Mitral regurgitation (MR) severity is an important determinant of symptom status and prognosis in heart failure with reduced ejection fraction (HFrEF). Functional MR is frequently progressive, associated with adverse myocardial remodeling, neurohormonal activation, worsened symptoms, and poor outcome.¹ Percutaneous MR repair may improve outcomes in HFrEF;² however, optimizing guideline-directed medical therapy (GDMT) before valve repair may reduce MR severity sufficiently to avoid need for such a procedure. Limited data suggest treatment of HFrEF with sacubitril/valsartan (sac/val) may result in improvement of MR regardless of background GDMT.³

We examined the association between treatment with sac/val on change in MR among participants in the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183).⁴ All study procedures were approved by local institutional review boards, and study participants provided informed consent. All supporting data are available within the article. In this study of 794 participants with HF and left ventricular (LV) ejection fraction (LVEF) <40%, sac/val was initiated and titrated to the maximally tolerated dose. An echocardiogram was performed at baseline, 6 months, and 12 months, and interpreted in a temporally and clinically blinded fashion. MR severity was graded using a combination of visual assessment of the color Doppler jet and MR/left atrial area and vena contracta width⁵ and categorized on a scale of 0 (none), 1+ (trace), 2+ (mild), 3+ (moderate), and 4+ (severe). Those with previous mitral procedures (N=40) were excluded from the analysis, as were 30 study participants missing baseline MR severity.

Study participants had a mean ±SD age of 65.0±12.4 years. Most (76.4%) were receiving an ACE inhibitor or angiotensin II receptor blocker at baseline. The median LVEF was 28.3%, with LV end diastolic volume index (LVEDVi) of 87.2 mL/kg², LV end systolic volume index of 61.8 mL/kg², left atrial volume index of 37.6 mL/kg², E/e' (the ratio of the early diastolic transmitral Doppler velocity [E] and the early diastolic septal velocity [e']) of 11.3, and LV mass index of 125.2 g/m². At baseline, 42 (5.8%) and 66 (9.1%) had 3+ and 4+ MR, respectively.

From baseline through 12 months, improvement in MR was observed (Figure); by 6 months, prevalence of 3 to 4+ MR decreased to 8.2% (relative 45.0% reduction), and by 12 months, it was 8.4% (relative 44.7% reduction). Those with 3 to 4+ MR at baseline with reduction to ≤2+ by 12 months (“responders”; N=52) had similar baseline clinical characteristics (including vital signs, baseline GDMT, or previous cardiac resynchronization therapy) to those with persistent MR grade 3 to 4+ at 12 months (“nonresponders”; N=33); baseline LVEF and LV volumes were similar between groups, but responders had lower baseline left atrial volume index (43.9 versus 49.3 mL/kg²; P=0.01) and LV mass index (145.0 versus 166.0 g/m²; P=0.02). Neither ratio of vena contracta/LVEDVi or left atrial area/LVEDVi was significantly different between responders and nonresponders at baseline (P=0.11 and 0.68, respectively). Between responders and nonresponders, the average sac/val dose during the study was 276 versus 277 mg/d (P=0.57). By 12 months, LVEF improvement was greater in responders versus nonresponders (+11.0% versus +7.6%; P=0.05), and responders had lower final LVEDVi (85.2 versus 96.9 mL/kg²; P=0.02), LV end systolic volume index (56.5 versus 66.0 mL/kg²; P=0.04), left atrial volume index (33.4 versus 42.3 mL/kg²; P<0.001), E/e' (12.6 versus 15.8; P=0.04), and LV mass index (125.7 versus 152.2 g/m²). Last, by 12 months, responders had lower median NT-proBNP (N-terminal pro-B-type natriuretic peptide; 912 versus 1512 pg/mL; P=0.01) and higher median Kansas City Cardiomyopathy Questionnaire Overall Summary Scores (82.3 versus 72.9; P=0.04) despite similar results for both measures at baseline.

Figure. Sankey diagram detailing severity of mitral regurgitation at baseline, 6 months, and 12 months among study participants with heart failure and reduced ejection fraction treated with sacubitril/valsartan.

