LA pressure (Keene et al. 2019). The coaptation gap refers to the ‘gap’ between the anterior and posterior mitral leaflets, representing the area where mitral leaflet coaptation is lacking. The larger the coaptation gap, the greater the regurgitant volume (Adamo et al. 2016).
To alleviate clinical symptoms, the use of diuretics is essential. If mitral valve repair is not performed, the valve condition worsens in most patients, and due to drug resistance and the ceiling effect of diuretics, it eventually progresses to American College of Veterinary Internal Medicine (ACVIM) Stage D, a refractory stage (Keene et al. 2019). In humans, the ceiling dose of furosemide can vary depending on the severity of the patient's condition and the presence of renal failure. Generally, in dogs, the ACVIM Stage D is considered refractory when the total daily dose of furosemide reaches 8 mg/kg or an equivalent dosage of torsemide is being administered (Keene et al. 2019; Oh and Han 2015).
This report documents the cases of three dogs that deviated from the typical progression. All echocardiographic examinations were performed by a single experienced operator using the same ultrasound system (GE Vivid E90). Standard imaging views and measurement protocols were applied consistently across all cases. All cases presented with clinical symptoms related to heart failure and showed partial rupture of the mitral valve chordae on echocardiography, resulting in severe MR. Significant LA and left ventricular enlargement were observed. Standard treatment for left heart failure was administered, and in all cases, clinical symptoms were alleviated. Continuous echocardiographic monitoring revealed further degeneration of the mitral valve, with more pronounced valve thickening. However, as the coaptation gap decreased, a significant reduction in MR was observed. For the evaluation of MR, regurgitant volume (mL) and regurgitant fraction (%) assessment were used as quantitative methods (Figure 1), while the ratio of the MR jet area to the LA area (%) was used as a semi‐quantitative method (Muzzi et al. 2003). As a result, in all three cases, diuretics were discontinued, and the patients are being managed with pimobendan alone. To our knowledge, our report is the first to document spontaneous reductions in MR in cases with ACVIM Stage C or D MMVD with heart failure.
[图：Echocardiographic image taken 28 months after the initial presentation of Case 2. To quantitatively assess mitral regurg]
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Case Presentation
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Case 1
A 14‐year‐old spayed female Maltese dog presented to our hospital with chief complaints of increased sleeping respiratory rate and coughing. The respiratory rate during sleep had previously remained at 20 breaths per minute, but for more than 3 consecutive days, it was reported to exceed 35 breaths per minute. On thoracic radiographs, the vertebral heart size (VHS) was 12.8, and a vertebral left atrial size (VLAS) of 3.2 indicated LA enlargement. As no distinct pulmonary infiltrates were identified, transthoracic echocardiography was promptly performed. On echocardiography, the thickening of the anterior cusp of the mitral valve was 4.63 mm, the coaptation gap was 4.18 mm and the ratio of the MR jet area to the LA area, representing the semi‐quantitative MR, was 72.16%. The regurgitant volume, which quantitatively measures the amount of MR, was 98.8 mL, and the regurgitant fraction was 95.4%. The LA‐to‐aortic (LA:AO) ratio was 2.52, the left ventricular internal dimension in diastole normalized to bodyweight (LVIDDN) was 2.01, and the E peak was 1.56 m/s, indicating enlargement of both the LA and left ventricle. The patient was started on oral furosemide treatment without prior intravenous administration. After initiating the standard treatment comprising furosemide 2 mg/kg twice daily (bid), benazepril 0.5 mg/kg bid, pimobendan 0.3 mg/kg bid and spironolactone 1 mg/kg bid, the clinical symptoms improved. Subsequently, the diuretic dosage was titrated upward in response to the recurrence of clinical signs, and ultimately, clinical improvement was observed when furosemide was administered at 8 mg/kg/day and torsemide at 0.4 mg/kg/day. Consistent monitoring followed, and 26 months after the initial visit, the patient's heart size was observed to have decreased. Radiographs obtained 26 months after the initial diagnosis showed that the patient's VHS decreased to 11.6 and VLAS decreased to 2.4. On echocardiography, the thickening of the anterior cusp of the mitral valve had increased to 9.55 mm, but the previously observed coaptation gap had decreased to the point that it was difficult to measure. As a result, the ratio of the MR jet area to the LA area (%) had decreased to 37.5%. The regurgitant volume was reduced to 5.67 mL and the regurgitant fraction to 34.5%, compared with previous measurements. The LA:AO ratio was 1.56, LVIDDN was 1.16 and the E peak was 0.85 m/s, showing a reduction compared with previous measurements. The patient has been managed with pimobendan alone for the last 6 months without diuretics (Figure 2).
