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Will introduction of ARNI reduce the need of device therapy in heart failure with reduced ejection fraction?
The Egyptian Heart Journal Pub Date : 2021-03-16 , DOI: 10.1186/s43044-021-00152-x
Navjyot Kaur , CR Pruthvi , Manojkumar Rohit

The last two decades saw major therapeutic advancements in the field of heart failure with reduced ejection fraction (HFrEF). While implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) became part of HFrEF therapy in the first decade of twentieth century, the second decade marked the introduction of angiotensin receptor neprilysin inhibitor (ARNI) in optimal medical therapy (OMT) for HFrEF. ICD prevents sudden cardiac deaths (SCDs), and CRT improves left ventricular ejection fraction (LVEF), reverses cardiac remodeling, and decreases heart failure (HF)-related hospitalizations and mortality. While ICD prevents 50–60% SCDs but not all, the CRT has shown its consistent efficacy only in selected subset of HFrEF patients and has a non-responder rate of 30% [1]. The novel pharmacological therapy ARNI reduced the HF-related mortality and hospitalization when compared with well-established angiotensin-converting enzyme inhibitor (ACEi) [2]. Though ARNI reduced mortality both due to HF progression and SCD, it was associated with a higher incidence of symptomatic hypotension. In this opinion paper, we discuss the two very recent contemporary therapies (device therapy and ARNI) for HFrEF, the gap in evidence, and the projected role of each therapy in coming years.

ICD

The role of ICD in primary prevention was established by Multicenter Automatic Defibrillator Implantation II (MADIT II) and Sudden Cardiac Death–Heart Failure trial (SCD-HeFT) trials [3]. While MADIT II included only ischemic patients with LVEF ≤ 35%, the SCD-HeFT trial included patients with both ischemic and non-ischemic etiology. However, Prophylactic Defibrillator Implantation in Patients with Non-ischemic Dilated Cardiomyopathy (DEFINITE) and Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality (DANISH) trials failed to show a significant reduction in total mortality in non-ischemic cardiomyopathy (NICM), though the SCDs were reduced in both trials [1]. In contrast to SCD-HeFT where the use of beta blockers was less than 70%, more than 85% of patients in DEFINITE and DANISH trials were on beta blockers [4]. A recent meta-analysis of 06 randomized controlled trials (RCTs) involving 2970 patients with NICM revealed 23% risk reduction in all-cause mortality with ICD [5], and hence, the present-day guidelines recommend the use of ICDs for primary prevention in HFrEF (New York Heart Classification (NYHA)-II/III) irrespective of the etiology. However, ICD is not advisable in patients with NYHA class IV symptoms or whose expected meaningful survival is less than 1 year.

CRT

Electromechanical dyssynchrony leads to non-synchronized left ventricular contraction, adverse cardiac remodeling, and increased myocardial energy expenditure. While Multisite stimulation in Cardiomyopathy (MUSTIC-SR), Multicenter In Sync Randomized Clinical Evaluation (MIRACLE), and CONTAK CD trials showed a significant improvement in NYHA functional class and peak oxygen consumption (pVO2) in selected patients of HFrEF (NYHA classes III and IV) with CRT, the subsequent two trials, Cardiac Resynchronization in Heart Failure Trial (CARE HF) and Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (CHAMPION) trials, provided evidence for a reduction in mortality and HF hospitalizations in same functional class of patients with HFrEF [6]. CRT in moderate to severely symptomatic HFrEF patients reduces the all-cause mortality by 28% and HF hospitalizations by 37% [7]. The role of CRT in mildly symptomatic patients (NYHA II) was established by Resynchronization Reverse Remodelling in Systolic Left Ventricular Dysfunction trial (REVERSE), MADIT-CRT, and Resynchronization/Defibrillation for Ambulatory Heart Failure Trial [RAFT] trials [6]. Based on available evidence, the present guidelines on HFrEF give the highest level recommendation for CRT in patients with LVEF ≤ 35% who have left bundle branch block (LBBB) and wide QRS ≥ 150 ms and remain symptomatic (NYHA class II, III, ambulatory IV) despite receiving OMT [6]. It is noteworthy that all the above mentioned RCTs were conducted between 2000 and 2010, when ARNI was not part of OMT. Moreover, the CRT has shown maximum and most consistent benefit only in a subset of patients with HFrEF and has a non-response rate of 30% even in this highly selected subgroup. Further, the CRT failed to show a consistent positive impact in HFrEF patients with non-LBBB and narrow QRS.