Although valve repair in those with 3 to 4+ MR may improve symptoms and reduce adverse outcomes in HFrEF, optimizing GDMT is important before such an intervention. In this analysis, despite the majority of study participants previously receiving an ACE inhibitor or angiotensin II receptor blocker, we observed a substantial shift to lesser degrees of MR after 12 months of treatment with sac/val, including a nearly 50% reduction in 3 to 4+ MR. Reduction in MR from 3 to 4+ was associated with considerable reverse cardiac remodeling, reduced NT-proBNP, and improved health status.

The baseline clinical and echocardiographic characteristics of those with 3 to 4+ MR who had a reduction to ≤2+ MR by 12 months were similar to those who had persistent 3 to 4+ MR by 12 months, and both groups had comparable baseline LVEF, LV volumes, and ratio of MR severity to LVEDVi despite comparable degrees of MR at baseline. Thus, predicting presence of MR caused by LV dilation versus intrinsic valve dysfunction without a course of sac/val treatment may be difficult.

Limitations of this study include the single-arm, observational design; thus, improvement in MR might have been due to factors other than sac/val. Nonetheless, the results of this study provide important insights into potential change in MR after initiation of sac/val in usual care.

With growth in use of percutaneous approaches for mitral valve repair for those with HFrEF and 3 to 4+ MR, the results of this study reinforce importance of ensuring optimal GDMT before such decisions.

This work was presented as an abstract at the Heart Failure Society of America’s Annual Scientific Meeting 2022, Washington, DC, September 30 through October 3, 2022.

Dr Januzzi is supported in part by the Hutter Family Professorship.

Nonstandard Abbreviations and Acronyms

GDMT	guideline-directed medical therapy
HFrEF	heart failure with reduced ejection fraction
LV	left ventricular
LVEDVi	left ventricular end diastolic volume index
LVEF	left ventricular ejection fraction
MR	mitral regurgitation
NT-proBNP	N-terminal pro-B-type natriuretic peptide
sac/val	sacubitril/valsartan

guideline-directed medical therapy

heart failure with reduced ejection fraction

left ventricular

left ventricular end diastolic volume index

left ventricular ejection fraction

mitral regurgitation

N-terminal pro-B-type natriuretic peptide

sacubitril/valsartan

Disclosures Dr Januzzi is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received research support from Abbott, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Bristol Myers Squibb (BMS), Boehringer-Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Siemens; and participates in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Janssen, and Takeda. Dr Butler is a consultant for Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell; and has served on clinical end point committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Ward is an employee of Novartis Pharmaceuticals Corporation. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Gilead, GSK, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr Contreras has received consulting fees from Alnylam Pharmaceuticals, Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. The other authors report no conflicts.

For Sources of Funding and Disclosures, see page 1640.

Circulation is available at www.ahajournals.org/journal/circ

中文翻译：

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沙库巴曲/缬沙坦起始治疗与射血分数降低心力衰竭二尖瓣反流严重程度之间的关联：PROVE-HF 研究

二尖瓣反流 (MR) 严重程度是射血分数降低 (HFrEF) 心力衰竭症状状态和预后的重要决定因素。功能性 MR 通常是进行性的，与不利的心肌重塑、神经激素激活、症状恶化和预后不良有关。¹经皮 MR 修复可能会改善 HFrEF 的结果；²然而，在瓣膜修复之前优化指南指导的药物治疗 (GDMT) 可能会充分降低 MR 的严重程度，以避免需要进行此类手术。有限的数据表明，无论 GDMT 背景如何，使用沙库巴曲/缬沙坦 (sac/val) 治疗 HFrEF 可能会改善 MR。^3个

我们在 PROVE-HF 研究（Sacubitril/Valsartan 治疗心力衰竭期间生物标志物、症状改善和心室重构的前瞻性研究；URL：https://www .clinicaltrials.gov；唯一标识符：NCT02887183）。^4个所有研究程序均由当地机构审查委员会批准，研究参与者提供了知情同意书。文章中提供了所有支持数据。在这项针对 794 名心衰和左心室 (LV) 射血分数 (LVEF) <40% 的参与者的研究中，开始使用 sac/val 并滴定至最大耐受剂量。在基线、6 个月和 12 个月时进行了超声心动图检查，并以时间和临床双盲方式进行解读。使用彩色多普勒射流和 MR/左心房区域和缩静脉宽度的视觉评估组合对 MR 严重程度进行分级⁵并按 0（无）、1+（微量）、2+（轻度）、3+（中度）和 4+（严重）的等级进行分类。之前进行过二尖瓣手术的患者 (N=40) 被排除在分析之外，还有 30 名研究参与者缺少基线 MR 严重程度。