[图：Chest radiographs and echocardiographic images for Case 1. The images labelled A, B, C and D are figures from the initia]
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Case 2
A 9‐year‐old castrated male Maltese dog presented to our hospital with dyspnoea and coughing. On thoracic radiographs, the VHS was 11.3, with the VLAS measured at 3.1, which was consistent with LA enlargement. A mild infiltrative lesion was observed in the right caudal lung lobe. After intravenous administration of furosemide at 0.5 mg/kg/h for 8 h and oxygen supplementation, the respiratory rate stabilized. During the subsequent hospitalization period, furosemide was administered intravenously at a dose of 2 mg/kg twice daily, along with continuous oxygen supplementation. On the third day of hospitalization, as the respiratory rate remained stable, a transthoracic echocardiographic examination was performed. On echocardiography, the thickening of the anterior cusp of the mitral valve was 2.78 mm, the coaptation gap was 3.61 mm and the ratio of the MR jet area to the LA area, representing the semi‐quantitative MR, was 88.5%. The regurgitant volume, which quantitatively measures the amount of MR, was 28.33 mL, and the regurgitant fraction was 96%. The LA:AO ratio was 2.13, LVIDDN was 1.55 and the E peak was 1.43 m/s, indicating enlargement of both the LA and left ventricle. Since the echocardiographic examination was performed approximately 2 days after hospitalization and treatment, the echocardiographic parameters may have been underestimated. Similar to the treatment protocol in the first case, the standard treatment comprising furosemide 2 mg/kg bid, enalapril 0.5 mg/kg bid, pimobendan 0.3 mg/kg bid and spironolactone 1 mg/kg bid was initiated, and the patient's clinical condition remained stable. Radiographs obtained 28 months after the initial diagnosis showed that the patient's VHS decreased to 10.0 and VLAS decreased to 2.2. On echocardiography, the thickening of the anterior cusp of the mitral valve had increased to 5.36 mm, but the previously observed coaptation gap had decreased to the point that it was difficult to measure. As a result, the ratio of the MR jet area to the LA area (%) had decreased to 11.1%. The regurgitant volume was reduced to 3.46 mL and the regurgitant fraction to 55.04%, compared with previous measurements. The LA:AO ratio was 1.39, LVIDDN was 1.25 and the E peak was 0.7 m/s, showing a reduction compared with previous measurements. This patient has been managed with only pimobendan for the last 22 months, without any diuretics (Figure 3).
[图：Chest radiographs and echocardiographic images for Case 2. The images labelled A, B, C and D are figures from the initia]
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Case 3
A 12‐year‐old castrated male Maltese dog presented to our hospital with dyspnoea and coughing. On thoracic radiographs, the VHS was 11.4, with a VLAS of 3, indicating LA enlargement. A mild infiltrative lesion was observed in the right caudal lung lobe. Clinical signs improved following two intravenous administrations of furosemide at a dose of 2 mg/kg given 2 h apart, along with supplemental oxygen therapy. After clinical improvement, a transthoracic echocardiographic examination was performed. On echocardiography, the thickening of the anterior cusp of the mitral valve was 2.63 mm, the coaptation gap was 2.49 mm and the ratio of the MR jet area to the LA area, representing the semi‐quantitative MR, was 69%. The regurgitant volume, which quantitatively measures the amount of MR, was 82.8 mL, and the regurgitant fraction was 96.36%. The LA:AO ratio was 2.53, LVIDDN was 1.96 and the E peak was 1.91 m/s, indicating enlargement of both the LA and left ventricle. The standard treatment comprising furosemide 1.5 mg/kg bid, enalapril 0.5 mg/kg bid, pimobendan 0.3 mg/kg bid and spironolactone 1 mg/kg bid was initiated, and the patient's clinical condition remained stable. Radiographs obtained 12 months after the initial diagnosis showed that the patient's VHS decreased to 10.8, and the VLAS decreased to 2. On echocardiography, the thickening of the anterior cusp of the mitral valve had increased to 5.37 mm, but the previously observed coaptation gap had decreased to the point that it was difficult to measure. As a result, the ratio of the MR jet area to the LA area (%) had decreased to 27.1%. The regurgitant volume was reduced to 8.91 mL and the regurgitant fraction to 62.61%, compared to previous measurements. The LA:AO ratio was 1.55, LVIDDN was 1.08 and the E peak was 0.63 m/s, showing a reduction compared with previous measurements. This patient has also been managed with only pimobendan since the last 9 months, without any diuretics (Figure 4). The overall heart measurements for each case are listed in Table 1.
