Heart failure with preserved ejection fraction and atrial fibrillation: recent advances and open questions
射血分数保留的心力衰竭和心房颤动：最新进展和悬而未决的问题

Abstract 抽象的

Atrial fibrillation (AF) and heart failure (HF) are frequently associated and can be caused or exacerbated by each other through different mechanisms. AF is particularly common in patients with heart failure with preserved ejection fraction (HFpEF) defined as left ventricular ejection fraction (LVEF) ≥ 50%, with a prevalence ranging around 40–60%.
心房颤动 (AF) 和心力衰竭 (HF) 经常相关，并且可以通过不同的机制相互引起或加剧。 AF 在射血分数保留 (HFpEF) 定义为左心室射血分数 (LVEF) ≥ 50% 的心力衰竭患者中尤为常见，患病率约为 40-60%。

In two recent trials, treatment with SGLT2 inhibitors resulted in a lower risk of worsening heart failure or cardiovascular death than placebo in patients with HFpEF, and SGLT2 inhibitors similarly improved prognosis whether patients had AF or not at enrolment. Analyses for subgroups of interest of patients with HFpEF likely to be at higher risk of AF (particularly those with older age or obesity) similarly indicated a consistent benefit with SGLT2 inhibitors. That subgroup in patients with HFpEF is those with a history of previous HF with LVEF ≤ 40%. The EAST-AFNET 4 trial indicated that early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with recent AF and cardiovascular conditions, including those with HF. In patients with AF and HF included in the CABANA trial, catheter ablation produced marked improvements in survival, freedom from AF recurrence, and quality of life compared to drug therapy. When strategies aiming at rhythm control eventually fail in patients with AF and HFpEF, a strategy of rate control with atrioventricular junction ablation and cardiac resynchronisation should be discussed since it may also reduce all-cause mortality.
在最近的两项试验中，与安慰剂相比，使用 SGLT2 抑制剂治疗 HFpEF 患者可降低心力衰竭恶化或心血管死亡的风险，并且无论患者在入组时是否患有 AF，SGLT2 抑制剂都可以类似地改善预后。对可能具有较高 AF 风险的 HFpEF 患者（特别是年龄较大或肥胖的患者）感兴趣的亚组的分析同样表明 SGLT2 抑制剂具有一致的益处。 HFpEF 患者的亚组是那些既往有 HF 病史且 LVEF≤≤40% 的患者。 EAST-AFNET 4 试验表明，对于近期患有房颤和心血管疾病（包括心衰患者）的患者来说，早期节律控制治疗与常规治疗相比，不良心血管结局的风险较低。在 CABANA 试验中纳入的 AF 和 HF 患者中，与药物治疗相比，导管消融显着改善了生存率、避免 AF 复发以及生活质量。当针对 AF 和 HFpEF 患者的节律控制策略最终失败时，应讨论房室交界处消融和心脏再同步的心率控制策略，因为它也可能降低全因死亡率。

Finally, and in conclusion, considering that patients with AF and HFpEF may have a variety of cardiovascular and non-cardiovascular additional comorbidities, they are among those likely to have the highest clinical benefit being adherent to a holistic and integrated care management of AF following the ABC (Atrial Fibrillation Better Care) pathway.
最后，总而言之，考虑到 AF 和 HFpEF 患者可能患有各种心血管和非心血管附加合并症，他们是那些在接受 AF 治疗后坚持全面综合护理管理的患者，可能会获得最高的临床获益。 ABC（心房颤动更好护理）途径。