ARNI

The pathophysiology of HFrEF is marked by up-gradation of the renin-angiotensin-aldosterone system and by down-gradation of cardio-protective molecules like natriuretic peptides. ARNI, the combination of angiotensin receptor blocker (ARB) and neprilysin inhibitor (sacubitril/valsartan), proved superior to well-established angiotensin-converting enzyme inhibitor (ACEi) and showed a 20% relative risk reduction in the primary endpoint of cardiovascular (CV) death and HF hospitalization and 16% reduction in all-cause mortality in the landmark PARADIGM-HF trial [2]. Both SCDs and deaths due to HF progression were reduced equally. Soon after, the American and European guidelines [8, 9] included ARNI into the pharmacological management of symptomatic HFrEF patients (NYHA II-IV) on an outpatient basis. PIONEER-HF trial demonstrated the safety of introduction of ARNI in patients with acute decompensated heart failure (after stabilization) [10]. The most significant side effect reported with ARNI has been symptomatic hypotension which may hamper the up-titration of the drug to target dosages and lead to high rates of non-compliance and non-adherence in real-world scenarios. There are concerns about decreased clearance and deposition of beta amyloid peptides in the brain due to neprilysin inhibition with long-term use of ARNI. Table 1 summarizes the major RCTs done on ARNI in the last decade.

Table 1 Summary of major randomized controlled trials on angiotensin receptor neprilysin inhibitor

Full size table

CRT is considered one of the most powerful cardiac remodeling agents, second only to beta blockers [4]. It reverses the adverse cardiac remodeling, decreases LV and left atrial dimensions, and improves LVEF and functional mitral regurgitation, and the same has been co-related with positive clinical outcomes in MADIT-CRT and REVERSE trials [6]. The effect of ARNI on cardiac remodeling has been recently illustrated in PROVE HF trial [11] wherein ARNI over a period of 12 months improved LVEF by 9.4% and reduced LV end-diastolic volume index, LV end-systolic volume index, and left atrial volume index. A recent Italian observational SAVE ICD study by Federico Guerra revealed that after 6 months of treatment with ARNI, 25% of patients with ICD for primary prevention had LVEF ≥ 35% [12].

We cannot compare the absolute effect on cardiac remodeling between two modalities because of the heterogeneities of populations studied. Also, the CRT is offered over and above the OMT and reduction in LV volumes and improvement in LVEF can be at the best considered add-on, rather than an absolute effect. On the other hand, ARNI has proven to be effective when compared with another well-established RAAS blocking agent [2].

The CHAMPION trial failed to show significant mortality benefit of CRT-D over CRT-P [1]. In a more recent CeRtiTude cohort study, the rate of SCD was no different in two groups of patients with CRT-P and CRT-D at 2-year follow-up, despite the fact that the patients in the former group were sicker and older and had multiple comorbidities [13]. A review by Barra et al. in 2019 revealed that the risk of SCD in CRT patients has reduced more than fourfold over the last 20 years; the rate of decline in mortality including SCD has been more in the CRT-P group and it related closely to increased LVEF, increased use of beta blockers, decreased QRS duration, and decreased use of antiarrythmic drugs [14]. The PARADIGM trial showed an impressive reduction of 22% in the rate of SCDs [2]. de Diego et al. [15] and Martens et al. [16] revealed a significant reduction in sustained and non-sustained VAs and appropriate ICD shocks in the ARNI group and the latter also documented better pacing parameters of ICDs in patients on ARNI [17]. Sacubitril/valsartan reduces the arrhythmia burden primarily by improvement in cardiac remodeling, though the smaller studies have also illustrated a decrease in QRS duration, QTc interval, and mechanical dispersion as assessed by LV global longitudinal strain imaging [18].

