Low-dose lithium feeding increases the SERCA2a to phospholamban ratio improving SERCA function in murine left ventricles.
低剂量锂喂养可增加 SERCA2a 与磷蛋白比值，改善小鼠左心室 SERCA 功能。
- 作者列表："Hamstra SI","Kurgan N","Baranowski RW","Qiu L","Watson CJF","Messner HN","MacPherson REK","MacNeil AJ","Roy BD","Fajardo VA
ABSTRACT:The sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA) pump is responsible for regulating calcium (Ca2+ ) within myocytes, with SERCA2a being dominant isoform in cardiomyocytes. Its inhibitor, phospholamban (PLN), acts by decreasing SERCA's affinity for Ca2+ . Changes in the SERCA2a:PLN ratio can cause Ca2+ dysregulation often seen in patients with dilated cardAiomyopathy (DCM) and heart failure (HF). The enzyme glycogen synthase kinase-3 (GSK3) is known to downregulate SERCA function by decreasing the SERCA2a:PLN ratio. In this study, we sought to determine whether feeding mice low-dose lithium, a natural GSK3 inhibitor, would improve left ventricular SERCA function by altering the SERCA2a:PLN ratio. To this end, male wild-type C57BL/6J mice were fed low-dose lithium via drinking water (10 mg/kg/day lithium chloride [LiCl] for 6 weeks) and left ventricles were collected. GSK3 activity was significantly reduced in LiCl-fed vs. control-fed mice. SERCA's apparent affinity for Ca2+ was also increased (pCa50; control, 6.09 ± 0.03 vs. LiCl, 6.26 ± 0.04, p < 0.0001) along with a 2.0-fold increase in SERCA2a:PLN in LiCl-fed vs. control-fed mice. These findings suggest that low-dose lithium supplementation can improve SERCA function by increasing the SERCA2a:PLN ratio. Future studies in murine preclinical models will determine whether GSK3 inhibition via low-dose lithium could be a potential therapeutic strategy for DCM and HF. This article is protected by copyright. All rights reserved.
摘要: sarco (endo) 胞浆网 Ca2 +-atp 酶 (SERCA) 泵负责调节心肌细胞内的钙 (Ca2 +)，其中 SERCA2a 是心肌细胞的主要亚型。其抑制剂磷蛋白 (PLN) 通过降低 SERCA 对 Ca2 + 的亲和力而起作用。SERCA2a: PLN 比值的变化可引起 Ca2 + 失调，常见于扩张型心肌病 (DCM) 和心力衰竭 (HF) 患者。已知糖原合成酶激酶-3 (GSK3) 通过降低 SERCA2a: PLN 比例下调 SERCA 功能。在这项研究中，我们试图确定喂养小鼠低剂量锂 (一种天然 GSK3 抑制剂) 是否会通过改变 SERCA2a: PLN 比例来改善左心室 SERCA 功能。为此，雄性野生型 C57BL/6J 小鼠通过饮用水喂养低剂量锂 (10 mg/kg/天氯化锂 [LiCl] 6 周) 收集左心室。LiCl 喂养与对照喂养小鼠的 GSK3 活性显著降低。SERCA 对 Ca2 + 的表观亲和力也增加 (pCa50; 对照，6.09 ± 0.03 vs.LiCl，6.26 ± 0.04，p
METHODS:Abstract Background Ischemic cardiomyopathy is a high-cost, resource-intensive public health burden that is associated with a 1-year mortality rate of about 16% in western population. Different in patient ethnicity and pattern of practice may impact the clinical outcome. We aim to determine 1-year mortality and to identify factors that significantly predicts 1-year mortality of Thai patients with ischemic cardiomyopathy. Methods This prospective multicenter registry enrolled consecutive Thai patients that were diagnosed with ischemic cardiomyopathy at 9 institutions located across Thailand. Patients with left ventricular function 75% in the left main or proximal left anterior descending artery or coronary angiography, and/or two major epicardial coronary stenoses; 2) prior myocardial infarction; 3) prior revascularization by coronary artery bypass graft or percutaneous coronary intervention; or, 4) magnetic resonance imaging pattern compatible with ischemic cardiomyopathy. Baseline clinical characteristics, coronary and echocardiographic data were recorded. The 1-year clinical outcome was pre-specified. Results Four hundred and nineteen patients were enrolled. Thirty-nine patients (9.9%) had died at 1 year, with 27 experiencing cardiovascular death, and 12 experiencing non-cardiovascular death. A comparison between patients who were alive and patients who were dead at 1 year revealed lower baseline left ventricular ejection fraction (LVEF) (26.7 ± 7.6% vs 30.2 ± 7.8%; p = 0.021), higher left ventricular end-diastolic volume (LVEDV) (185.8 ± 73.2 ml vs 155.6 ± 64.2 ml; p = 0.014), shorter mitral valve deceleration time (142.9 ± 57.5 ml vs 182.4 ± 85.7 ml; p = 0.041), and lower use of statins (94.7% vs 99.7%; p = 0.029) among deceased patients. Patients receiving guideline-recommended β-blockers had lower mortality than patients receiving non-guideline-recommended β-blockers (8.1% vs 18.2%; p = 0.05). Conclusions The results of this study revealed a 9.9% 1-year mortality rate among Thai ischemic cardiomyopathy patients. Doppler echocardiographic parameters significantly associated with 1-year mortality were LVEF, LVEDV, mitral E velocity, and mitral valve deceleration time. The use of non-guideline-recommended β-blockers rather than guideline recommended β-blockers were associated with increased with 1-year mortality. Guidelines recommended β-blockers should be preferred. Trial registration Thai Clinical Trials Registry TCTR20190722002. Registered 22 July 2019. “Retrospectively registered”.