研究参与者的平均 ±SD 年龄为 65.0±12.4 岁。大多数 (76.4%) 在基线时接受 ACE 抑制剂或血管紧张素 II 受体阻滞剂。中位 LVEF 为 28.3%，左室舒张末期容积指数 (LVEDVi) 为 87.2 mL/kg ²，左室收缩末期容积指数为 61.8 mL/kg ²，左心房容积指数为 37.6 mL/kg ²，E/e' （舒张早期二尖瓣多普勒速度 [E] 与舒张早期间隔速度 [e'] 的比值）为 11.3，LV 质量指数为 125.2 g/m ²。在基线时，42 人 (5.8%) 和 66 人 (9.1%) 分别有 3+ 和 4+ MR。

从基线到 12 个月，观察到 MR 有所改善（图）；到 6 个月时，3 到 4+ MR 的患病率下降到 8.2%（相对减少 45.0%），到 12 个月时，为 8.4%（相对减少 44.7%）。基线时 MR 为 3 至 4+ 并在 12 个月内减少至 ≤2+ 的患者（“反应者”；N=52）与持续12 个月时 MR 等级 3 至 4+（“无反应者”；N=33）；组间基线 LVEF 和 LV 容积相似，但有反应者的基线左心房容积指数（43.9 对 49.3 mL/kg ²；P = 0.01）和 LV 质量指数（145.0 对 166.0 g/m ²；P=0.02)。在基线时，反应者和无反应者之间的缩静脉/LVEDVi 或左心房面积/LVEDVi 比率均无显着差异（分别为P = 0.11 和 0.68）。在反应者和无反应者之间，研究期间的平均 sac/val 剂量分别为 276 和 277 mg/d ( P =0.57)。到 12 个月时，应答者的 LVEF 改善大于无应答者（+11.0% 对 +7.6%；P =0.05），应答者的最终 LVEDVi（85.2 对 96.9 mL/kg ²；P =0.02）、左室收缩末期容积较低指数（56.5 对 66.0 mL/kg ²；P =0.04），左心房容积指数（33.4 对 42.3 mL/kg ²；P<0.001)、E/e'（12.6 对 15.8；P =0.04）和 LV 质量指数（125.7 对 152.2 g/m ²）。最后，到 12 个月时，缓解者的 NT-proBNP（N 末端 B 型钠尿肽原原；912 对 1512 pg/mL；P =0.01）中位数较低，堪萨斯城心肌病问卷总得分中位数较高（82.3 对 72.9） ; P = 0.04) 尽管基线时两种措施的结果相似。

数字。 桑基图详细说明了接受沙库巴曲/缬沙坦治疗的心力衰竭和射血分数降低的研究参与者在基线、6 个月和 12 个月时二尖瓣反流的严重程度。

尽管对 MR 为 3 至 4+ 的患者进行瓣膜修复可能会改善 HFrEF 的症状并减少不良后果，但在进行此类干预之前优化 GDMT 很重要。在此分析中，尽管大多数研究参与者之前接受过 ACE 抑制剂或血管紧张素 II 受体阻滞剂，但我们观察到在 sac/val 治疗 12 个月后 MR 显着转变为较低程度，包括 3 至 50% 的减少近 50% 4+先生。MR 从 3 降低到 4+ 与显着的心脏重构逆转、NT-proBNP 降低和健康状况改善有关。

到 12 个月时 MR 为 3 至 4+ 并降低至 ≤ 2+ MR 的患者的基线临床和超声心动图特征与 12 个月时 MR 持续为 3 至 4+ 的患者相似，并且两组的基线 LVEF 相当，尽管基线 MR 程度相当，但 LV 体积和 MR 严重程度与 LVEDVi 的比率。因此，预测由 LV 扩张引起的 MR 与没有 sac/val 治疗过程的固有瓣膜功能障碍可能很困难。

本研究的局限性包括单臂观察设计；因此，MR 的改善可能是由于 sac/val 以外的因素。尽管如此，这项研究的结果为在常规护理中开始 sac/val 后 MR 的潜在变化提供了重要的见解。