CRT and ICD have shown to reduce mortality and morbidity in a selected subgroup of HFrEF patients who remain symptomatic while on OMT. ARNI improves clinical outcomes as compared to the well-established ACEi. Whether these devices would have significant positive clinical outcomes when used along with ARNI is still not known. In the case of ICDs, the meaningful reduction of mortality when used for primary prevention can only occur if the baseline risk of SCD is > 35% or the rate of SCD ≥ 1.2% per year [1]. With the increased use of beta blockers, the absolute risk of SCDs reduces and the additional ICD may have insignificant benefit [1, 4]. Similarly, with the addition of ARNI, the absolute CV mortality may reduce with no added benefit of any device therapy. Since ARNI is associated with a significantly increased risk of hypotension, compliance with the drug and achievement of target dosage may be an issue in real-world scenario especially in the Asian population. Likewise, the clinical benefit achieved with suboptimal dosages needs to be studied in prospective registries.

ARNI can be used in all symptomatic patients of HFrEF while CRT has shown maximum benefit in patients with LBBB and wide QRS. It causes time-dependent improvement in LVEF [11, 12], may reduce the need of ICD for primary prevention [12], and has shown to improve the biventricular pacing by reducing ventricular ectopy and thus can improve the percentage of responders in the CRT group. ARNI may also reduce the appropriate ICD therapy in patients with HFrEF by reducing VAs. However, till the time a robust evidence draws an entirely different conclusion, we should follow the present guidelines on the appropriate use of ICD, CRT, and ARNI in patients with HFrEF, though we may use ARNI more often as part of OMT with an aim to achieve the best possible benefit. Figure 1 illustrates the respective role of various therapies in the management of HFrEF.

ARNI and device therapy for HFrEF are two complementary therapies. While ARNI and CRT improve LVEF, reduce LV volumes, and produce significant improvement in cardiovascular mortality and HF hospitalizations, the ICDs reduce the additional risk of SCD in selected patients. Given the evidence, the ARNI shall be the future foundation of OMT for HFrEF, with CRT/ICD reserved for special situations where patients remain symptomatic while on OMT. The role of CRT/ICD in the era of ARNI needs to be re-established since the definition of OMT stands changed with much better and potent pharmacological therapy.

Not applicable for the above-said reasons

ACEi:: Angiotensin-converting enzyme inhibitor
ARB:: Angiotensin receptor blocker
ARNI:: Angiotensin receptor neprilysin inhibitor
CRT:: Cardiac resynchronization therapy
CV:: Cardiovascular
HF:: Heart failure
HFrEF:: Heart failure with reduced ejection fraction
ICD:: Implantable cardioverter-defibrillator
LBBB:: Left bundle branch block
NICM:: Non-ischemic dilated cardiomyopathy
NYHA:: New York Heart Classification
OMT:: Optimal medical therapy
pVO2:: Peak oxygen consumption
RCTs:: Randomized controlled trials
SCDs:: Sudden cardiac deaths

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Cardiology Unit II, Department of Cardiology, Level-3, Faculty Offices, Advanced Cardiac Center, Post Graduate Institute of Medical Education & Research, Sector-12, Chandigarh, 160012, India
Navjyot Kaur, CR Pruthvi & Manojkumar Rohit

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NK: planning, conceptualization, review of the literature, and writing the original draft preparation; PCR: conceptualizationn, writing the original draft preparation, and final review; MKR: planning, conceptualization, methodology, supervision, final review, and editing. All authors read and approved the final manuscript.

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Correspondence to Manojkumar Rohit.

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This particular manuscript is not a study or case report nor does it involves any human/animal trial or plant study. It is a commentary on contemporary literature on heart failure therapies. However, the ethics committee of our institution approves the submission of this article for publication.

