Current therapeutic options for advanced heart failure (HF) are limited and the development of alternative therapies for this critical clinical condition is eagerly awaited. 目前晚期心力衰竭（HF）的治疗选择有限，迫切需要为这一关键临床状况开发替代疗法。
Cell therapy offers a promising new alternative for HF treatment, with mesenchymal stem cells (MSCs) in adipose tissue considered one of the most promising cell types for HF cell therapy. 细胞疗法为心力衰竭治疗提供了一种有前景的新选择，其中脂肪组织中的间充质干细胞（MSCs）被认为是最有希望用于心力衰竭细胞治疗的细胞类型之一。
However, MSCs in adipose tissue are a major source of adipocyte generation and obesity is known as an independent risk factor for HF, while MSCs might be related to the enigmatic obesity paradox. 然而，脂肪组织中的间充质干细胞是脂肪细胞生成的主要来源，而肥胖被认为是心力衰竭的独立危险因素，同时间充质干细胞可能与神秘的肥胖悖论有关。
Emerging evidence suggests an important link between MSC–adipogenesis–obesity and HF. 新出现的证据表明，MSC-脂肪生成-肥胖与心力衰竭之间存在重要联系。
The therapeutic efficacy of adipose MSCs in clinical trials has not been established; however, preconditioning or genetic modification to improve the therapeutic effects of MSCs showed encouraging results. 脂肪间充质干细胞在临床试验中的治疗效果尚未确定；然而，通过预处理或基因修饰来提高间充质干细胞的治疗效果显示出令人鼓舞的结果。
Abstract 摘要
Mesenchymal stem cells (MSCs) are considered a promising cell type for the treatment of heart failure (HF). In particular, MSCs in adipose tissue are being evaluated as an effective therapeutic tool. However, adipose MSCs are a major source of adipocyte generation and linked to obesity, which is an independent risk factor for HF. MSCs express all of the components of the renin–angiotensin system (RAS), which plays a pivotal role in the pathophysiology of HF. The local RAS also regulates MSC adipogenesis, indicating a connection between MSC–adipogenesis–obesity and HF. This review examines evidence of the complex relationship between HF and adipose MSCs and discusses how to explore this association for favorable therapeutic outcomes for HF. 间充质干细胞（MSCs）被认为是治疗心力衰竭（HF）的一种有前景的细胞类型。特别是，脂肪组织中的 MSCs 正在被评估为一种有效的治疗工具。然而，脂肪 MSCs 是脂肪细胞生成的主要来源，并与肥胖相关，而肥胖是 HF 的独立危险因素。MSCs 表达肾素-血管紧张素系统（RAS）的所有组分，该系统在 HF 的病理生理学中起着关键作用。局部 RAS 还调节 MSCs 的脂肪生成，表明 MSCs-脂肪生成-肥胖与 HF 之间存在联系。本综述探讨了 HF 与脂肪 MSCs 之间复杂关系的证据，并讨论了如何探索这种关联以实现对 HF 的有利治疗效果。
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
]. Although HF is a heterogeneous condition and its pathophysiology is not fully understood, a significant contribution of neurohormonal activation has been identified [1
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure
]. Activation of the circulating and/or tissue RAS causes salt and water retention, vasoconstriction, and cardiac and vascular hypertrophy, fibrosis, and remodeling, as well as enhancing the deleterious effects of other neurohormonal systems such as the sympathetic nervous system [4
4.
Packer, M. ∙ McMurray, J.J.V.
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure
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
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure
]. Mechanical circulatory support and heart transplantation are currently the main treatment strategies for severely progressed HF, but they are restricted by patient eligibility, donor availability, and cost [7
]. MSCs are nonhematopoietic, multipotent self-renewing cells with the ability to differentiate into multiple mesodermal lineage cell types and to transdifferentiate into ectodermal and endodermal cells [12
12.
Matsushita, K. ∙ Dzau, V.J.
Mesenchymal stem cells in obesity: insights for translational applications
]. Importantly, while MSCs display cardiomyogenic differentiation potential in vitro, the mechanisms underlying their beneficial effects against HF in vivo are likely to be associated to paracrine-dependent mechanisms [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
]. MSCs secrete various cytokines, chemokines, and growth factors that can provide beneficial effects for failing hearts by attenuating local inflammation and fibrosis, inhibiting cardiomyocyte apoptosis, and/or enhancing neovascularization [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
Originally, cardiomyogenic differentiation was anticipated to be the main mechanism for MSCs to repair damaged myocardium on the basis of in vitro results showing the cardiomyocyte differentiation of MSCs [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
]. MSCs secrete various cytokines, chemokines, and growth factors with purported anti-inflammatory, antifibrosis, antiapoptotic, and/or neovascularization roles, leading to the repair of damaged myocardium [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
] revealed that conditioned medium obtained from cultured rat bone marrow-derived MSCs attenuated damage to cultured adult rat cardiomyocytes induced by monocyte chemoattractant protein-1, while Ortiz et al. [64
64.
Ortiz, L.A. ...
Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury
Proc. Natl. Acad. Sci. U. S. A. 2007; 104:11002-11007
] showed that murine bone marrow-derived MSCs secrete high levels of interleukin-1 receptor antagonist, which inhibited activated murine macrophages from secreting the proinflammatory cytokine tumor necrosis factor-alpha. In addition, Dayan et al. [65
65.
Dayan, V. ...
Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction
] demonstrated that the frequency of Ly6C+ (a marker of classically activated cells) macrophages decreased but proliferation of CD206+ (a marker of anti-inflammatory M2 macrophages) macrophages was significantly higher than controls (co-culture with control medium) after co-culture of mouse bone marrow-derived macrophages with human bone marrow MSC-conditioned medium, suggesting that MSCs can shift macrophages from the M1 proinflammatory state to the M2 anti-inflammatory state via secreted factors. Ohnishi 等人[ 63
63.
Ohnishi, S. ...
Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis
Regarding its antifibrotic effects, conditioned medium obtained from rat bone marrow-derived MSC culture can significantly downregulate the expression of type I and III collagen, suppress the promoter activity of type III collagen, and upregulate the expression of antiproliferation-related genes, resulting in the attenuated proliferation of rat cardiac fibroblasts [66
66.
Ohnishi, S. ...
Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions
] demonstrated that a single penile vein injection of human MSC-conditioned medium resulted in a 90% reduction in apoptotic hepatocellular death in a D-galactosamine-induced rat model of acute liver injury. In addition, lower expression of Bax, which is a proapoptotic member of the B cell lymphoma 2 (Bcl-2) family of genes, was found at both the transcriptional and translational levels in human MSC-conditioned medium-treated human hepatic LO2 cells in response to H2O2 exposure, which was used as a model to mimic ischemia/reperfusion injury in the liver, compared with that in controls, resulting in protection against H2O2-induced hepatocyte apoptosis [68
68.
Pan, G.Z. ...
Bone marrow mesenchymal stem cells ameliorate hepatic ischemia/reperfusion injuries via inactivation of the MEK/ERK signaling pathway in rats
Another important paracrine effect of MSCs is neovascularization. MSCs secrete high levels of proangiogenic and proarteriogenic factors such as VEGF, basic fibroblast growth factor, hepatocyte growth factor, and angiopoietins, which were associated with MSC-mediated neovascularization [14
14.
Mirotsou, M. ...
Paracrine mechanisms of stem cell reparative and regenerative actions in the heart
Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury
Am. J. Physiol. Heart Circ. Physiol. 2006; 291:H886-H893
] showed that conditioned medium obtained from rat bone marrow mononuclear cell culture increased vessel density in an AMI rat model, while Kinnaird et al. [70
70.
Kinnaird, T. ...
Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms
] demonstrated that murine bone marrow-derived MSC-conditioned media augmented collateral flow recovery and remodeling, and improved limb function in a murine hindlimb ischemia model. Finally, Markel et al. [71
71.
Markel, T.A. ...
VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function
Am. J. Physiol. Heart Circ. Physiol. 2008; 295:H2308-H2314
] identified VEGF as a critical paracrine mediator of MSC-mediated cardioprotection in the injured rat hearts by demonstrating that the knockdown of VEGF negatively impacts MSC-mediated post-ischemic myocardial recovery. MSCs 的另一个重要的旁分泌效应是新生血管形成。MSCs 分泌高水平的促血管生成和促动脉生成因子，如 VEGF、碱性成纤维细胞生长因子、肝细胞生长因子和血管生成素，这些因子与 MSCs 介导的新生血管形成相关[ 14
14.
Mirotsou, M. ...
Paracrine mechanisms of stem cell reparative and regenerative actions in the heart
Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury
Am. J. Physiol. Heart Circ. Physiol. 2006; 291:H886-H893
]表明，从大鼠骨髓单核细胞培养物中获得的条件培养基增加了 AMI 大鼠模型中的血管密度，而 Kinnaird 等人[ 70
70.
Kinnaird, T. ...
Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms
VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function
Am. J. Physiol. Heart Circ. Physiol. 2008; 295:H2308-H2314
The regulatory mechanisms governing paracrine factor release remain poorly understood and are likely to be highly complex; nevertheless, the paracrine effects of MSCs show great promise for the future treatment of HF. 调控旁分泌因子释放的机制仍然知之甚少，并且可能非常复杂；然而，间充质干细胞的旁分泌效应在未来的心力衰竭治疗中显示出巨大的潜力。
Figure IThe Paracrine Effects of Mesenchymal Stem Cells (MSCs). 图 I 间充质干细胞（MSCs）的旁分泌效应。
In this context, MSCs in adipose tissue are of particular note. MSCs were initially identified and most extensively investigated in the bone marrow, but they can now be isolated from various adult tissues including adipose tissue [17
17.
Pittenger, M.F. ...
Multilineage potential of adult human mesenchymal stem cells
]. MSCs in adipose tissue are receiving increased attention because of the abundance of adipose tissue in the body and the comparatively simple and safe procedure for cell isolation [11
11.
Kobayashi, K. ∙ Suzuki, K.
Mesenchymal stem/stromal cell-based therapy for heart failure – what is the best source?
]. The mechanisms governing MSC adipogenesis are complex and remain uncertain. Major signaling pathways converge to regulate a range of transcription factors such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and several members of the CCAAT/enhancer-binding proteins, with PPAR-γ being a key regulator of adipogenesis [12
12.
Matsushita, K. ∙ Dzau, V.J.
Mesenchymal stem cells in obesity: insights for translational applications
]. Various signaling pathways, such as Wnt/beta-catenin, Hedgehog, insulin-like growth factor, and transforming growth factor-beta/bone morphogenetic protein, are also reported to control the adipogenic differentiation of MSCs, and further studies are required to elucidate the mechanisms involved [12
12.
Matsushita, K. ∙ Dzau, V.J.
Mesenchymal stem cells in obesity: insights for translational applications
] and is ascribed to both increased adipocyte size and numbers, with new adipocytes considered to originate from a pre-existing pool of MSCs in adipose tissue [18
18.
Matsushita, K.
Mesenchymal stem cells and metabolic syndrome: current understanding and potential clinical implications
]. We previously reported that MSCs express all components of the RAS, which plays a vital role in HF, as described and that local angiotensin (Ang) II production is augmented during MSC adipogenesis with a concomitant increase in AT2 receptors [24
24.
Matsushita, K. ...
Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes
]. We further demonstrated that AngII suppresses adipogenesis in MSCs and that blocking AT2 receptors accelerates adipogenesis while attenuating osteogenesis in MSCs [24
24.
Matsushita, K. ...
Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes
Blockade of angiotensin II type 2 receptor by PD123319 inhibits osteogenic differentiation of human mesenchymal stem cells via inhibition of extracellular signal-regulated kinase signaling
]. The pathophysiology governing obesity is not well understood and the most efficacious treatment for severely obese patients is at present invasive bariatric surgery [28
28.
Batsis, J.A. ...
Cardiovascular risk after bariatric surgery for obesity
]. Of note, this surgical procedure may also improve hypertension, dyslipidemia, and diabetes, leading to a reduction in overall cardiovascular risk [28
28.
Batsis, J.A. ...
Cardiovascular risk after bariatric surgery for obesity
] found upregulated expression of RAS-related genes in adipose-derived MSCs and differentiated adipocytes in obese patients and that this upregulation was reversed in post-bariatric surgery patients. Considering that the RAS plays an important role in HF, the effective treatment of obesity could improve HF outcomes, possibly through the modulation of MSC adipogenesis. 然而，肥胖是心力衰竭（HF）的独立危险因素[ 20
20.
He, J. ...
Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study
Blockade of angiotensin II type 2 receptor by PD123319 inhibits osteogenic differentiation of human mesenchymal stem cells via inhibition of extracellular signal-regulated kinase signaling
Thus, the central role of the RAS in the pathophysiology of HF indicates a connection between MSC–adipogenesis–obesity and HF, although any such relationship would be complex. This article explores recent evidence on the association between MSCs in adipose tissue and HF, as well as the related therapeutic implications of this association (Figure 1, Key Figure). 因此，RAS 在心力衰竭（HF）病理生理学中的核心作用表明，MSC-脂肪生成-肥胖与 HF 之间存在联系，尽管这种关系可能很复杂。本文探讨了脂肪组织中 MSCs 与 HF 之间关联的最新证据，以及这种关联的相关治疗意义（图 1，关键图）。
Figure 1Key Figure. Schematic Diagram of the Relationship between Mesenchymal Stem Cells (MSCs) in Adipose Tissue and Heart Failure. 图 1 关键图。脂肪组织中间充质干细胞（MSCs）与心力衰竭关系的示意图。
MSCs in adipose tissue are considered one of the most promising cell types for treating heart failure. However, MSCs in adipose tissue are suggested to be a major source for adipocyte generation and obesity is known as an independent risk factor for heart failure, while MSCs might be related to the enigmatic obesity paradox.
The Obesity Paradox and MSCs in HF 肥胖悖论与心力衰竭中的间充质干细胞
Obesity is a known independent risk factor for HF [20
20.
He, J. ...
Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study
]; however, once HF is diagnosed, a paradoxical association between obesity and survival benefits appears in a phenomenon known as the obesity paradox [31–33
31.
Lavie, C.J. ...
Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure
]. Although the underlying cause and clinical significance of this paradox remain poorly understood, several possible mechanisms have been proposed linking survival and obesity. First, HF is a catabolic state; thus, obese individuals might have better outcomes because of their increased metabolic reserves [31
31.
Lavie, C.J. ...
Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure
]. Second, high levels of circulating lipoproteins in obese individuals might bind and detoxify lipopolysaccharides, thus attenuating the detrimental cytokine response in HF [31
31.
Lavie, C.J. ...
Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure
] reported higher levels of circulating MSCs in obese patients than in nonobese patients, which may be related to another important mechanism. While the increase in circulating MSCs in obese patients and its relationship with the obesity paradox remain unknown, MSCs are one of the most promising cell types in terms of cell therapy for the treatment of HF, with many encouraging results reported in preclinical and clinical studies, as discussed below [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
]. Increasing endogenous MSCs could have beneficial effects on HF, as is the case with systemically administered exogenous MSCs. Further studies are expected to clarify the roles of MSCs in obese patients with HF. 肥胖是心力衰竭（HF）的一个已知独立危险因素[ 20
20.
He, J. ...
Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study
]. Many of the studies were performed using bone marrow-derived MSCs; however, the preclinical in vivo therapeutic efficacy of adipose tissue-derived MSCs has also been demonstrated in studies related to HF. 许多临床前研究已经检验了 MSC 疗法在各种类型实验性心力衰竭模型中的有效性[ 10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
] demonstrated that the transendocardial injection of swine adipose-derived stromal cells (ADSCs) could improve left ventricular (LV) ejection fraction (LVEF) (increase in LVEF: 18.04 ± 2.16% for ADSCs vs 8.02 ± 2.94% for controls, P = 0.021), increase capillary density (235.22 ± 53.28 vessels/high-power field for ADSCs vs 153.28 ± 29.3 vessels/high-power field for controls, P = 0.003), and decrease fibrosis (47.84 ± 7.13% for ADSCs vs 57.79 ± 5.18% for controls, P = 0.007) at 3 months after transplantation in a swine model of ischemia/reperfusion. Rasmussen et al. [37
37.
Rasmussen, J.G. ...
Comparison of human adipose-derived stem cells and bone marrow-derived stem cells in a myocardial infarction model
] further reported that the intramyocardial injection of human adipose-derived MSCs improved LVEF (54.7 ± 12.3% prior to cell treatment vs 65.6 ± 15.2 at 4 weeks after cell treatment, P < 0.05) in rats with acute myocardial infarction (AMI), while Paul et al. [38
38.
Paul, A. ...
Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells
] revealed that human adipose-derived stem cells (hASCs) implanted into immunocompetent rat hearts with AMI improved LVEF (39.7 ± 2.03% for hASCs vs 31.0 ± 1.24% for controls, P < 0.01), decreased the myocardial proinflammatory cytokine marker tumor necrosis factor-alpha, measured as pg/mg of total protein, in homogenized ventricular tissues (12.13 ± 1.95 pg/mg for hASCs vs 22.32 ± 1.83 pg/mg for controls, P < 0.01), and increased the myocardial anti-inflammatory cytokine marker interleukin-10 (12.94 ± 1.15 pg/mg for hASCs vs 8.11 ± 2.1 pg/mg for controls, P < 0.01) at 6 weeks after treatment. Mazo 等人[ 36
36.
Mazo, M. ...
Treatment of reperfused ischemia with adipose-derived stem cells in a preclinical swine model of myocardial infarction
]进一步报道，在急性心肌梗死（AMI）大鼠模型中，心肌内注射人脂肪来源的间充质干细胞（MSCs）改善了 LVEF（细胞治疗前 54.7 ± 12.3% vs 细胞治疗后 4 周 65.6 ± 15.2，P < 0.05），而 Paul 等人[ 38
38.
Paul, A. ...
Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells
]. Previous trials have reported that the transplantation of MSCs is feasible and safe for HF therapy, which is generally in agreement with the results of clinical trials using MSCs as a therapy to treat damage in other organs; however, the efficacy of MSC therapy in patients with HF remains to be established [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction
] reported that the intracoronary infusion of autologous adipose tissue-derived regenerative cells (ADRCs) in conjunction with primary percutaneous coronary intervention was safe and could significantly reduce infarct size (31.6 ± 5.3% to 15.3 ± 2.6% at 6-month follow up in the ADRC-treated patients, P = 0.002 for the difference between groups; 24.7 ± 9.2% to 24.7 ± 4.1% at 6-month follow up in the placebo-treated AMI patients; P = 0.48 for the difference between groups), but did not increase LVEF in a randomized, double-blind, placebo-controlled, Phase I/IIa study (NCT00442806i) of the treatment of patients in the acute phase of a large ST-segment elevation AMI. Perin et al. [40
40.
