Mechanism and Effects of Manipulating Chloride Homeostasis in Heart Failure

控制心力衰竭氯离子稳态的机制和作用

• 批准号: 10371886
• 负责人: JEFFREY M TESTANI
• 金额: $ 83.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371886
• 关键词: Address; Alanine; Avidity; Blood Volume; Chlorides; Consumption; Data; Dietary Sodium; Distal; Diuretics; Dose; Down-Regulation; Effectiveness; Electrolyte Balance; Environment; Epidemiology; Equilibrium; Excretory function; Family; Feedback; Goals; Gold; Heart failure; Homeostasis; Inpatients; Kidney; Lesion; Literature; Lithium; Lysine; Manuscripts; Molecular; Nephrons; Outcome; Oxidative Stress; Participant; Patients; Pattern; Phosphorylation; Phosphotransferases; Physiology; Pilot Projects; Placebo Control; Placebos; Population; Proline; Protein-Serine-Threonine Kinases; Proteins; Randomized; Renal function; Renin; Research; Resistance; SLC12A3 gene; Series; Signal Transduction; Sodium; Sodium Chloride; Supplementation; Techniques; Therapeutic; Translations; Tubular formation; Urine; efficacy study; exosome; improved; in vivo; innovation; mortality; prevent; response; salt intake; sensor; solute; therapeutic candidate; therapeutic target; thiazide; treatment as usual; treatment comparison; urinary

Perturbations in sodium homeostasis are, unarguably, a central pathophysiologic lesion in heart failure (HF). Unfortunately, attempts to prevent or treat volume overload with salt restriction can further worsen the sodium avid state. Recent literature, spanning experimental to epidemiologic, has highlighted the double edged sword of salt restriction, finding that neurohormonal activation, volume status and even outcomes can sometimes improve with higher salt intake. While it is clear that sodium drives volume overload, a significant body of literature has confirmed renal salt sensing relies on chloride rather than sodium. It has been known for decades that renal responses such as tubuloglomerular feedback and renin release are governed by chloride. Recently, a family of serine-threonine kinases (With-No-Lysine (K), WNK) have been identified as the molecular sensor for chloride and master regulator of sodium transporters in the kidney. The above observations led us to hypothesize that chloride may be an important target in HF and over a series of 7 manuscripts we have demonstrated that chloride, rather than sodium, is primarily associated with diuretic resistance, neurohormonal activation and mortality in HF. Moreover, in a pilot study we demonstrated that administration of three days of 115 mmol/day of sodium-free chloride (as lysine chloride) caused a substantial downregulation in renal sodium transporters and multiple signals supporting improvement in volume status. The overarching goal of the current proposal is to address the fundamental gaps in our understanding of chloride homeostasis in HF, facilitating the translation of a large body of promising experimental and observational literature into a potentially viable therapeutic approach in HF. To achieve this goal, we propose a classic and rigorous placebo controlled crossover inpatient “GCRC” balance study (n=20 participants), a placebo controlled “real world” efficacy study in decompensated HF patients receiving aggressive IV diuretics (n=100 patients) and innovative interrogation of renal structural (quantitation of renal tubular solute transporters using urinary exosomes) and functional changes (using lithium clearance, the “gold standard” technique to query in vivo proximal tubular sodium handling). Our aims are to 1) To understand the quantitative effects of sodium free chloride supplementation on electrolyte balance, volume status, and sodium avidity in stable HF patients in a highly controlled inpatient environment. 2) To determine if sodium free chloride supplementation will improve volume status in the real world setting of decompensated HF treated with aggressive use of IV loop diuretics. 3) To determine if sodium free chloride supplementation induces an intra-renal pattern of change consistent with suppression of WNK including deactivation of downstream kinases, reduction of the quantity of WNK regulated sodium cotransporters, and a redistribution of intra-renal sodium reabsorption.

钠稳态紊乱是心力衰竭的中心病理生理损害，这是无可争议的

项目成果

Association of Urine Galectin-3 With Cardiorenal Outcomes in Patients With Heart Failure.

尿半乳糖凝集素 3 与心力衰竭患者心肾结局的关系。

• DOI: 10.1016/j.cardfail.2023.05.018
• 发表时间: 2024
• 期刊: Journal of cardiac failure
• 影响因子: 6
• 作者: Rao,VeenaS;Ivey-Miranda,JuanB;Cox,ZacharyL;Moreno-Villagomez,Julieta;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM

Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease.

• DOI: 10.1161/circulationaha.121.052792
• 发表时间: 2022-03
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Beldhuis, Iris E.;Lam, Carolyn S. P.;Testani, Jeffrey M.;Voors, Adriaan A.;Van Spall, Harriette G. C.;ter Maaten, Jozine M.;Damman, Kevin
• 通讯作者: Damman, Kevin

Congestion and Decongestion Assessment in Heart Failure: Pressure, Volume, or Both?

心力衰竭的充血和减充血评估：压力、容量或两者兼而有之？

• DOI: 10.1016/j.jchf.2023.05.034
• 发表时间: 2023
• 期刊: JACC. Heart failure
• 作者: Biegus,Jan;Borlaug,BarryA;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM

Improvement in Renal Function During the Treatment of Acute Decompensated Heart Failure: Relationship With Markers of Renal Tubular Injury and Prognostic Importance.

急性失代偿性心力衰竭治疗期间肾功能的改善：与肾小管损伤标志物和预后重要性的关系。

• DOI: 10.1161/circheartfailure.122.009776
• 发表时间: 2023
• 期刊: Circulation. Heart failure
• 作者: Natov,PeterS;Ivey-Miranda,JuanB;Cox,ZacharyL;Moreno-Villagomez,Julieta;Maulion,Christopher;Bellumkonda,Lavanya;Shlipak,MichaelG;Estrella,MichelleM;Borlaug,BarryA;Rao,VeenaS;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM

First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload.

使用零钠溶液进行腹膜直接钠去除的人体首次经验：容量超负荷的新候选疗法。

• DOI: 10.1161/circulationaha.119.043062
• 发表时间: 2020
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Rao,VeenaS;Turner,JeffreyM;Griffin,Matthew;Mahoney,Devin;Asher,Jennifer;Jeon,Sangchoon;Yoo,PeterS;Boutagy,Nabil;Feher,Attila;Sinusas,Albert;Wilson,FPerry;Finkelstein,Fredric;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM