Recent Evidence on Angiotensin Receptor-neprilsin Inhibitor in Heart Failure with Preserved Ejection Fraction

doi:10.12114/j.issn.1007-9572.2021.00.587

Abstract

Abstract: Heart failure is the end stage of most cardiac diseases with high morbidity and mortality. Heart failure with preserved ejection fraction（HFpEF），as a clinical focus，accounts for about 50% of all cases of heart failure，and is associated with increased incidence of hospitalization due to low rate of diagnosis and multiple comorbidities. Angiotensin receptor-neprilsin inhibitor（ARNI） has been proved to significantly decrease the rates of death and readmission，and is widely used as the recommended drugs of class Ⅰ in heart failure with reduced ejection fraction（HFrEF）. However，the mechanism of action of ARNI in HFpEF is still unclear. Thus we summarized the latest clinical evidence on its mechanism of action in HFpEF. This article reviews the mechanism of the effect of ARNI in HFpEF and the latest clinical evidence for it，expounds the advantages of ARNI in improving heart and kidney function and reversing ventricular remodeling in patients with HFpEF，in order to provide new treatment ideas for HFpEF.

Key words: Heart failure, Heart failure with preserved ejection fraction, Angiotensin receptor neprilsin inhibitor, Sacubitril valsartan, LCZ696, Review

摘要： 心力衰竭作为心脏疾病的终末阶段，具有较高的患病率和死亡率。射血分数保留的心力衰竭（HFpEF）发病率约占所有心力衰竭的50%，但其临床诊断率低，合并症多，住院率逐年上升，已成为临床关注的重点。血管紧张素受体脑啡肽酶抑制剂（ARNI）在降低射血分数降低的心力衰竭（HFrEF）患者的住院率和死亡率方面效果显著，已被作为指南的Ⅰ类推荐药物广泛应用于临床，但其在HFpEF中的作用尚不明确。本文就ARNI在HFpEF中的作用机制及临床最新证据进行综述，阐述了ARNI在HFpEF患者中改善心、肾功能和逆转心室重构方面的优势，以期为HFpEF提供新的治疗思路。

关键词: 心力衰竭, 射血分数保留的心力衰竭, 血管紧张素受体脑啡肽酶抑制剂, 沙库巴曲缬沙坦钠, LCZ696, 综述

GAO Man,BAI Wenlou,CHENG Siyao, et al. Recent Evidence on Angiotensin Receptor-neprilsin Inhibitor in Heart Failure with Preserved Ejection Fraction　[J]. Chinese General Practice, 2021, 24(23): 2967-2971. DOI: 10.12114/j.issn.1007-9572.2021.00.587.
高曼,白文楼,成思瑶等. 血管紧张素受体脑啡肽酶抑制剂治疗射血分数保留的心力衰竭的最新证据[J]. 中国全科医学, 2021, 24(23): 2967-2971. DOI: 10.12114/j.issn.1007-9572.2021.00.587.