Background  背景

Atrial fibrillation (AF) and heart failure (HF) are frequently associated and can be caused or exacerbated by each other through different mechanisms including cardiac remodelling and rate-related left ventricular incompetency [1,2,3]. AF is particularly common in patients with heart failure with preserved ejection fraction (HFpEF, defined as left ventricular ejection fraction [LVEF] ≥ 50%), with a prevalence ranging around 40–60% [4, 5]. AF and HFpEF may manifest with similar symptoms, and diagnostic uncertainties may exist for the diagnosis of HFpEF due to their interrelations influencing test results for echocardiography and natriuretic peptides [2]. HF patients with AF have a poorer prognosis than those with sinus rhythm and, importantly, the higher risk brought by AF is generally higher in patients with HFpEF than in those with HF and a reduced ejection fraction (HFrEF defined as LVEF ≤ 40%) [4]. This commentary discusses some recent advances in the understanding for the natural history of patients with HFpEF associated with AF and for the several different aspects of their medical management.
心房颤动 (AF) 和心力衰竭 (HF) 经常相关，并且可以通过不同的机制相互引起或加剧，包括心脏重塑和心率相关的左心室功能不全 [1,2,3]。 AF 在射血分数保留的心力衰竭患者中尤其常见（HFpEF，定义为左心室射血分数 [LVEF] ≥ 50%），患病率约为 40-60% [4, 5]。 AF 和 HFpEF 可能表现出相似的症状，并且由于它们之间的相互关系影响超声心动图和利尿钠肽的测试结果，因此 HFpEF 的诊断可能存在诊断不确定性[2]。合并房颤的心力衰竭患者预后比窦性心律患者差，重要的是，房颤带来的较高风险在 HFpEF 患者中通常高于心力衰竭且射血分数降低的患者（HFrEF 定义为 LVEF ≤ 40%）。 4]。本评论讨论了对 HFpEF 合并 AF 患者的自然史及其医疗管理的几个不同方面的理解的最新进展。

How does AF pattern affect prognosis in HFpEF?
AF 模式如何影响 HFpEF 的预后？

In unselected patients with AF, those with permanent AF are more likely to be older and to have HF than those with paroxysmal AF [6]. By contrast, patients with paroxysmal AF may have a higher prevalence of coronary artery disease [7]. The rates of death, stroke, and worsening HF are generally higher in patients with persistent and permanent AF than in patients with paroxysmal AF [6]. Progression from paroxysmal to persistent/permanent AF is also associated with adverse cardiovascular events, hospitalisations, and death [1]. The picture is a bit different when AF is associated with HF. Although paroxysmal AF is often characterised by lower atrial structural remodelling or less severe atrial cardiomyopathy when compared to non-paroxysmal AF, patients with HF and paroxysmal AF may have a higher crude and adjusted risk of HF hospitalisation [7]. This has also been reported recently in patients with HFpEF [8]. Why paroxysmal (versus non-permanent) AF is associated with a higher risk is uncertain. It is possible that episodes of paroxysmal of AF reflect HF instability (e.g. rises in atrial pressure triggering together episodes of AF and decompensation leading to hospital admission) or that acute changes in heart rhythm per se worsen HF in case of alternating fast ventricular rate due to AF with normal sinus rhythm. This may be particularly true for patients with HFpEF known to be easily decompensated in case of acute hemodynamic changes.
在未经选择的 AF 患者中，永久性 AF 患者比阵发性 AF 患者年龄更大且更容易发生 HF [6]。相比之下，阵发性房颤患者的冠状动脉疾病患病率可能更高[7]。持续性和永久性房颤患者的死亡率、中风和心力衰竭恶化率通常高于阵发性房颤患者[6]。从阵发性房颤进展为持续性/永久性房颤也与不良心血管事件、住院和死亡相关[1]。当 AF 与 HF 关联时，情况略有不同。尽管与非阵发性 AF 相比，阵发性 AF 的特点通常是心房结构重构程度较低或心房心肌病较轻，但心力衰竭和阵发性 AF 患者的心力衰竭住院治疗的粗略和调整风险可能较高 [7]。最近在 HFpEF 患者中也有报道 [8]。为什么阵发性（相对于非永久性）房颤与较高风险相关尚不清楚。阵发性 AF 发作可能反映了 HF 不稳定性（例如，心房压力升高同时触发 AF 发作和失代偿导致入院），或者心律本身的急性变化在交替性快速心室率的情况下导致 HF 恶化，这是由于房颤伴正常窦性心律。对于已知在发生急性血流动力学变化时很容易失代偿的 HFpEF 患者来说尤其如此。

Patients with HFpEF and history of previously reduced EF: was it AF and tachycardiomyopathy?