随着对 HFrEF 和 3 至 4+ MR 患者使用经皮方法进行二尖瓣修复的增长，本研究的结果强调了在做出此类决定之前确保最佳 GDMT 的重要性。

这项工作作为摘要在 2022 年 9 月 30 日至 10 月 3 日在华盛顿特区举行的美国心力衰竭协会 2022 年年度科学会议上发表。

Januzzi 博士部分得到了 Hutter Family Professorship 的支持。

非标准缩写和首字母缩略词

GDMT	指南指导的药物治疗
HFrEF	射血分数降低的心力衰竭
低压	左心室
LVEDVi	左心室舒张末期容积指数
左心室射血分数	左心室射血分数
先生	二尖瓣反流
NT-proBNP	N 末端 B 型钠尿肽前体
囊/值	沙库巴曲/缬沙坦

指南指导的药物治疗

射血分数降低的心力衰竭

左心室

左心室舒张末期容积指数

左心室射血分数

二尖瓣反流

N 末端 B 型钠尿肽前体

沙库巴曲/缬沙坦

披露Januzzi 博士是美国心脏病学会的理事；是 Imbria Pharmaceuticals 的董事会成员；已获得雅培、Applied Therapeutics、Innolife、Novartis Pharmaceuticals 和 Roche Diagnostics 的研究支持；已从雅培、贝克曼、百时美施贵宝 (BMS)、勃林格殷格翰、杨森、诺华、辉瑞、默克、罗氏诊断和西门子获得咨询收入；并参与了 Abbott、AbbVie、Bayer、CVRx、Intercept、Janssen 和 Takeda 的临床终点委员会/数据安全监测委员会。Butler 博士是 Abbott、Adrenomed、Amgen、Applied Therapeutics、Array、AstraZeneca、Bayer、Boehringer Ingelheim、Bristol Myers Squibb、CVRx、G3 Pharmaceutical、Impulse Dynamics、Innolife、Janssen、LivaNova、Luitpold、Medtronic、Merck、Novartis、诺和诺德、罗氏和 Vifor。Felker 博士获得了国家心肺血液研究所、美国心脏协会、Amgen、Bayer、BMS、Merck、Cytokinetics 和 CSL-Behring 的研究资助；曾担任诺华、安进、BMS、Cytokinetics、美敦力、Cardionomic、勃林格殷格翰、American Regent、雅培、阿斯利康、Reprieve、Myovant、Sequana、Windtree Therapuetics 和 Whiteswell 的顾问；并曾在 Amgen、Merck、Medtronic、EBR Systems、V-Wave、LivaNova、Siemens 和 Rocket Pharma 的临床终点委员会/数据安全监测委员会任职。Ward 博士是诺华制药公司的员工。Solomon 博士获得了 Alnylam、Amgen、AstraZeneca、Bellerophon、Bayer、BMS、Celladon、Cytokinetics、Eidos、Gilead、GSK、Ionis、Lone Star Heart、Mesoblast、MyoKardia 的研究资助 美国国立卫生研究院/国家心肺血液研究所、诺华、赛诺菲巴斯德和 Theracos；并为 Akros、Alnylam、Amgen、AstraZeneca、Bayer、BMS、Cardior、Corvia、Cytokinetics、Gilead、GSK、Ironwood、Merck、Myokardia、Novartis、Roche、Takeda、Theracos、Quantum Genetics、Cardurion、AoBiome、Janssen、Cardiac 提供咨询尺寸和Tenaya。Contreras 博士已从 Alnylam Pharmaceuticals、Novo Nordisk、Boehringer Ingelheim 和 AstraZeneca 获得咨询费。其他作者报告没有冲突。和特纳亚。Contreras 博士已从 Alnylam Pharmaceuticals、Novo Nordisk、Boehringer Ingelheim 和 AstraZeneca 获得咨询费。其他作者报告没有冲突。和特纳亚。Contreras 博士已从 Alnylam Pharmaceuticals、Novo Nordisk、Boehringer Ingelheim 和 AstraZeneca 获得咨询费。其他作者报告没有冲突。

有关资金来源和披露，请参阅第 1640 页。

流通可在 www.ahajournals.org/journal/circ