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Kaur, N., Pruthvi, C. & Rohit, M. Will introduction of ARNI reduce the need of device therapy in heart failure with reduced ejection fraction?. Egypt Heart J 73, 26 (2021). https://doi.org/10.1186/s43044-021-00152-x

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Received: 05 January 2021
Accepted: 01 March 2021
Published: 16 March 2021
DOI: https://doi.org/10.1186/s43044-021-00152-x

中文翻译：

引入ARNI会减少射血分数，从而减少心力衰竭时对设备疗法的需求吗？

在过去的二十年中，心力衰竭领域的主要治疗进展是射血分数（HFrEF）降低。尽管植入式心脏复律除颤器（ICD）和心脏再同步治疗（CRT）在20世纪前十年成为HFrEF治疗的一部分，但第二个十年标志着血管紧张素受体中性溶酶抑制剂（ARNI）被引入了最佳药物治疗（OMT）中， HFrEF。ICD可预防心脏性猝死（SCD），CRT可改善左心室射血分数（LVEF），逆转心脏重塑并降低与心力衰竭（HF）相关的住院和死亡率。尽管ICD可以预防50-60％的SCD，但不能全部预防，但CRT仅在选定的HFrEF患者子集中显示出一致的疗效，无应答率为30％[1]。与成熟的血管紧张素转换酶抑制剂（ACEi）相比，新型药物疗法ARNI降低了与HF相关的死亡率和住院率[2]。尽管ARNI降低了因HF进展和SCD引起的死亡率，但它与症状性低血压的发生率较高有关。在这篇意见书中，我们讨论了针对HFrEF的两种最新的现代疗法（设备疗法和ARNI），证据方面的差距以及每种疗法在未来几年中的预计作用。

心脏疾病

ICD在一级预防中的作用已由多中心自动除颤器植入II（MADIT II）和心脏骤停-心力衰竭试验（SCD-HeFT）试验确定[3]。尽管MADIT II仅包括LVEF≤35％的缺血患者，但SCD-HeFT试验同时包括了缺血性和非缺血性病因的患者。但是，非缺血性扩张型心肌病（DEFINITE）患者的预防性除颤器植入以及丹麦评估ICD对非缺血性收缩性心力衰竭死亡率的疗效的丹麦研究（DANISH）未能显示出总死亡率显着降低。非缺血性心肌病（NICM），尽管在两个试验中SCD均降低了[1]。与SCD-HeFT相比，β受体阻滞剂的使用率不到70％，在DEFINITE和DANISH试验中，超过85％的患者使用了β受体阻滞剂[4]。最近一项包含2970例NICM患者的06项随机对照试验（RCT）的荟萃分析显示，使用ICD可以将全因死亡率降低23％[5]，因此，目前的指南建议使用ICD进行一级预防不论病因如何，HFrEF（纽约心脏分类（NYHA）-II / III）中的作用都没有。但是，对于患有NYHA IV级症状或预期有意义的生存期少于1年的患者，不建议使用ICD。目前的指南建议，无论病因如何，均应将ICD用于HFrEF（纽约心脏分类法（NYHA）-II / III）的一级预防。但是，对于患有NYHA IV级症状或预期有意义的生存期少于1年的患者，不建议使用ICD。目前的指南建议，无论病因如何，均应将ICD用于HFrEF（纽约心脏分类法（NYHA）-II / III）的一级预防。但是，对于患有NYHA IV级症状或预期有意义的生存期少于1年的患者，不建议使用ICD。

显像管

机电不同步导致左心室收缩不同步，不良的心脏重塑和增加的心肌能量消耗。心肌病的多部位刺激（MUSTIC-SR），同步同步多中心随机临床评估（MIRACLE）和CONTAK CD试验显示，HFrEF的部分患者（NYHA III级和IV）使用CRT，随后的两项试验，即心力衰竭的心脏再同步试验（CARE HF）和心力衰竭的药物治疗，起搏和去纤颤的比较（CHAMPION）试验，为降低死亡率和HF住院率提供了证据HFrEF患者的功能分类[6]。中度至重度有症状的HFrEF患者进行CRT可使全因死亡率降低28％，HF住院率降低37％[7]。CRT在轻度症状患者（NYHA II）中的作用是通过在收缩期左心室功能不全试验（REVERSE），MADIT-CRT和非同步性/去纤颤的动态性心力衰竭试验[RAFT]试验中[6]建立的。根据现有证据，本指南对左室束支传导阻滞（LBBB）和宽QRS≥150 ms且仍然有症状的LVEF≤35％的LVEF≤35％的患者，建议进行CRT的最高水平推荐（NYHA II，III级，门诊IV）尽管接受了OMT [6]。值得注意的是，上述所有RCT都是在2000年至2010年之间进行的，当时ARNI并非OMT的一部分。而且，CRT仅在一部分HFrEF患者中显示出最大和最一致的益处，即使在这个高度选择的亚组中，CRT的无应答率也为30％。此外，CRT在非LBBB和狭窄QRS的HFrEF患者中未能显示出持续的积极影响。

阿尼

HFrEF的病理生理学特征是肾素-血管紧张素-醛固酮系统的升级和心脏保护分子（如利钠肽）的降级。ARNI是血管紧张素受体阻滞剂（ARB）和中性溶酶抑制剂（sacubitril / valsartan）的组合，被证明优于公认的血管紧张素转化酶抑制剂（ACEi），并且在心血管疾病的主要终点指标（CV）中相对危险度降低了20％）在具有里程碑意义的PARADIGM-HF试验中[2]，死亡和HF住院，全因死亡率降低了16％[2]。SCD和因HF进展而导致的死亡均降低了。不久之后，美国和欧洲指南[8，9]在门诊患者中将ARNI纳入有症状的HFrEF患者（NYHA II-IV）的药理管理中。PIONEER-HF试验证明了急性失代偿性心力衰竭（稳定后）患者中引入ARNI的安全性[10]。ARNI报道的最严重的副作用是症状性低血压，这可能会阻碍药物调高至目标剂量，并导致现实情况中的高违规率和不依从性。由于长期使用ARNI，对中性溶酶的抑制，令人担忧的是β淀粉样蛋白肽在大脑中的清除率和沉积降低。表1总结了过去十年在ARNI上进行的主要RCT。ARNI报道的最严重的副作用是症状性低血压，这可能会阻碍药物调高至目标剂量，并导致现实情况中的高违规率和不依从性。由于长期使用ARNI，对中性溶酶的抑制，令人担忧的是β淀粉样蛋白肽在大脑中的清除率和沉积降低。表1总结了过去十年在ARNI上进行的主要RCT。ARNI报道的最严重的副作用是症状性低血压，这可能会阻碍药物调高至目标剂量，并导致现实情况中的高违规率和不依从性。由于长期使用ARNI，对中性溶酶的抑制，令人担忧的是β淀粉样蛋白肽在大脑中的清除率和沉积降低。表1总结了过去十年在ARNI上进行的主要RCT。

表1血管紧张素受体中性溶酶抑制剂的主要随机对照试验总结

全尺寸表

CRT被认为是最强大的心脏重塑剂之一，仅次于β受体阻滞剂[4]。它逆转了不良的心脏重塑，降低了左心室和左心房的尺寸，并改善了左心室射血分数和功能性二尖瓣关闭不全，并且在MADIT-CRT和REVERSE试验中，这些都与积极的临床结果相关[6]。最近在PROVE HF试验中证明了ARNI对心脏重塑的影响[11]，其中ARNI在12个月的时间里使LVEF改善了9.4％，并降低了LV舒张末期容积指数，LV收缩末期容积指数和左心房音量指数。Federico Guerra最近在意大利进行的一项SAVE ICD观察性研究显示，ARNI治疗6个月后，用于一级预防的ICD患者中有25％的LVEF≥35％[12]。

由于研究人群的异质性，我们无法比较两种方式对心脏重构的绝对影响。此外，CRT是在OMT之上提供的，并且减少LV体积和改善LVEF可以被认为是最好的附加措施，而不是绝对的效果。另一方面，与另一种公认的RAAS阻断剂相比，ARNI已被证明是有效的[2]。

CHAMPION试验未能显示出CRT-D优于CRT-P的死亡率优势[1]。在最近的CeRtiTude队列研究中，两组CRT-P和CRT-D患者在2年的随访中SCD的发生率没有差异，尽管前一组的患者病情和年龄更大并有多种合并症[13]。巴拉等人的评论。2019年的数据显示，在过去20年中，CRT患者发生SCD的风险降低了四倍多; 在CRT-P组中，包括SCD在内的死亡率下降率更高，并且与LVEF增加，β受体阻滞剂使用增加，QRS持续时间减少和抗心律失常药物的使用密切相关[14]。PARADIGM试验显示，SCD的发生率显着降低了22％[2]。de Diego等。[15]和马滕斯等。[16]发现ARNI组持续性和非持续性VA以及适当的ICD休克显着减少，后者也证实了ARNI患者ICD的起搏参数更好[17]。沙奎普利/缬沙坦主要通过改善心脏重塑来减轻心律不齐的负担，尽管较小的研究还表明，通过LV全局纵向应变成像评估，QRS持续时间，QTc间隔和机械分散减少[18]。

