Since 2019, coronavirus disease 2019 (COVID-19) has affected millions of individuals worldwide, leading to multiple deaths and numerous long-term multiorgan sequelae. In patients with COVID-19, cardiovascular diseases, including heart failure (HF), are common and associated with an increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections¹ and high mortality rates.² Epidemiological data revealed that prevalent HF was an independent predictor of increased in-hospital mortality²: in an Italian cohort, nearly 42% of patients with known HF who had been hospitalized with COVID-19 died during hospitalization.² Although SARS-CoV-2 infection affects primarily the respiratory system, infected individuals can develop multiple de-novo cardiovascular complications, including HF,³ arrhythmia, acute coronary syndrome or (peri-) myocarditis.⁴ Persistent cardiac injury, defined as long-term high-sensitivity cardiac troponin T (hs-cTnT) elevation or persistent abnormalities in cardiac magnetic resonance³—even after the primary SARS-CoV-2 infection was cured—has been described.³ Proposed underlying mechanisms include activation of inflammatory and thrombotic cascades,¹ direct viral infiltration or emerging/worsening of underlying baseline myocardial structural or atherosclerotic abnormalities.¹

In a detailed review of the European Society of Cardiology task force for the management of COVID-19,^{5, 6} the dysregulation of angiotensin-converting enzyme (ACE)/ACE2 system due to direct SARS-CoV-2 interaction is highlighted as one of the central pathways.⁷ In brief, SARS-CoV-2 binds to the ACE2 receptor—located among others on myocytes—to mediate cellular internalization (Figure 1).^{7, 8} Thus, viral infiltration can lead to inflammation, cardiac fibrosis and direct cardiac damage by microvascular and macrovascular dysfunction (e.g. myocarditis with consequent arrhythmias or HF).⁵ In combination with immune over-reactivity or ‘cytokine storm’, these processes can destabilize atherosclerotic plaques resulting in acute coronary syndrome.⁵

All these described changes can result in HF with preserved ejection fraction (HFpEF)—particularly in those patients with underlying risk factors as hypertension, obesity or diabetes—or unmask subclinical preexisting HFpEF.⁹ Consecutively, its adequate diagnostics and treatment are essential.⁹ As quantitative markers of cardiomyocyte injury and haemodynamic myocardial stress measurement of hs-cTnT and N-terminal pro-B-type natriuretic peptide (NT-proBNP) should not be delayed. These biomarkers are common, accurate and easy to perform. In cohort studies, they were independently associated with adverse outcome in acute COVID-19,^{3, 10} as well as in long-term cardiac injury,³ strengthening their relevance for precise prognostic risk stratification.

At the beginning of the pandemic, arterial hypertension was rapidly revealed as one of the most prevalent risk factor for COVID-19-associated cardiovascular events.^{2, 11} As renin–angiotensin system inhibitors (RASi), including ACE inhibitors (ACEi) or angiotensin receptor blockers (ARBs), are the basis for antihypertensive (and HF) treatment and are known to increase the tissue levels of ACE2, they have been claimed to be responsible for adverse outcomes in individuals with arterial hypertension and COVID-19.¹¹ It was stated that the treatment with RASi may promote SARS-CoV-2 infection, therefore being detrimental in patients who are exposed to SARS-CoV-2.¹¹ But up to now, this hypothesis has not been confirmed and epidemiological studies showed that there is no clear evidence that ACEi or ARBs affect the risk of SARS-CoV-2 infection.¹² On the contrary, randomized controlled trials on patients on RASi hospitalized for SARS-CoV-2 infection showed that stopping the treatment with ACEi or ARBs resulted in a rise of natriuretic peptides and increasing the risk of acute HF compared to treatment continuation.¹³ Additionally, it has been shown that the discontinuation of ACEi and ARBs (and beta-blockers) increases the risk of adverse outcomes (Table 1).^12-17 In a meta-analysis compromising data of 11 randomized controlled trials which enrolled a total of 1838 participants, continuation versus discontinuation of RASi showed no difference in all-cause mortality and a non-significant reduction in acute myocardial infarction, but an increased risk of acute kidney injury.¹⁸ While trials focusing on sodium–glucose cotransporter 2 inhibitors in COVID-19 showed a treatment benefit¹⁹ and those on mineralocorticoid receptor antagonists²⁰ were neutral, data on sacubitril/valsartan (angiotensin receptor–neprilysin inhibitor [ARNI]) are sparse.²¹ Sacubitril increases neprilysin-degraded peptides, such as natriuretic peptides and angiotensin 1–7 by neprilysin inhibition. These peptides are associated with anti-inflammatory, antihypertrophic and antifibrotic effects.

Based on the hypothesis that treatment with ARNI can protect SARS-CoV-2 infected individuals against long-term cardiac injury,⁷ the PARACOR-19 trial¹⁴ has been conducted. High-sensitivity cardiac troponin T, soluble suppression of tumorigenicity 2 (sST2) and NT-proBNP were measured at baseline, at least 4–16 weeks after SARS-CoV-2 infection, followed by a 12-week-period of ARNI therapy compared to placebo. The treatment with ARNI failed to lower high levels of hs-cTnT and sST2 following SARS-CoV-2 infection from baseline to week 12, but it resulted in significant reduction of both NT-proBNP levels (−167 pg/ml [mean] from baseline to week 12) and systolic blood pressure (−19 mmHg [mean] from baseline to week 12) due to decreasing cardiac wall stress and reduced afterload. Although there was various discussion about ACE2 and RASi treatment in the past, treatment with ARNI was safe in the present trial. In a subgroup analysis, cardiac magnetic resonance was performed at baseline and at week 12 without any significant differences between the intervention group and the control arm. Unfortunately, the trial was underpowered (42 participants included; subgroup analysis included 18 participants in total only), ARNI treatment was only started 69 (54–90) days (median 25th–75th) after proven COVID-19 infection, the interventional period of only 12 weeks was relatively short and less than half of the participants had residual COVID-19 symptoms at time of enrolment. Additionally, echocardiographic data as well as clinical symptoms such as dyspnoea (New York Heart Association stages) or angina pectoris (Canadian Cardiovascular Society stages) had not been captured, but left ventricular ejection fraction <40% had been an exclusion criterion. The randomized participants in PARACOR-19 were at low cardiovascular risk (only 14% had been hospitalized for COVID-19, 30% in the intervention arm had known hypertension, 30% diabetes and 14% prevalent cardiovascular diseases). In this analysis, ARNI failed to lower hs-cTnT. These data are in contrast to previously published post-hoc analysis of the PARAGON-HF trial. In over 4000 participants with known HFpEF, a reduction of 9% of hs-cTnT in the ARNI treatment arm compared to the valsartan treatment arm has been observed from baseline to week 16.²² The hs-cTnT reduction was significantly associated with a lower cardiovascular event rate, leading to the author's conclusion that hs-cTnT may be helpful in identifying individuals with HFpEF who are more likely to benefit from ARNI treatment.

Maybe these treatment effects would have been observed by earlier treatment implementation (during acute SARS-CoV-2 infection) or by focused treatment in those with early concomitant cardiac symptoms. Hence, strategies for appropriate treatment for COVID-19-associated cardiac injury are still missing and require further investigation.

Nevertheless, the results of PARACOR-19 strengthen the safety of ARNI intake in recently SARS-CoV-2 infected patients with residual hs-cTnT elevation. These results could be transferred to other respiratory virus infections—as influenza or respiratory syncytial virus—that were also associated with myocardial involvement and increased cardiovascular outcome.²⁰

We congratulate the authors for having completed their randomized hypothesis-generating trial and helping us to find evidence for treatment options in COVID-19-associated cardiovascular diseases.