References

［1］METRA M，TEERLINK J R. Heart failure［J］. Lancet，2017，390（10106）：1981-1995. DOI：10.1016/S0140-6736（17）31071-1.
［2］DUNLAY S M，ROGER V L，REDFIELD M M. Epidemiology of heart failure with preserved ejection fraction［J］. Nat Rev Cardiol，2017，14（10）：591-602. DOI：10.1038/nrcardio.2017.65.
［3］CHIONCEL O，LAINSCAK M，SEFEROVIC P M，et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved，mid-range and reduced ejection fraction：an analysis of the ESC Heart Failure Long-Term Registry［J］. Eur J Heart Fail，2017，19（12）：1574-1585. DOI：10.1002/ejhf.813.
［4］TROMP J，TENG T H，TAY W T，et al. Heart failure with preserved ejection fraction in Asia［J］. Eur J Heart Fail，2019，21（1）：23-36. DOI：10.1002/ejhf.1227.
［5］Meta-analysis Global Group in Chronic Heart Failure（MAGGIC）. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction：an individual patient data meta-analysis［J］. Eur Heart J，2012，33（14）：1750-1757. DOI：10.1093/eurheartj/ehr254.
［6］STEINBERG B A，ZHAO X，HEIDENREICH P A，et al. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction：prevalence，therapies，and outcomes［J］. Circulation，2012，126（1）：65-75. DOI：10.1161/CIRCULATIONAHA.111.080770.
［7］王华，梁延春.中国心力衰竭诊断和治疗指南2018［J］. 中华心血管病杂志，2018，46（10）：760-789. DOI：10.3760/cma.j.issn.0253-3758.2018.10.004.
［8］WINTRICH J，KINDERMANN I，UKENA C，et al. Therapeutic approaches in heart failure with preserved ejection fraction：past，present，and future［J］. Clin Res Cardiol，2020，109（9）：1079-1098. DOI：10.1007/s00392-020-01633-w.
［9］PONIKOWSKI P，VOORS A A，ANKER S D，et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure：the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology（ESC）Developed with the special contribution of the Heart Failure Association（HFA）of the ESC［J］. Eur Heart J，2016，37（27）：2129-2200. DOI：10.1093/eurheartj/ehw128.
［10］YANCY C W，JESSUP M，BOZKURT B，et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure：a report of the american college of cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America［J］. J Card Fail，2017，23（8）：628-651. DOI：10.1016/j.cardfail.2017.04.014.
［11］VERGARO G，AIMO A，PRONTERA C，et al. Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved，mid-range and reduced ejection fraction［J］. Int J Cardiol，2019，296：91-97. DOI：10.1016/j.ijcard.2019.08.040.
［12］SHEARER F，LANG C C，STRUTHERS A D. Renin-angiotensin-aldosterone system inhibitors in heart failure［J］. Clin Pharmacol Ther，2013，94（4）：459-467. DOI：10.1038/clpt.2013.135.
［13］ZILE M R，BAICU C F，GAASCH W H. Diastolic heart failure——abnormalities in active relaxation and passive stiffness of the left ventricle［J］. N Engl J Med，2004，350（19）：1953-1959. DOI：10.1056/NEJMoa032566.
［14］SHIBATA S，HASTINGS J L，PRASAD A，et al. Congestive heart failure with preserved ejection fraction is associated with severely impaired dynamic Starling mechanism［J］. J Appl Physiol（1985），2011，110（4）：964-971. DOI：10.1152/japplphysiol.00826.2010.
［15］柴坷，王华，杨杰孚. 射血分数保留性心力衰竭的病理生理机制和治疗进展［J］. 中国循环杂志，2016，31（9）：921-923. DOI：10.3969/j.issn.1000-3614.2016.09.022.
［16］TSAI E J，KASS D A. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics［J］. Pharmacol Ther，2009，122（3）：216-238. DOI：10.1016/j.pharmthera.2009.02.009.
［17］TAKIMOTO E. Cyclic GMP-dependent signaling in cardiac myocytes［J］. Circ J，2012，76（8）：1819-1825. DOI：10.1253/circj.cj-12-0664.
［18］PAULUS W J，TSCH?PE C. A novel paradigm for heart failure with preserved ejection fraction：comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation［J］. J Am Coll Cardiol，2013，62（4）：263-271. DOI：10.1016/j.jacc.2013.02.092.
［19］LEVIN E R，GARDNER D G，SAMSON W K. Natriuretic peptides［J］. N Engl J Med，1998，339（5）：321-328. DOI：10.1056/NEJM199807303390507.
［20］STEPHENSON S L，KENNY A J. Metabolism of neuropeptides.Hydrolysis of the angiotensins，bradykinin，substance P and oxytocin by pig kidney microvillar membranes［J］. Biochem J，1987，241（1）：237-247. DOI：10.1042/bj2410237.
［21］PACKER M，CALIFF R M，KONSTAM M A，et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure：the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events（OVERTURE）［J］. Circulation，2002，106（8）：920-926. DOI：10.1161/01.cir.0000029801.86489.50.