METHODS:Abstract Background Peripartum cardiomyopathy (PPCM) is rare and potentially life-threatening; its etiology remains unclear. Imaging characteristics on cardiovascular magnetic resonance (CMR) and their prognostic significance have rarely been studied. We sought to determine CMR’s prognostic value in PPCM by using T1 and T2 mapping techniques. Methods Data from 21 PPCM patients from our CMR registry database were analyzed. The control group comprised 20 healthy age-matched females. All subjects underwent comprehensive contrast-enhanced CMR. T1 and T2 mapping using modified Look-Locker inversion recovery and T2 prep balanced steady-state free precession sequences, respectively. Ventricular size and function, late gadolinium enhancement (LGE), myocardial T1 value, extracellular volume (ECV), and T2 value were analyzed. Transthoracic echocardiography was performed at baseline and during follow-up. The recovered left ventricular ejection fraction (LVEF) was defined as LVEF ≥50% on echocardiography follow-up after at least 6 months of the diagnosis. Results CMR imaging showed that the PPCM patients had severely impaired LVEF and right ventricular ejection fraction (LVEF: 26.8 ± 10.6%; RVEF: 33.9 ± 14.6%). LGE was seen in eight (38.1%) cases. PPCM patients had significantly higher native T1 and ECV (1345 ± 79 vs. 1212 ± 32 ms, P < 0.001; 33.9 ± 5.2% vs. 27.1 ± 3.1%, P < 0.001; respectively) and higher myocardial T2 value (42.3 ± 3.7 vs. 36.8 ± 2.3 ms, P < 0.001) than did the normal controls. After a median 2.5-year follow-up (range: 8 months-5 years), six patients required readmission for heart failure, two died, and 10 showed left ventricular function recovery. The LVEF-recovered group showed significantly lower ECV (30.7 ± 2.1% vs. 36.8 ± 5.6%, P = 0.005) and T2 (40.6 ± 3.0 vs. 43.9 ± 3.7 ms, P = 0.040) than the unrecovered group. Multivariable logistic regression analysis showed ECV (OR = 0.58 for per 1% increase, P = 0.032) was independently associated with left ventricular recovery in PPCM. Conclusions Compared to normal controls, PPCM patients showed significantly higher native T1, ECV, and T2. Native T1, ECV, and T2 were associated with LVEF recovery in PPCM. Furthermore, ECV could independently predict left ventricular function recovery in PPCM.
METHODS:BACKGROUND:Atrial fibrillation (AF) is the most common arrhythmia in hypertrophic cardiomyopathy (HCM) and is associated with adverse outcomes in HCM patients. Although the left atrial (LA) diameter has consistently been identified as a strong predictor of AF in HCM patients, the relationship between LA dysfunction and AF still remains unclear. The aim of this study is to evaluate the LA function in patients with non-obstructive HCM (NOHCM) utilizing cardiovascular magnetic resonance feature tracking (CMR-FT).,METHODS:Thirty-three patients with NOHCM and 28 healthy controls were studied. The global and regional LA function and left ventricular (LV) function were compared between the two groups. The following LA global functional parameters were quantitively analyzed: reservoir function (total ejection fraction [LA total EF], total strain [ε], peak positive strain rate [SRs]), conduit function (passive ejection fraction [LA passive EF], passive strain [ε], peak early-negative SR [SRe]), and booster pump function (active ejection fraction [LA active EF], active strain [ε], peak late-negative SR [SRa]). The LA wall was automatically divided into 6 segments: anterior, antero-roof, inferior, septal, septal-roof and lateral. Three LA strain parameters (ε, ε, ε) and their corresponding strain rate parameters (SRs, SRe, SRa) during the reservoir, conduit and booster pump LA phases were segmentally measured and analyzed.,RESULTS:The LA reservoir (LA total EF: 57.6 ± 8.2% vs. 63.9 ± 6.4%, p < 0.01; ε: 35.0 ± 12.0% vs. 41.5 ± 11.2%, p = 0.03; SRs: 1.3 ± 0.4 s vs. 1.5 ± 0.4 s, p = 0.02) and conduit function (LA passive EF: 28.7 ± 9.1% vs. 37.1 ± 10.0%, p < 0.01; ε: 18.7 ± 7.9% vs. 25.9 ± 10.0%, p < 0.01; SRe: - 0.8 ± 0.3 s vs. -1.1 ± 0.4 s, p < 0.01) were all impaired in patients with NOHCM when compared with healthy controls, while LA booster pump function was preserved. The LA segmental strain and strain rate analysis demonstrated that the ε, ε, SRe of inferior, SRs, SRe of septal-roof, and SRa of antero-roof walls (all p < 0.05) were all decreased in the NOHCM cohort. Correlations between LA functional parameters and LV conventional function and LA functional parameters and baseline parameters (age, body surface area and NYHA classification) were weak. The two strongest relations were between ε and LA total EF(r = 0.84, p < 0.01), ε and LA active EF (r = 0.83, p < 0.01).,CONCLUSIONS:Compared with healthy controls, patients with NOHCM have LA reservoir and conduit dysfunction, and regional LA deformation before LA enlargement. CMR-FT identifies LA dysfunction and deformation at an early stage.