[图：Chest radiographs and echocardiographic images for Case 3. The images labelled A, B, C and D are figures from the initia]
TABLE 1. Changes in heart indexes for Cases 1, 2 and 3.
| Case 1 | Case 2 | Case 3 | ||
|---|---|---|---|---|
| LA:AO (< 1.70 = Score 1, 1.70–1.90 = Score 2, 1.91–2.5 = Score 3, > 2.50 = Score 4) | Before | 2.52 | 2.13 | 2.53 |
| After | 1.56 | 1.39 | 1.55 | |
| LVIDDN (< 1.70 = Score 1, 1.70–2.00 = Score 2, 2.10–2.30 = Score 3, > 2.30 = Score 4) | Before | 2.01 | 1.55 | 1.96 |
| After | 1.16 | 1.25 | 1.08 | |
| E peak (m/s) (< 1.20 = Score 1, 1.20–1.50 = Score 2, > 1.5 = Score 3) | Before | 1.56 | 1.43 | 1.91 |
| After | 0.85 | 0.7 | 0.63 | |
| Valve thickness (width; mm) (Normal width in 10 kg—1.44 [1.16–1.72]) | Before | 4.63 | 2.78 | 2.63 |
| After | 9.55 | 5.36 | 5.37 | |
| Coaptation gap (mm) | Before | 4.18 | 3.61 | 2.49 |
| After | 0 | 0 | 0 | |
| Regurgitant volume (mL) (mild = 5.39 ± 3.24, moderate = 15.21 ± 10.05, severe = 32.92 ± 20.28) | Before | 98.8 | 28.33 | 82.8 |
| After | 5.67 | 3.46 | 8.91 | |
| Regurgitant fraction (%) (mild = 33 ± 11.74, moderate = 57 ± 14.32, severe = 75 ± 8.08) | Before | 95.4 | 96 | 96.36 |
| After | 34.5 | 55.04 | 62.61 | |
| Ratio of MR jet area to LA area (%) (< 30% = mild MR, 30%–70% = moderate MR, > 70% = severe MR) | Before | 72.16 | 88.5 | 69 |
| After | 37.5 | 11.1 | 27.1 | |
| VHS (No heart enlargement < 10.5) | Before | 12.8 | 11.3 | 11.4 |
| After | 11.6 | 10 | 10.8 | |
| VLAS (Left atrial enlargement > 3) | Before | 3.2 | 3.1 | 3 |
| After | 2.4 | 2.2 | 2 |
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Discussion
These cases demonstrate that unexpected clinical outcomes can occur in dogs with severe MMVD. In particular, dogs in ACVIM Stages C and D typically require ongoing medical therapy, including diuretics and other standard treatments, due to progressive disease. However, in the present cases, MR unexpectedly decreased despite this advanced stage. This reduction in regurgitation occurred even as valve degeneration continued, leading to a decrease in the size of the LA and left ventricle, which prompted the discontinuation of diuretic therapy. Although such cases are rare, they suggest that spontaneous improvement in MR is possible, offering hope in the management of severe MMVD. Though rare in human medical literature as well, similar case reports of severe MR caused by a flail mitral valve improving spontaneously have been documented. A flail mitral valve often results in severe regurgitation and potential left ventricular dysfunction if untreated. This case highlights mitral valve adaptation, where anterior leaflet enlargement reduced regurgitation and promoted reverse ventricular remodelling without surgery. This process has been suggested to involve reactivation of embryonic developmental pathways, including endothelial–mesenchymal transformation, leading to increased leaflet area and thickness. Such changes may improve leaflet coaptation and reduce regurgitation (Asmer et al. 2010). However, the exact mechanisms underlying these structural changes in the present cases remain unclear, and the proposed explanations should be interpreted with caution.