自 2019 年以来，2019 冠状病毒病 （COVID-19） 已影响全球数百万人，导致多人死亡和许多长期多器官后遗症。在 COVID-19 患者中，包括心力衰竭 （HF） 在内的心血管疾病很常见，并且与严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 感染的风险增加¹ 和高死亡率有关。² 流行病学数据显示，流行的 HF 是院内死亡率增加的独立预测因子²：在意大利的一个队列中，近 42% 的已知 HF 患者因 COVID-19 住院而在住院期间死亡。² 虽然 SARS-CoV-2 感染主要影响呼吸系统，但感染者可能会出现多种新发心血管并发症，包括 ^HF，3 心律失常、急性冠脉综合征或（周围）心肌炎。⁴ 已经描述了持续性心脏损伤，定义为长期高敏心肌肌钙蛋白 T （hs-cTnT） 升高或心脏磁共振持续异常³ ——即使在原发性 SARS-CoV-2 感染治愈后也是如此。³ 提出的潜在机制包括炎症和血栓形成级联反应的激活，¹ 直接病毒浸润或潜在基线心肌结构或动脉粥样硬化异常的出现/恶化。¹

在欧洲心脏病学会 COVID-19,5,6 管理工作组的详细审查中，由于直接 SARS-CoV-2 相互作用导致的血管紧张素转换酶 （ACE）/ACE2 系统失调被强调为中心途径之一。⁷ 简而言之，SARS-CoV-2 与位于心肌细胞上的 ACE2 受体结合，以介导细胞内化（图 1）。^7、8因此，病毒浸润可导致炎症、心脏纤维化和微血管和大血管功能障碍引起的直接心脏损伤（例如 心肌炎伴随之而来的心律失常或 HF）。⁵ 结合免疫过度反应或“细胞因子风暴”，这些过程会破坏动脉粥样硬化斑块的稳定性，从而导致急性冠脉综合征。⁵

所有这些描述的变化都可能导致射血分数保留的 HF （HFpEF） — 尤其是在那些具有高血压、肥胖或糖尿病等潜在危险因素的患者中 — 或揭示亚临床先前存在的 HFpEF。⁹ 连续地，对其适当的诊断和治疗是必不可少的。⁹ 作为心肌细胞损伤和血流动力学心肌负荷的定量标志物，不应延迟 hs-cTnT 和 N 末端 B 型利钠肽前体 （NT-proBNP） 的测量。这些生物标志物常见、准确且易于执行。在队列研究中，它们与急性 COVID-19,3^、10 以及长期心脏损伤的不良结局独立相关，³ 加强了它们与精确预后风险分层的相关性。

在大流行开始时，动脉高血压迅速被揭示为 COVID-19 相关心血管事件最普遍的危险因素之一。^2、11由于肾素-血管紧张素系统抑制剂 （RASi），包括 ACE 抑制剂 （ACEi） 或血管紧张素受体阻滞剂 （ARB），是抗高血压（和 HF）治疗的基础，并且已知会增加 ACE2 的组织水平，因此据称它们会导致动脉高血压和 COVID-19 患者的不良后果。¹¹ 据称，RASi 治疗可能会促进 SARS-CoV-2 感染，因此对暴露于 SARS-CoV-2 的患者有害。¹¹ 但到目前为止，这一假设尚未得到证实，流行病学研究表明，没有明确的证据表明 ACEi 或 ARB 会影响 SARS-CoV-2 感染的风险。¹² 相反，针对因 SARS-CoV-2 感染住院的 RASi 患者的随机对照试验表明，与继续治疗相比，停止 ACEi 或 ARBs 治疗会导致利钠肽增加并增加急性 HF 的风险。¹³ 此外，已经表明，停用 ACEi 和 ARB（以及 β 受体阻滞剂）会增加不良后果的风险（表 1）。^12-17 在一项荟萃分析中，损害了 11 项随机对照试验的数据，共招募了 1838 名参与者，继续与停止 RASi 显示全因死亡率没有差异，急性心肌梗死没有显着降低，但急性肾损伤的风险增加。¹⁸ 虽然专注于 COVID-19 中钠-葡萄糖协同转运蛋白 2 抑制剂的试验显示治疗益处¹⁹ 并且盐皮质激素受体拮抗剂²⁰ 的试验是中性的，但关于沙库巴曲/缬沙坦（血管紧张素受体-脑啡肽酶抑制剂 [ARNI]）的数据很少。²¹ Sacubitril 通过抑制脑啡肽酶来增加脑啡肽酶降解的肽，例如利钠肽和血管紧张素 1-7。这些肽具有抗炎、抗肥大和抗纤维化作用。