Perin, E.C. ...
Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE trial
] proved the feasibility of the transendocardial injection of ADRCs and found that treated patients exhibited significant improvements in the total LV mass (from 128.1 ± 26.0 to 149.5 ± 32.4 g at 6-month follow up in ADRC-treated patients, P < 0.001; from 144.8 ± 52.7 to 152.6 ± 59.6 g at 6-month follow up in the control group, P = 0.1) based on magnetic resonance imaging and reductions in inducible ischemia (from 9.3 ± 7.0 to 5.8 ± 5.8 at 6-month follow up in ADRC-treated patients, P = 0.02; from 12.8 ± 5.6 to 9.0 ± 9.2 at 6-month follow up in the control group, P = 0.1) based on single-photon emission computed tomography in a prospective, randomized, double-blind, placebo-controlled Phase I study (NCT00426868ii) in patients with ischemic cardiomyopathy, however, no improvement in LVEF was observed compared with control patients. Henry et al. [41
41.
Henry, T.D. ...
The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction
] also designed two parallel prospective, randomized (2:1, active: placebo), double-blind, controlled Phase II trials (ATHENA, NCT01556022iii; ATHENA II, NCT02052427iv) to assess the safety and effectiveness of the harvesting, on-site processing, and intramyocardial delivery of ADRCs to patients with chronic myocardial ischemia and reduced LV function [41
41.
Henry, T.D. ...
The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction
]. In their study, data on symptoms [New York Heart Association (NYHA) HF classes] were evaluated and 57% of ADRC patients had improved NYHA at 12 months compared with 15% in the placebo group [41
41.
Henry, T.D. ...
The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction
Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure – a safety study
] demonstrated the safety and feasibility of an off-the-shelf cryopreserved Cardiology Stem Cell Center ADSC product (CSCC_ASC) from healthy donors for patients with ischemic HF in a Phase I study (NCT02387723v). Although there was a trend toward improved LVEF after CSCC_ASC treatment at the 6-month follow-up period, this difference was not statistically significant (from 28.8% to 31.7%, with a difference of 2.9%, 95% CI: 0.2 to 6.1, P = 0.065) [42
42.
Kastrup, J. ...
Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure – a safety study
First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction
]还设计了两项平行的前瞻性、随机（2:1，活性药物：安慰剂）、双盲、对照的 II 期试验（ATHENA，NCT01556022 iii ；ATHENA II，NCT02052427 iv ），以评估采集、现场处理和心肌内注射脂肪源性再生细胞（ADRCs）对慢性心肌缺血和左心室功能降低患者的安全性和有效性[ 41
41.
Henry, T.D. ...
The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction
Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure – a safety study
]在一项 I 期研究（NCT02387723 v ）中证明了使用来自健康供者的现成冷冻保存的心脏干细胞中心脂肪源性干细胞（CSCC_ASC）产品对缺血性心力衰竭患者的安全性和可行性。尽管在 6 个月的随访期间，CSCC_ASC 治疗后 LVEF 有改善的趋势，但这种差异并不具有统计学意义（从 28.8%提高到 31.7%，差异为 2.9%，95% CI：0.2 至 6.1，P = 0.065）[ 42
42.
Kastrup, J. ...
Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure – a safety study
The transplantation of adipose tissue-derived MSCs thus seems to be feasible and safe for the treatment of HF, comparable with that of bone-marrow derived MSCs. However, its therapeutic efficacy has not been properly established. Several issues, such as the method of MSC isolation and expansion, dosage, and cell delivery routes, were raised for consideration by previous clinical trials [10
10.
Narita, T. ∙ Suzuki, K.
Bone marrow-derived mesenchymal stem cells for the treatment of heart failure
] and future well-organized clinical trials are required for the establishment of adipose tissue-derived MSCs as a clinical treatment for HF. 脂肪组织来源的间充质干细胞移植治疗心力衰竭似乎是可行且安全的，与骨髓来源的间充质干细胞相当。然而，其治疗效果尚未得到充分证实。之前的临床试验提出了几个需要考虑的问题，如间充质干细胞的分离和扩增方法、剂量和细胞递送途径，未来需要组织良好的临床试验来确立脂肪组织来源的间充质干细胞作为心力衰竭的临床治疗方法。
In this context, specific types of HF, such as HF with preserved ejection fraction (HFpEF) and HF in the elderly, are of note (Box 2). These types of HF are now serious health problems and thus important areas of investigation. Although the pathophysiological mechanisms underlying these specific types of HF are not well understood, the potential roles of MSC therapy have been suggested. Further research is warranted to evaluate the therapeutic potential of MSCs, especially adipose tissue-derived MSCs, for patients with these specific types of HF. 在这种情况下，特定类型的心力衰竭（HF），如射血分数保留的心力衰竭（HFpEF）和老年人心力衰竭，值得关注（见方框 2）。这些类型的心力衰竭现已成为严重的健康问题，因此是重要的研究领域。尽管这些特定类型心力衰竭的病理生理机制尚不明确，但间充质干细胞（MSC）治疗的潜在作用已被提出。有必要进一步研究以评估 MSCs，特别是脂肪组织来源的 MSCs，对这些特定类型心力衰竭患者的治疗潜力。
Box 2 框 2
Specific Types of HF and MSCs 特定类型的心力衰竭和间充质干细胞
HFpEF 射血分数保留的心力衰竭
HFpEF now accounts for approximately half of all HF cases and is an important cause of morbidity and mortality [9
9.
Benjamin, E.J. ...
Heart disease and stroke statistics – 2019 update: a report from the American Heart Association
Comparison of the reliability of E/E′ to estimate pulmonary capillary wedge pressure in heart failure patients with preserved ejection fraction versus those with reduced ejection fraction
Different prognostic associations of beta-blockers and diuretics in heart failure with preserved ejection fraction with versus without high blood pressure
]. While several treatments have improved the survival rates of patients with HF with reduced ejection fraction, no agents have been found to increase survival in HFpEF patients [9
9.
Benjamin, E.J. ...
Heart disease and stroke statistics – 2019 update: a report from the American Heart Association
Different prognostic associations of beta-blockers and diuretics in heart failure with preserved ejection fraction with versus without high blood pressure
] reported that injecting human placenta-expanded MSC-like cells improved diabetes mellitus-associated diastolic performance via decreased cardiomyocyte stiffness in mice. In addition, a single intracoronary dose of allogeneic MSCs reduced the myocardial collagen volume fraction and normalized LV diastolic function without affecting cardiomyocyte hypertrophy in Dahl salt-sensitive rats with HFpEF [76
76.