An interesting subgroup in patients with HFpEF is those with a history of previous HFrEF with LVEF ≤ 40%. Who are these patients with HFpEF and history of previously reduced LVEF? We think that two main reasons possibly overlapping may explain this profile. The first one is the setting where medical drugs indicated for HFpEF were able to improve LVEF, a scenario that may be seen for around 1/3 of patients with HFrEF (compared to grossly 1/3 with stable LVEF and 1/3 with worsening LVEF in spite of optimal drug therapy) [9]. The other possibility is that HFrEF was related to a transient or a curable cause that may include for example ischemic aetiology with efficient revascularisation or valve disease treated with surgery or percutaneous intervention [2, 9]. However, one of the most striking examples of HFrEF with complete recovery is cardiomyopathy directly and purely induced by persistent arrhythmias (so-called tachycardiomyopathy) among which AF is the most common cause [2, 9, 10]. When AF causes HF, the clinical course may be more favourable than with other causes of HF although patients may not have a complete healing and may shift from HFrEF to HFpEF. In contrast, the development of AF in patients with pre-existing HF (whether this is HFrEF or HFpEF) is frequently associated with a worse prognosis, including a higher risk of stroke and increased mortality [2, 11]. These elements should inspire future trials of specific therapeutics for HFpEF that would include the poorly evaluated population of patients with an improved LVEF, particularly when temporary AF has been involved in the development of transient HFrEF.
HFpEF 患者中一个有趣的亚组是既往有 HFrEF 病史且 LVEF ≤ 40% 的患者。这些患有 HFpEF 且既往有 LVEF 降低史的患者是谁？我们认为两个可能重叠的主要原因可以解释这一情况。第一个是治疗 HFpEF 的药物能够改善 LVEF 的情况，大约 1/3 的 HFrEF 患者可能会出现这种情况（相比之下，LVEF 稳定的患者为 1/3，LVEF 恶化的患者为 1/3）尽管有最佳的药物治疗）[9]。另一种可能性是 HFrEF 与暂时性或可治愈的原因有关，例如可能包括通过有效血运重建的缺血性病因或通过手术或经皮介入治疗的瓣膜疾病 [2, 9]。然而，完全恢复的 HFrEF 最引人注目的例子之一是直接且纯粹由持续性心律失常诱发的心肌病（所谓的心动过速性心肌病），其中 AF 是最常见的原因 [2,9,10]。当 AF 引起 HF 时，尽管患者可能没有完全康复并且可能从 HFrEF 转变为 HFpEF，但临床过程可能比其他原因引起的 HF 更有利。相比之下，已有心力衰竭（无论是 HFrEF 还是 HFpEF）的患者发生房颤通常与预后较差相关，包括卒中风险较高和死亡率增加 [2, 11]。这些因素应该会激发未来对 HFpEF 特定疗法的试验，其中包括对 LVEF 改善的患者进行不良评估，特别是当暂时性 AF 参与短暂性 HFrEF 的发展时。

Are there benefits of SGLT2 inhibitors when HFpEF is associated with AF?
当 HFpEF 与 AF 相关时，SGLT2 抑制剂是否有益处？