［22］HUA Y，WANG I，LIU B，et al. Angiotensin receptor neprilysin inhibitor LCZ696：pharmacology，pharmacokinetics and clinical development［J］. Futur Cardiol，2017，13（2）：103-115. DOI：10.2217/fca-2016-0057.
［23］NOUGUé H，PEZEL T，PICARD F，et al. Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure：a mechanistic clinical study［J］. Eur J Heart Fail，2019，21（5）：598-605. DOI：10.1002/ejhf.1342.
［24］MOCHEL J P，TENG C H，PEYROU M，et al. Sacubitril/valsartan（LCZ696）significantly reduces aldosterone and increases cGMP circulating levels in a canine model of RAAS activation［J］. Eur J Pharm Sci，2019，128：103-111. DOI：10.1016/j.ejps.2018.11.037.
［25］BURKE R M，LIGHTHOUSE J K，MICKELSEN D M，et al. Sacubitril/valsartan decreases cardiac fibrosis in left ventricle pressure overload by restoring PKG signaling in cardiac fibroblasts［J］. Circ Heart Fail，2019，12（4）：e005565. DOI：10.1161/CIRCHEARTFAILURE.118.005565.
［26］RUILOPE L M，DUKAT A，B?HM M，et al. Blood-pressure reduction with LCZ696，a novel dual-acting inhibitor of the angiotensinⅡ receptor and neprilysin：a randomised，double-blind，placebo-controlled，active comparator study［J］. Lancet，2010，375（9722）：1255-1266. DOI：10.1016/S0140-6736（09）61966-8.
［27］HUO Y，LI W，WEBB R，et al. Efficacy and safety of sacubitril/valsartan compared with olmesartan in Asian patients with essential hypertension：a randomized，double-blind，8-week study［J］. J Clin Hypertens （Greenwich），2019，21（1）：67-76. DOI：10.1111/jch.13437.
［28］WILLIAMS B，COCKCROFT J R，KARIO K，et al. Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension：the PARAMETER study［J］. Hypertension，2017，69（3）：411-420. DOI：10.1161/HYPERTENSIONAHA.116.08556.
［29］WANG T D，TAN R S，LEE H Y，et al. Effects of sacubitril/valsartan（LCZ696） on natriuresis，diuresis，blood pressures，and NT-proBNP in salt-sensitive hypertension［J］. Hypertension，2017，69（1）：32-41. DOI：10.1161/HYPERTENSIONAHA.116.08484.
［30］CHIONCEL O，LAINSCAK M，SEFEROVIC P M，et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved，mid-range and reduced ejection fraction：an analysis of the ESC Heart Failure Long-Term Registry［J］. Eur J Heart Fail，2017，19（12）：1574-1585. DOI: 10.1002/ejhf.813.
［31］SOLOMON S D，ZILE M，PIESKE B，et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction：a phase 2 double-blind randomised controlled trial［J］. Lancet，2012，380（9851）：1387-1395. DOI：10.1016/S0140-6736（12）61227-6.
［32］VOORS A A，GORI M，LIU L C，et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction［J］. Eur J Heart Fail，2015，17（5）：510-517. DOI：10.1002/ejhf.232.
［33］JHUND P S，CLAGGETT B L，VOORS A A，et al. Elevation in high-sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696［J］. Circ Heart Fail，2014，7（6）：953-959. DOI：10.1161/CIRCHEARTFAILURE.114.001427.
［34］SOLOMON S D，MCMURRAY J J V，ANAND I S，et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction［J］. N Engl J Med，2019，381（17）：1609-1620. DOI：10.1056/NEJMoa1908655.
［35］VADUGANATHAN M，CLAGGETT B L，DESAI A S，et al. Prior heart failure hospitalization，clinical outcomes，and response to sacubitril/valsartan compared with valsartan in HFpEF［J］. J Am Coll Cardiol，2020，75（3）：245-254. DOI：10.1016/j.jacc.2019.11.003.
［36］CUNNINGHAM J W，VADUGANATHAN M，CLAGGETT B L，et al. Effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide in heart failure with preserved ejection fraction［J］. JACC Heart Fail，2020，8（5）：372-381. DOI：10.1016/j.jchf.2020.03.002.
［37］WANG Y W，ZHOU R，LU C，et al. Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling：meta-analysis［J］. J Am Heart Assoc，2019，8（13）：e012272.
［38］KANG H N，ZHANG J H，ZHANG X T，et al. Effects of sacubitril/valsartan in patients with heart failure and chronic kidney disease：a meta-analysis［J］. Eur J Pharmacol，2020，884：173444. DOI：10.1016/j.ejphar.2020.173444.
［39］CHEN X G，JIN C N，XIE L，et al. LCZ696 and preservation of renal function in heart failure：a meta-analysis of 6 randomized trials［J］. Rev Cardiovasc Med，2020，21（1）：113-118. DOI：10.31083/j.rcm.2020.01.2.
［40］石宇杰，王剑飞，韩运峰，等. 沙库巴曲缬沙坦钠治疗射血分数保留心功能衰竭的疗效研究［J］. 中国循证心血管医学杂志，2020，12（1）：83-86. DOI：10.3969/j.issn.1674-4055.2020.01.21.
［41］郝珍，李巍，于洪伟，等. 沙库巴曲缬沙坦钠对左心室射血分数保留心力衰竭患者的近期疗效［J］. 临床荟萃，2020，35（6）：503-507. DOI：10.3969/j.issn.1004-583X.2020.06.004.

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