Gallet, R. ...
Cardiosphere-derived cells reverse heart failure with preserved ejection fraction (HFpEF) in rats by decreasing fibrosis and inflammation
]. Although the pathophysiological mechanisms of HFpEF remain poorly understood, a systemic proinflammatory state has been implicated as the origin of microvascular endothelial cell inflammation and subsequent concentric cardiac remodeling and dysfunction [78
78.
Tschope, C. ∙ Van Linthout, S.
New insights in (inter)cellular mechanisms by heart failure with preserved ejection fraction
]. Taken together, the findings regarding the anti-inflammatory effects of MSCs are expected to lead to new therapies for HFpEF. HFpEF 目前约占所有心力衰竭病例的一半，是发病率和死亡率的重要原因[ 9
9.
Benjamin, E.J. ...
Heart disease and stroke statistics – 2019 update: a report from the American Heart Association
Comparison of the reliability of E/E′ to estimate pulmonary capillary wedge pressure in heart failure patients with preserved ejection fraction versus those with reduced ejection fraction
Different prognostic associations of beta-blockers and diuretics in heart failure with preserved ejection fraction with versus without high blood pressure
Different prognostic associations of beta-blockers and diuretics in heart failure with preserved ejection fraction with versus without high blood pressure
]. Frailty is of note as a state of vulnerability to poor resolution of homoeostasis after a stressor event and one of the most problematic expressions of population aging [82
] and aging is associated with an increase in systemic proinflammatory states, potentially leading to a decline in the physiological reserve and function of multiple organ systems, even without the presence of a specific disease [79
79.
Upadhya, B. ...
Heart failure with preserved ejection fraction in the elderly: scope of the problem
], suggesting a strong relationship between frailty and HF in elderly patients. Importantly, intravenous human allogeneic MSCs have yielded significant beneficial effects in measures of physical performance and inflammatory biomarkers in individuals with aging-associated frailty in a Phase II randomized, double-blind, placebo-controlled study (NCT02065245vi) [87
87.
Tompkins, B.A. ...
Allogeneic mesenchymal stem cells ameliorate aging frailty: a Phase II randomized, double-blind, placebo-controlled clinical trial
J. Gerontol. A Biol. Sci. Med. Sci. 2017; 72:1513-1522
]. As MSCs undergo senescence, they gradually show a reduced multilineage differentiation and homing ability as well as reduced immunomodulatory and wound-healing characteristics [89
89.
Yu, K.R. ∙ Kang, K.S.
Aging-related genes in mesenchymal stem cells: a mini-review
Improving the Therapeutic Efficacy of MSCs in HF 提高 MSCs 在心力衰竭中的治疗效果
While MSCs show therapeutic promise, several additional strategies are being examined to further improve their efficiency. 虽然间充质干细胞显示出治疗前景，但正在研究几种额外策略以进一步提高其效率。
Preconditioning or Genetic Manipulation of MSCs 间充质干细胞的预处理或基因操作
To improve the therapeutic effects of MSCs, preconditioning and genetic modification have been examined and promising results reported [15
15.
Liang, X. ...
Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives
]. For example, hypoxic preconditioning is known to increase the levels of a prosurvival factor, phosphorylated Akt, as well as a proangiogenic growth factor, vascular endothelial growth factor (VEGF), in MSCs [44
44.
Chacko, S.M. ...
Hypoxic preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells
Am. J. Physiol. Cell Physiol. 2010; 299:C1562-C1570
] showed that lipopolysaccharide preconditioning stimulated the expression of VEGF in murine bone marrow-derived MSCs, while Lee et al. [46
46.
Lee, T.M. ...
Preconditioned adipose-derived stem cells ameliorate cardiac fibrosis by regulating macrophage polarization in infarcted rat hearts through the PI3K/STAT3 pathway
] demonstrated that the intramyocardial injection of hASCs preconditioned with n-butylidenephthalide significantly increased the shift of macrophages toward the M2 anti-inflammatory phenotype, reduced cardiac fibrosis, and improved cardiac function compared with control cells in a rat myocardial infarction model. 为了提高间充质干细胞的治疗效果，已经研究了预处理和基因修饰，并报告了有希望的结果[ 15
15.
Liang, X. ...
Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives
Preconditioned adipose-derived stem cells ameliorate cardiac fibrosis by regulating macrophage polarization in infarcted rat hearts through the PI3K/STAT3 pathway
] revealed that rat bone marrow-derived MSCs overexpressing Akt (Akt-MSCs) were more effective than control MSCs in preventing ventricular remodeling and restoring cardiac function when injected into ischemic rat myocardia. Gnecchi et al. [13
13.
Gnecchi, M. ...
Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells
] further demonstrated that myocardial protection by Akt-MSCs was achieved by injecting concentrated conditioned medium obtained from Akt-MSC culture into infarcted rat hearts, providing evidence that the therapeutic effects of Akt-MSCs on the myocardium are due to paracrine mechanisms. In addition, Yang et al. [48
48.
Yang, J. ...
Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction
] reported that the myocardial injection of rat bone marrow-derived MSCs overexpressing VEGF in a rat myocardial infarction model stimulated a more robust improvement in angiogenesis than the injection of control MSCs, while Kelly et al. [49
49.
Kelly, M.L. ...
TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia
] reported that treatment with MSCs derived from tumor necrosis factor receptor 1-knockout mice showed a greater improvement in cardiac function than treatment with control MSCs against ischemia/reperfusion injury using an isolated Langendorff rat heart model. 关于 MSCs 的基因操作，Mangi 等人[ 47
47.
Mangi, A.A. ...
Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts
Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction
Therefore, preconditioning and/or genetic modification serve as attractive options to improve MSC therapy for HF; nevertheless, it must be noted that these strategies have their inherent risks, such as toxicity and potential tumorigenicity [50
50.
Pan, Q. ...
Detection of spontaneous tumorigenic transformation during culture expansion of human mesenchymal stromal cells
], and that great caution is required to evaluate their safety. The use of preconditioning and/or genetically manipulated MSCs is an important therapeutic challenge and further studies will hopefully resolve concerns about the safety of these strategies and develop options for MSC therapy in clinical practice (Figure 2). 因此，预处理和/或基因修饰是改善心力衰竭 MSC 治疗的有吸引力的选择；然而，必须注意这些策略有其固有的风险，如毒性和潜在的致瘤性[ 50
50.