Sodium–glucose cotransporter 2 (SGLT2) inhibitors, initially developed for the treatment of type 2 diabetes mellitus, have shown major clinical benefits for patients with HFrEF in the last years (with or without diabetes), and in the last months for those with HFpEF [12]. Two trials indeed evaluated empagliflozin and dapagliflozin in patients with heart failure and a left ventricular ejection fraction of more than 40%, with similar inclusion and exclusion criteria and a similar primary composite outcome. Treatment with SGLT2 inhibitors resulted in a lower risk of worsening heart failure (defined as hospitalisation or unexpected visit for heart failure) or cardiovascular death than placebo in the two trials [13, 14]. Dapagliflozin brought a significant clinical benefit in the subgroup of patients with HFpEF and history of previous HFrEF with LVEF ≤ 40% (with a numerically lower HR of the primary combined endpoint of 0.74 compared to 0.84 for the other group of patients) [14]. A major point to be mentioned is that SGLT2 inhibitors similarly improved prognosis whether patients had AF or not at enrolment [13,14,15]. The treatment effect for the composite endpoint of cardiovascular death or first hospitalisation for HF was indeed consistent for patients with AF (HR 0.77, 95% CI 0.69–0.87) and those with no AF (HR 0.83, 95% CI 0.72–0.95), and there was no statistical heterogeneity between empagliflozin and dapagliflozin in the subgroups of patients with AF [15]. Analyses for subgroups of interest of patients with HFpEF likely to be at higher risk of AF (particularly those with older age or obesity) similarly indicated a consistent benefit with SGLT2 inhibitors and no apparent heterogeneity between empagliflozin and dapagliflozin [15].
钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂最初是为治疗 2 型糖尿病而开发的，在过去几年（患有或不患有糖尿病）以及过去几个月中对 HFpEF 患者显示出对 HFrEF 患者的重大临床益处[12]。两项试验确实评估了恩格列净和达格列净治疗心力衰竭且左心室射血分数超过 40% 的患者，具有相似的纳入和排除标准以及相似的主要复合结局。在这两项试验中，与安慰剂相比，SGLT2抑制剂治疗可降低心力衰竭恶化（定义为因心力衰竭住院或意外就诊）或心血管死亡的风险[13, 14]。达格列净为患有 HFpEF 且既往有 HFrEF 且 LVEF ≤ 40% 病史的患者亚组带来了显着的临床获益（主要组合终点的 HR 数值较低，为 0.74，而另一组患者的 HR 为 0.84）[14]。需要提到的一个要点是，无论患者在入组时是否患有 AF，SGLT2 抑制剂都能类似地改善预后 [13,14,15]。对于 AF 患者（HR 0.77，95% CI 0.69–0.87）和非 AF 患者（HR 0.83，95% CI 0.72–0.95），心血管死亡或因心力衰竭首次住院这一复合终点的治疗效果确实是一致的。在 AF 患者亚组中，恩格列净和达格列净之间不存在统计学异质性[15]。对可能存在较高 AF 风险的 HFpEF 患者（特别是年龄较大或肥胖的患者）感兴趣亚组的分析同样表明 SGLT2 抑制剂具有一致的益处，并且恩格列净和达格列净之间没有明显的异质性[15]。

Rhythm control therapy for all patients with atrial fibrillation and HFpEF?
所有心房颤动和 HFpEF 患者都接受节律控制治疗吗？

The occurrence of paroxysmal AF may reflect deterioration in HF with congestion and higher atrial pressure precipitating both episodes of AF and decompensation of HF. Alternatively, the occurrence of paroxysmal AF related to electrical instability may lead to a sudden increase in ventricular rate with loss of atrial systole and may be the direct cause of decompensation [8]. If the latter is true, prevention of AF by rhythm control using an antiarrhythmic agent or catheter ablation might reduce the risk of HF decompensation.
阵发性房颤的发生可能反映了心力衰竭的恶化，充血和心房压力升高导致房颤发作和心力衰竭失代偿。或者，与电不稳定相关的阵发性房颤的发生可能导致心室率突然增加并伴有心房收缩期丧失，并且可能是失代偿的直接原因[8]。如果后者属实，则通过使用抗心律失常药物或导管消融控制节律来预防 AF 可能会降低 HF 失代偿的风险。