基于 ARNI 治疗可以保护 SARS-CoV-2 感染者免受长期心脏损伤的假设，⁷ 已经进行了 PARACOR-19 试验¹⁴。在基线时、SARS-CoV-2 感染后至少 4-16 周测量高敏心肌肌钙蛋白 T、可溶性致瘤性抑制 2 （sST2） 和 NT-proBNP，然后与安慰剂相比，进行为期 12 周的 ARNI 治疗。从基线到第 12 周，ARNI 治疗未能降低 SARS-CoV-2 感染后高水平的 hs-cTnT 和 sST2，但由于心壁应力降低和后负荷降低，导致 NT-proBNP 水平（从基线到第 12 周 -167 pg/ml [平均值]）和收缩压（从基线到第 12 周-19 mmHg [平均值]）显著降低。尽管过去对 ACE2 和 RASi 治疗进行了各种讨论，但在本试验中 ARNI 治疗是安全的。在亚组分析中，在基线和第 12 周进行心脏磁共振，干预组和对照组之间没有任何显着差异。不幸的是，该试验的把握度不足（包括 42 名参与者;亚组分析仅包括总共 18 名参与者），ARNI 治疗在确诊 COVID-19 感染后 69 （54-90） 天（中位第 25-75 天）才开始，只有 12 周的干预期相对较短，不到一半的参与者在入组时有残留的 COVID-19 症状。 此外，超声心动图数据以及呼吸困难 （纽约心脏协会分期） 或心绞痛 （加拿大心血管学会分期） 等临床症状尚未捕获，但左心室射血分数 <40% 已作为排除标准。PARACOR-19 的随机参与者心血管风险较低（只有 14% 因 COVID-19 住院，干预组中 30% 患有高血压，30% 患有糖尿病，14% 患有心血管疾病）。在该分析中，ARNI 未能降低 hs-cTnT。这些数据与先前发表的 PARAGON-HF 试验的事后分析形成鲜明对比。在 4000 多名已知 HFpEF 的参与者中，从基线到第 16 周，与缬沙坦治疗组相比，ARNI 治疗组的 hs-cTnT 降低了 9%。²² hs-cTnT 降低与较低的心血管事件发生率显著相关，因此作者得出结论，hs-cTnT 可能有助于识别更有可能从 ARNI 治疗中受益的 HFpEF 个体。

也许这些治疗效果可以通过早期治疗实施（在急性 SARS-CoV-2 感染期间）或通过对早期伴随心脏症状的患者进行集中治疗来观察到。因此，仍缺乏针对 COVID-19 相关心脏损伤的适当治疗策略，需要进一步调查。

尽管如此，PARACOR-19 的结果加强了最近 SARS-CoV-2 感染且残留 hs-cTnT 升高的患者摄入 ARNI 的安全性。这些结果可以转移到其他呼吸道病毒感染——如流感或呼吸道合胞病毒——这些感染也与心肌受累和心血管结局增加有关。²⁰

我们祝贺作者完成了他们的随机假设生成试验，并帮助我们找到了 COVID-19 相关心血管疾病治疗方案的证据。