Pan, Q. ...
Detection of spontaneous tumorigenic transformation during culture expansion of human mesenchymal stromal cells
Currently, the dominant mechanisms underlying MSC therapy for heart failure are deemed to be paracrine effects. Previous studies demonstrated the feasibility and safety of MSC therapy for heart failure; however, its therapeutic efficacy has not been established. Further studies to optimize MSC treatments and to improve their therapeutic efficacy using preconditioning or genetically manipulated MSCs could lead to novel effective MSC therapies for heart failure.
miRNAs and MSCs in HF miRNAs 和 MSCs 在心力衰竭中的作用
The role of epigenetics in the pathophysiology of cardiovascular diseases including HF has been receiving increasing attention [52–54
52.
Di Salvo, T.G. ∙ Haldar, S.M.
Epigenetic mechanisms in heart failure pathogenesis
]. In addition to DNA methylation and histone modification as the classical epigenetic mechanisms, miRNAs, which are small noncoding RNAs involved in the post-transcriptional regulation of gene expression, are considered to be emerging players in epigenetics [12
12.
Matsushita, K. ∙ Dzau, V.J.
Mesenchymal stem cells in obesity: insights for translational applications
] and autologous stem cells derived from patients with diabetes mellitus and HF show intrinsic downregulation of miR-126 levels, which might be related to their impaired proangiogenic abilities [57
57.
Meng, S. ...
Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1
Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity
] reported that murine bone marrow-derived MSCs overexpressing miR-126 exhibited increased secretion of angiogenic factors such as VEGF and basic fibroblast growth factor under hypoxic conditions and that the transplantation of murine bone marrow-derived MSCs overexpressing miR-126 enhanced functional angiogenesis in the ischemic myocardium of a mouse model of AMI. By contrast, miRNA-34 (miR-34), which is highly expressed in the heart tissue of patients with HF, exerts detrimental effects on stem cells [54
54.
Zhu, K. ...
Developing miRNA therapeutics for cardiac repair in ischemic heart disease
], while the inhibition of miR-34 family members (miR-34a, -34b, and -34c) resulted in improved cardiac function and reduced lung congestion accompanied by decreased cardiac fibrosis and enhanced angiogenesis in mice subjected to pressure overload by transverse aortic constriction [61
61.
Bernardo, B.C. ...
Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function
Proc. Natl. Acad. Sci. U. S. A. 2012; 109:17615-17620
]. Research on the associations between miRNAs and diseases is still an emerging field and much remains to be investigated before we fully understand the functions and therapeutic applications of miRNA modulation in MSC therapy for patients with HF [53
]. In addition, although adipose tissue-derived MSCs are receiving increased attention as described, many of the MSC-related studies in this field did not use adipose tissue-derived MSCs but used bone marrow-derived MSCs. Nevertheless, this field awaits further studies to decipher the mechanisms at play, which may eventually lead to novel miRNA-based MSC therapies, especially adipose MSC therapies, for patients with HF. 表观遗传学在包括心力衰竭（HF）在内的心血管疾病病理生理学中的作用日益受到关注[ 52–54
52.
Di Salvo, T.G. ∙ Haldar, S.M.
Epigenetic mechanisms in heart failure pathogenesis
Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity
Recent evidence suggests an important link between MSC–adipogenesis–obesity and HF, while MSCs might also influence the obesity paradox. Current therapeutic options for advanced HF have limitations and the development of alternative therapies for this critical clinical condition is eagerly anticipated. MSCs in adipose tissue are now considered one of the most promising cell types for the treatment of HF and current results are encouraging regarding their therapeutic potential, although their therapeutic efficacy in clinical trials remains to be established. Ongoing studies are expected to optimize the protocol for MSC treatment, while future research in emerging fields such as preconditioning or genetically manipulated MSC-based therapy could revolutionize therapeutic strategies for patients with HF (Figure 2) (see Outstanding Questions). 最近的证据表明，MSC-脂肪生成-肥胖与心力衰竭（HF）之间存在重要联系，而 MSC 可能也影响肥胖悖论。目前针对晚期心力衰竭的治疗方案存在局限性，因此人们迫切期待为这一关键临床状况开发替代疗法。脂肪组织中的 MSCs 现被认为是治疗 HF 最有前景的细胞类型之一，尽管其在临床试验中的疗效仍有待确定，但当前结果对其治疗潜力令人鼓舞。正在进行的研究有望优化 MSC 治疗方案，而未来在预处理或基因改造 MSC 疗法等新兴领域的研究可能会彻底改变 HF 患者的治疗策略（图 2）（见未解决问题）。
Clinician’s Corner 临床医生专栏
Heart failure (HF) is a complex clinical syndrome and, despite progress in pharmacological treatments and therapeutic devices, current therapeutic options for severely progressed HF are limited. Therefore, research aiming to develop alternative therapies for this critical clinical condition is of high priority. The use of mesenchymal stem cells (MSCs) in adipose tissue has shown many encouraging results for the treatment of HF in preclinical and clinical studies. 心力衰竭（HF）是一种复杂的临床综合征，尽管在药物治疗和治疗设备方面取得了进展，但对于严重进展的 HF，当前的治疗选择仍然有限。因此，针对这一关键临床状况开发替代疗法的研究具有高度优先性。在临床前和临床研究中，使用脂肪组织中的间充质干细胞（MSCs）治疗 HF 已显示出许多令人鼓舞的结果。