The EAST-AFNET4 trial recently indicated that early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with recent AF (diagnosed within 1 year) and cardiovascular conditions [16]. This applied to patients with HF (n = 798), a majority of whom having HFpEF (56% of those with HF). An ancillary analysis has been presented for these patients [17]. The primary outcome (composite endpoint of death from cardiovascular causes, stroke, hospitalisation with worsening of HF or acute coronary syndrome) occurred in 94 of 396 HF patients randomly assigned to early rhythm control and in 130 of 402 HF patients randomly assigned to usual care (hazard ratio [HR] 0.74, 95% CI 0.56–0.97, p = 0.03). The treatment effect was not different from that in patients with normal left ventricular function and with no signs of HF (HR 0.81, 95% CI 0.66–1.0, p = 0.06; interaction p between treatment and HF = 0.63). Patients with HFpEF had a lower risk for the first primary outcome compared with those with HFrEF. However, the highest improvement in NYHA class occurred in patients with HFpEF.
EAST-AFNET4 试验最近表明，对于近期患有 AF（1 年内诊断）和心血管疾病的患者，早期节律控制治疗与常规治疗相比，不良心血管结局的风险较低[16]。这适用于 HF 患者 (n = 798)，其中大多数患有 HFpEF（其中 56% 患有 HF）。对这些患者进行了辅助分析[17]。主要结局（心血管原因死亡、中风、心力衰竭恶化住院或急性冠状动脉综合征的复合终点）发生在随机分配接受早期心律控制的 396 名心力衰竭患者中的​​ 94 名，以及随机分配接受常规治疗的 402 名心力衰竭患者中的​​ 130 名。风险比 [HR] 0.74，95% CI 0.56–0.97，p = 0.03）。治疗效果与左心室功能正常且无心力衰竭迹象的患者没有差异（HR 0.81，95% CI 0.66-1.0，p = 0.06；治疗与心力衰竭之间的相互作用 p = 0.63）。与 HFrEF 患者相比，HFpEF 患者出现第一个主要结局的风险较低。然而，NYHA 分级的最大改善发生在 HFpEF 患者中。

Drugs or catheter ablation for rhythm and rate control in AF with HFpEF?
药物或导管消融治疗 AF 伴 HFpEF 的节律和心率控制？

Interestingly, exploratory analyses of AF patients in the EAST-AFNET 4 study suggested that treatment with amiodarone, but not treatment with flecainide, propafenone, or dronedarone, was potentially associated with early HF hospitalisations in patients with HFpEF [17]. This may be a surprising finding since amiodarone is considered a relatively safe antiarrhythmic drug in patients with HF [1]. It thus suggests that further clinical research is needed to define the optimal antiarrhythmic drug therapy in patients with HFpEF.
有趣的是，EAST-AFNET 4 研究中对 AF 患者的探索性分析表明，胺碘酮治疗（而非氟卡尼、普罗帕酮或决奈达隆治疗）可能与 HFpEF 患者的早期心力衰竭住院相关[17]。这可能是一个令人惊讶的发现，因为胺碘酮被认为是心衰患者相对安全的抗心律失常药物[1]。因此，这表明需要进一步的临床研究来确定 HFpEF 患者的最佳抗心律失常药物治疗。

Previously available evidence of AF ablation in HFpEF until recently consisted of a few small observational reports. An ancillary analysis of the randomised CABANA trial reported outcomes with catheter ablation and antiarrhythmic drug therapy in 778 patients with AF and stable HF at baseline, the majority of whom (79%) having HFpEF [18]. Catheter ablation produced marked improvements in survival, freedom from AF recurrence, and quality of life compared to drug therapy. In the intention-to-treat analysis, the ablation arm had a significant 36% relative reduction in the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest and a 43% relative reduction in all-cause mortality. These results tended to be better than in the group of patients with no HF, highlighting the possible benefit of AF ablation in case symptoms and functional impairment may be attributed to the combined effects of AF and HFpEF. However, the effects on HF hospitalisations were small and not significant and the authors concluded that the results should be reproduced in a confirmatory trial.
直到最近，之前 HFpEF 中 AF 消融的可用证据还包括一些小型观察报告。随机 CABANA 试验的辅助分析报告了 778 名基线时患有 AF 和稳定 HF 的患者的导管消融和抗心律失常药物治疗的结果，其中大多数 (79%) 患有 HFpEF [18]。与药物治疗相比，导管消融显着改善了生存率、房颤复发率和生活质量。在意向治疗分析中，消融组的主要复合终点（死亡、致残性中风、严重出血或心脏骤停）相对显着降低了 36%，全因死亡率相对降低了 43%。这些结果往往比无心力衰竭的患者组更好，突显了房颤消融可能带来的益处，以防症状和功能障碍可能归因于房颤和 HFpEF 的综合影响。然而，对心力衰竭住院的影响很小且不显着，作者得出结论，应在验证性试验中重现结果。