MR can occur when the complex interactions of the mitral valve structure are disrupted. In humans, surgical mitral valve repair, introduced by Alain Carpentier in the early 1970s, can reduce MR, leading to dramatic changes in the prognosis and management of patients with severe MR (Lancellotti et al. 2010). The importance of coaptation length after mitral valve repair has been documented (Wei et al. 2017). This importance has also been increasingly emphasized in recent veterinary studies (Mihara et al. 2024). According to the documented evidence, an increase in the coaptation gap can lead to a higher regurgitation volume, and without surgical intervention, the limitations of medical treatment will inevitably become apparent. In addition, through 3D echocardiography, the anatomic regurgitant orifice area was evaluated, which was larger in patients with severe MR than in patients with mild MR (Müller et al. 2017). Although further research is needed on the impact of this variable on diagnosis and prognosis, it can be inferred that the size of the regurgitant orifice itself may influence this pathological condition. These findings are consistent with the present cases, in which reduction of the coaptation gap was associated with decreased MR severity. Notably, in the present cases, reduction of the coaptation gap occurred without any surgical intervention. This observation may have important clinical implications, as it suggests that functional improvement in mitral valve coaptation can, in rare cases, arise through non‐surgical mechanisms in dogs with advanced MMVD.
In addition, in dogs with severe MR, the relatively recent Mitral INsufficiency Echocardiographic (MINE) score has made it easier to predict the severity of MMVD and the median survival duration (Vezzosi et al. 2021). All three cases described in this report showed severe valve degeneration and partial chordae rupture, forming a distinct coaptation gap, with significant regurgitation. In addition, using the MINE score, it was confirmed that these cases were in the severe stage; the expected median survival duration was approximately 623 days (95% confidence interval, 432–710 days). Without mitral valve repair, all of these cases were assumed to have the typically predicted survival duration. However, in the three described cases, despite further progression of valve degeneration, the coaptation gap decreased, as if the patients had undergone mitral valve repair. This was accompanied by reduced left‐sided cardiac dimensions. Currently, the dogs are being managed solely with pimobendan, without any diuretics, and are alive without any notable clinical symptoms of dyspnoea, coughing or syncope.
This exceptional outcome offers new insights into the current understanding of the natural progression of MMVD. The first is the possibility of spontaneous healing. It is noteworthy that in all three cases, despite ongoing degenerative changes in the mitral valve, there was a reduction in MR along with a decrease in the size of the LA and left ventricle. This suggests that the patients achieved clinical stability with medical treatment alone. Disease progression may have halted or even reversed. This phenomenon is difficult to explain with the current knowledge and highlights the need to explore potential mechanisms by which natural reduction in valve regurgitation could alleviate disease progression. Second, the possibility of reversing cardiac remodelling. Recent evidence supports the reversibility of cardiac remodelling in dogs with advanced MMVD (Mihara et al. 2024) demonstrated that surgical mitral valve repair significantly restored coaptation length, reduced regurgitant volume, improved haemodynamics and decreased medication requirements, providing a mechanistic basis that remodelling can be modified even in late‐stage disease. However, the present cases are particularly noteworthy in that they demonstrated spontaneous reverse remodelling without surgical intervention, underscoring the possibility of natural structural recovery in advanced MMVD. One important limitation of this study is the potential confounding effect of medical treatment. Although diuretics were discontinued and the observed improvements were sustained, the contribution of pimobendan cannot be fully excluded. While pimobendan is known to improve haemodynamics, there is currently limited clinical evidence demonstrating its ability to induce marked and sustained reductions in MR severity and cardiac remodelling in advanced MMVD. Therefore, the relative contribution of treatment versus intrinsic structural changes remains uncertain. Third, the connection with long‐term survival. It is also significant that long‐term survival was observed in all three cases after improvement in cardiac remodelling. Typically, in patients with left heart failure due to MMVD, only short‐term survival is expected. However, these three patients survived for several months to years even after discontinuing diuretics. This may be linked to the improvement in cardiac function and provides an important clue about the need to explore new indicators to more accurately predict the prognosis of patients with MMVD. Further research is needed to understand the underlying mechanisms of this phenomenon and identify factors that can help predict such outcomes.
To our knowledge, this is the first report of spontaneous reduction in MR with severe MMVD. It is important to recognize that the prognosis remains poor in MMVD accompanied by chordae tendineae rupture. However, in rare cases, favourable outcomes may occur.
Author Contributions
Hyo‐Seung Nam: conceptualization, investigation, writing – original draft, methodology, visualization, data curation. Yein Oh: conceptualization, investigation, writing – review and editing, methodology, supervision.
Funding
The authors have nothing to report.
Ethics Statement
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a case report.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.