CRT和ICD已显示可以降低在OMr期间仍保持症状的一部分HFrEF患者亚组的死亡率和发病率。与公认的ACEi相比，ARNI改善了临床结局。与ARNI一起使用时，这些设备是否会产生明显的积极临床结果尚不清楚。就ICD而言，只有在SCD的基线风险大于35％或SCD的年发生率≥1.2％的情况下，才可将其用于一级预防时有意义地降低死亡率[1]。随着β受体阻滞剂的使用增加，SCD的绝对风险降低，并且额外的ICD可能获益不大[1，4]。同样，添加ARNI可以降低绝对CV死亡率，而不会增加任何器械治疗的益处。由于ARNI与低血压的风险显着增加有关，在现实世界中，尤其是在亚洲人口中，对药物的依从性和目标剂量的实现可能是一个问题。同样，需要在前瞻性注册表中研究使用次优剂量获得的临床益处。

ARNI可用于所有有症状的HFrEF患者，而CRT在LBBB和宽QRS患者中显示出最大的获益。它引起LVEF的时间依赖性改善[11，12]，可减少ICD用于一级预防的需要[12]，并已显示可通过减少心室异位来改善双室起搏，从而可提高CRT的反应者比例团体。ARNI还可以通过减少VA来减少HFrEF患者的适当ICD治疗。但是，直到有力的证据得出完全不同的结论之前，尽管我们可能会更频繁地将ARNI用作OMT的一部分，但我们仍应遵循目前有关HFrEF患者使用ICD，CRT和ARNI的指南。以获得最大的利益。图1说明了各种疗法在HFrEF治疗中的各自作用。

HFrEF的ARNI和设备疗法是两种互补疗法。尽管ARNI和CRT改善了LVEF，减少了LV的体积，并显着改善了心血管疾病的死亡率和HF住院率，但ICD降低了某些患者发生SCD的额外风险。在有证据的情况下，ARNI将成为HFrEF的OMT的未来基础，而CRT / ICD将保留用于患者在使用OMT期间仍保持症状的特殊情况。CRT / ICD在ARNI时代的作用需要重新确立，因为OMT的定义随着更好，更有效的药物治疗而发生了变化。

由于上述原因不适用

ACEi：: 血管紧张素转换酶抑制剂
ARB：: 血管紧张素受体阻滞剂
阿尼：: 血管紧张素受体中性溶酶抑制剂
CRT：: 心脏再同步治疗
简历：: 心血管的
高频：: 心脏衰竭
高频射频: 心力衰竭，射血分数降低
ICD：: 植入式心脏复律除颤器
LBBB：: 左束支传导阻滞
NICM：: 非缺血性扩张型心肌病
NYHA：: 纽约心脏分类
OMT：: 最佳药物治疗
pVO2：: 峰值耗氧量
RCT：: 随机对照试验
SCD：: 心脏猝死

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隶属关系

印度昌迪加尔市12区，医学教育与研究研究生学院，高级心脏中心，高级心脏病中心，教务处，心脏病学系，心脏病学二科，160012，印度
Navjyot Kaur，CR Pruthvi和Manojkumar Rohit

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会费

NK：计划，概念化，文献回顾和编写原始准备草案；PCR：概念化，编写原始草案准备，并进行最终审查；MKR：计划，概念化，方法论，监督，最终审查和编辑。所有作者阅读并认可的终稿。

通讯作者

对应于Manojkumar Rohit。

道德规范的批准和参与同意

该手稿既不是研究也不是病例报告，也不涉及任何人类/动物试验或植物研究。这是对有关心力衰竭治疗的当代文学的评论。但是，我们机构的道德委员会批准将本文提交发表。

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由于上述原因不适用

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