When strategies aiming at rhythm control eventually fail, a strategy of rate control with atrioventricular junction ablation and cardiac resynchronisation should be discussed in case of AF with HFpEF since it reduced all-cause mortality in the APAF-CRT trial for patients with permanent AF and narrow QRS hospitalised for HF, irrespective of their baseline EF [19] (Fig. 1).
当旨在节律控制的策略最终失败时，对于伴有 HFpEF 的 AF 病例，应讨论房室交界处消融和心脏再同步的心率控制策略，因为在 APAF-CRT 试验中，该策略降低了永久性 AF 和狭窄患者的全因死亡率。因心力衰竭住院的 QRS 波，无论其基线 EF 是多少 [19]（图 1）。

Fig. 1 图。1

Principles for the holistic ABC approach including rate/rhythm control in AF management for patients with HFpEF
整体 ABC 方法的原则，包括 HFpEF 患者 AF 管理中的速率/节律控制

HFpEF: a setting where the holistic ABC approach is of major interest for the management of AF with HF
HFpEF：整体 ABC 方法对 AF 合并 HF 的管理具有重要意义的环境

Oral anticoagulation is also a major pillar to improve outcomes in patients with AF and HFpEF, but we need to look beyond anticoagulation in these patients [1]. However, a simple unique and one-size-fits-all approach may not be applicable or sufficient in the case of HFpEF with AF. Regarding early rhythm control for possibly improving outcomes in AF patients, most benefit occurs if intervention is early and in younger patients and those with fewer coexisting conditions and if it also includes an association of care with attention to anticoagulation management, risk-factor control, lifestyle factors, and regular follow-up visits needed to ensure adherence and effective care approaches [20].
口服抗凝药也是改善 AF 和 HFpEF 患者预后的主要支柱，但我们需要超越这些患者的抗凝治疗 [1]。然而，对于 HFpEF 合并 AF 的情况，一种简单、独特且一刀切的方法可能并不适用或不够。关于早期节律控制可能改善 AF 患者预后的问题，如果早期干预、针对年轻患者和共存疾病较少的患者，并且还包括将护理与抗凝管理、危险因素控制、生活方式相结合，则可获得最大益处。因素，并定期随访以确保依从性和有效的护理方法[20]。

Conclusions 结论

Perhaps one of the most important messages is indeed that patients with AF and HFpEF may have a variety of cardiovascular and non-cardiovascular additional comorbidities. Clinical events are common, despite anticoagulation and other medical therapies needed for HF [1, 2]. There has been a move toward a more holistic approach to the management of AF, summed up as the ABC (Atrial Fibrillation Better Care) pathway: (A) avoidance of stroke with the use of anticoagulation; (B) better management of symptoms with patient-centred, symptom-directed decisions on rate or rhythm control; and (C) cardiovascular and coexisting-condition risk management, including attention to psychological factors and lifestyle [21]. Adherence to the ABC pathway is associated with better clinical outcomes, including lower risks of all-cause death and cardiovascular death, stroke, and hospitalisation for cardiovascular cause [22], which explains its inclusion in most recent guidelines [1]. Patients with AF and HFpEF are probably those who may have the highest clinical benefit being adherent to the integrated care management of AF following the ABC pathway.
也许最重要的信息之一确实是 AF 和 HFpEF 患者可能患有各种心血管和非心血管其他合并症。尽管心力衰竭需要抗凝和其他药物治疗，但临床事件仍很常见 [1, 2]。目前已经出现了一种更全面的 AF 治疗方法，总结为 ABC（心房颤动更好护理）途径：(A) 使用抗凝药物避免中风； (B) 通过以患者为中心、以症状为导向的心率或节律控制决策来更好地管理症状； (C) 心血管和共存疾病风险管理，包括关注心理因素和生活方式[21]。坚持 ABC 途径与更好的临床结果相关，包括降低全因死亡和心血管死亡、中风以及心血管原因住院的风险 [22]，这解释了它被纳入最新指南的原因 [1]。 AF 和 HFpEF 患者可能是那些坚持遵循 ABC 途径的 AF 综合护理管理的患者，可能会获得最高的临床获益。