Importantly, HF with preserved ejection fraction (HFpEF) is now recognized as a major health burden worldwide and no agents have been found to increase the survival of HFpEF patients. The pathophysiological mechanisms of HFpEF remain poorly understood; however, a systemic proinflammatory state has been implicated as the origin of microvascular endothelial cell inflammation and subsequent concentric cardiac remodeling and dysfunction. In this context, the anti-inflammatory effects of MSCs are expected to aid their application as a therapeutic modality for HFpEF. 重要的是，射血分数保留的心力衰竭（HFpEF）现已被认为是全球主要的健康负担，目前尚未发现能够提高 HFpEF 患者生存率的药物。HFpEF 的病理生理机制仍知之甚少；然而，全身性促炎状态被认为是微血管内皮细胞炎症以及随后的向心性心脏重构和功能障碍的起源。在此背景下，间充质干细胞（MSCs）的抗炎作用有望帮助其作为 HFpEF 的治疗手段。
In addition, HF in the elderly is an emerging global health problem due to the progressively aging population. Understanding the pathophysiology and improving the treatment of HF in the elderly is, therefore, important for maximizing healthy life expectancy. Both the prevalence and the prognostic impact of frailty are high in elderly patients with HF, suggesting a strong relationship between frailty and HF in elderly patients. MSC therapy has recently been reported to have potential for ameliorating frailty in elderly patients with HF. Taken together with the evidence that HFpEF is the most common form of HF in elderly patients and that anti-inflammatory effects of MSCs may be beneficial for HFpEF, the therapeutic potential of MSCs in elderly HF patients is also suggested. 此外，由于人口逐渐老龄化，老年人中的心力衰竭（HF）已成为一个新兴的全球健康问题。因此，了解老年人 HF 的病理生理学并改善其治疗对于最大限度地延长健康预期寿命至关重要。在老年 HF 患者中，虚弱的发生率及其对预后的影响都很高，这表明虚弱与老年 HF 患者之间存在密切关系。最近有报道称，间充质干细胞（MSC）疗法可能有助于改善老年 HF 患者的虚弱状况。结合 HFpEF 是老年患者中最常见的 HF 形式以及 MSCs 的抗炎作用可能对 HFpEF 有益的证据，也提示了 MSCs 在老年 HF 患者中的治疗潜力。
Although the efficacy of MSC therapy in patients with HF remains to be established, improved MSC therapy using preconditioning or genetically manipulated MSCs shows great promise for the future treatment of HF. 尽管 MSC 疗法在心力衰竭患者中的疗效尚待确定，但通过预处理或基因改造的 MSCs 改进疗法显示出未来治疗心力衰竭的巨大潜力。
Outstanding Questions 未解决的问题
What are the mechanisms underlying the adipogenic differentiation of adipose MSCs? Transcriptional regulation and signaling pathways that govern adipogenic differentiation of MSCs are complex and remain poorly understood, and an in-depth understanding is a crucial first step to elucidating the complicated relationship between MSC–adipogenesis–obesity and HF. 脂肪间充质干细胞成脂分化的机制是什么？调控间充质干细胞成脂分化的转录调控和信号通路复杂且尚未完全理解，深入理解这一过程是阐明间充质干细胞-成脂分化-肥胖与心力衰竭之间复杂关系的关键第一步。
How can we clarify the roles of MSCs in obese patients with HF? Are MSCs associated with the obesity paradox? The clinical significance of the increase in circulating MSCs in obese patients remains uncertain and these questions need to be explored. 我们如何阐明 MSCs 在肥胖心衰患者中的作用？MSCs 是否与肥胖悖论相关？肥胖患者循环中 MSCs 增加的临床意义仍不明确，这些问题需要进一步探索。
What is the best protocol for MSC therapy for HF in terms of the method of MSC isolation and expansion, dosage, and cell delivery routes? How can we conduct well-organized clinical trials to examine the efficacy of MSC therapy in patients with HF? 关于 MSC 分离和扩增方法、剂量和细胞递送途径，治疗心力衰竭的最佳 MSC 治疗方案是什么？我们如何开展组织良好的临床试验来检验 MSC 治疗对心力衰竭患者的疗效？
What are the regulatory mechanisms governing paracrine factor release from MSCs? Although recent evidence indicates that the dominant mechanisms by which MSCs exert beneficial effects against HF are paracrine, the regulatory mechanisms of paracrine factor release from MSCs remain poorly understood and are likely to be highly complex. Unraveling the mechanisms at play in paracrine factor release from MSCs could provide novel therapeutic targets for HF. 调控 MSCs 旁分泌因子释放的机制是什么？尽管最近的证据表明，MSCs 发挥对心力衰竭有益作用的主要机制是旁分泌，但 MSCs 旁分泌因子释放的调控机制仍然知之甚少，并且可能非常复杂。揭示 MSCs 旁分泌因子释放的机制可能为心力衰竭提供新的治疗靶点。
Can preconditioning or genetic manipulation of MSCs improve the therapeutic efficacy of MSCs against HF without causing deleterious effects? The therapeutic efficacy of MSCs for the treatment of HF has not been established in clinical trials; however, the use of preconditioned and/or genetically manipulated MSCs is an important therapeutic challenge. Further studies are required to resolve concerns about the safety of such strategies to develop novel, effective MSC therapies for the treatment of HF. MSCs 的预处理或基因操作能否在不引起有害影响的情况下提高 MSCs 对心力衰竭的治疗效果？MSCs 治疗心力衰竭的疗效尚未在临床试验中得到证实；然而，使用预处理和/或基因操作的 MSCs 是一个重要的治疗挑战。需要进一步研究以解决此类策略的安全性问题，从而开发出新型、有效的 MSCs 疗法用于治疗心力衰竭。
Acknowledgments 致谢
This work was supported, in part, by grants from the Japan Society for the Promotion of Science (KAKENHI 26461086 and 17K09523), the Kyorin University School of Medicine (No. B102090002), and the Vehicle Racing Commemorative Foundation (No. 5991). 本工作部分得到了日本学术振兴会（KAKENHI 26461086 和 17K09523）、杏林大学医学院（编号 B102090002）以及赛车纪念基金会（编号 5991）的资助。
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 2016 年 ESC 急性和慢性心力衰竭诊断和治疗指南：欧洲心脏病学会（ESC）急性和慢性心力衰竭诊断和治疗工作组。由 ESC 心力衰竭协会（HFA）特别贡献制定。
Packer, M. ∙ McMurray, J.J.V. 帕克, M. ∙ 麦克默里, J.J.V.
Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin–angiotensin system for the treatment of heart failure 内源性代偿性血管活性肽在扩大肾素-血管紧张素系统抑制剂治疗心力衰竭效果中的重要性
Mesenchymal stem cells differentiate into renin-producing juxtaglomerular (JG)-like cells under the control of liver X receptor-alpha 在肝 X 受体α的控制下，间充质干细胞分化为产生肾素的肾小球旁（JG）样细胞
Blockade of angiotensin II type 2 receptor by PD123319 inhibits osteogenic differentiation of human mesenchymal stem cells via inhibition of extracellular signal-regulated kinase signaling PD123319 阻断血管紧张素 II 2 型受体通过抑制细胞外信号调节激酶信号通路抑制人间充质干细胞的成骨分化
Deletion of angiotensin II type 2 receptor accelerates adipogenesis in murine mesenchymal stem cells via Wnt10b/beta-catenin signaling 血管紧张素 II 2 型受体的缺失通过 Wnt10b/β-连环蛋白信号通路加速小鼠间充质干细胞的脂肪生成
Functional assessment of adipose stem cells for xenotransplantation using myocardial infarction immunocompetent models: comparison with bone marrow stem cells 使用心肌梗死免疫活性模型对脂肪干细胞进行异种移植的功能评估：与骨髓干细胞的比较
First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction 首次在人体中使用脂肪组织来源的再生细胞治疗 ST 段抬高型心肌梗死患者的经验
The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction 雅典娜试验：自体脂肪源性再生细胞治疗伴有左心室功能障碍的难治性慢性心肌缺血
Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure – a safety study 冷冻保存的现成异体脂肪来源基质细胞用于治疗缺血性心脏病和心力衰竭患者的安全性研究
Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction 脂多糖预处理增强间充质干细胞移植在急性心肌梗死大鼠模型中的疗效
Preconditioned adipose-derived stem cells ameliorate cardiac fibrosis by regulating macrophage polarization in infarcted rat hearts through the PI3K/STAT3 pathway 预处理的脂肪源性干细胞通过 PI3K/STAT3 通路调节巨噬细胞极化，改善梗死大鼠心脏的纤维化
Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction 血管内皮生长因子转染的骨髓间充质干细胞心肌移植对心肌梗死后心功能改善和血管生成的影响
Genetic stability of mesenchymal stromal cells for regenerative medicine applications: a fundamental biosafety aspect 间充质基质细胞在再生医学应用中的遗传稳定性：一个基本的生物安全性方面
Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1 糖尿病患者内皮祖细胞中 microRNA-126 的下调通过靶基因 Spred-1 损害其功能特性
Loss of angiomiR-126 and 130a in angiogenic early outgrowth cells from patients with chronic heart failure: role for impaired in vivo neovascularization and cardiac repair capacity 慢性心力衰竭患者血管生成早期外植细胞中血管生成 miR-126 和 130a 的缺失：对体内新生血管和心脏修复能力受损的作用
Micro-RNA-34a contributes to the impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease 微小 RNA-34a 在心血管疾病患者骨髓来源的单核细胞功能受损中起重要作用
Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis 间充质干细胞移植减轻大鼠急性心肌炎模型中的心肌损伤和功能障碍
Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury 白细胞介素 1 受体拮抗剂介导间充质干细胞在肺损伤期间的抗炎和抗纤维化作用
Proc. Natl. Acad. Sci. U. S. A. 2007; 104:11002-11007 美国国家科学院院刊 2007; 104:11002-11007
Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction 间充质基质细胞在急性心肌梗死后介导向替代激活单核细胞/巨噬细胞的转换
Bone marrow mesenchymal stem cells ameliorate hepatic ischemia/reperfusion injuries via inactivation of the MEK/ERK signaling pathway in rats 骨髓间充质干细胞通过抑制 MEK/ERK 信号通路减轻大鼠肝脏缺血/再灌注损伤
Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury 骨髓细胞产生的细胞因子可通过保护心肌细胞免受缺血性损伤，促进梗死心脏的功能改善
Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms 骨髓来源的基质细胞表达编码多种动脉生成细胞因子的基因，并通过旁分泌机制促进体外和体内动脉生成
VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function VEGF 对于干细胞介导的心脏保护至关重要，并且是定义成人和新生儿干细胞功能年龄阈值的关键旁分泌因子
Comparison of the reliability of E/E′ to estimate pulmonary capillary wedge pressure in heart failure patients with preserved ejection fraction versus those with reduced ejection fraction 比较 E/E′在估计射血分数保留型心力衰竭患者与射血分数降低型心力衰竭患者中肺毛细血管楔压的可靠性
Different prognostic associations of beta-blockers and diuretics in heart failure with preserved ejection fraction with versus without high blood pressure 在射血分数保留的心力衰竭中，伴或不伴高血压患者使用β受体阻滞剂和利尿剂的预后关联不同
Cardiosphere-derived cells reverse heart failure with preserved ejection fraction (HFpEF) in rats by decreasing fibrosis and inflammation 心脏球源细胞通过减少纤维化和炎症逆转大鼠保留射血分数心力衰竭（HFpEF）
derived from different individuals of the same species. 来自同一物种的不同个体。
Apoptosis 细胞凋亡
a form of genetically regulated programmed cell death. This type of cell death is used to remove unneeded or abnormal cells and contributes to an organism’s natural growth and development. 一种基因调控的程序性细胞死亡形式。这种细胞死亡用于清除不需要或异常的细胞，并有助于生物体的自然生长和发育。
Autologous 自体
derived from the same individual. In other words, it is a situation in which the donor and recipient are the same individual. 源自同一个个体。换句话说，这是一种供体和受体为同一个个体的情况。
Bariatric surgery 减重手术
surgery on the stomach and/or intestine to aid weight loss by (i) reducing stomach volume so that patients feel full while consuming less food and/or (ii) modifying the digestive system, including the secretions and actions of gut peptides, to reduce the absorption of food. 胃和/或肠道手术，通过以下方式帮助减重：(i) 减少胃容量，使患者在摄入较少食物时感到饱腹，和/或 (ii) 改变消化系统，包括肠道肽的分泌和作用，以减少食物的吸收。
Conditioned medium 条件培养基
spent medium in which cells have been cultured and that contains factors secreted by those cells. 细胞在其中培养并含有这些细胞分泌因子的培养基。
Frailty 虚弱
a state of vulnerability resulting from poor resolution of homoeostasis following a stressor event; it is one of the most problematic characteristics of an aging population. 一种由于应激事件后稳态调节不良导致的脆弱状态；这是老年人口最具问题性的特征之一。
Genetic modification 基因修饰
the process of changing an organism’s genes to introduce particular traits. It might involve silencing a gene or inserting a foreign gene into an organism’s genome. 改变生物体基因以引入特定特征的过程。它可能涉及沉默一个基因或将外源基因插入生物体的基因组中。
Heart failure with preserved ejection fraction (HFpEF) 射血分数保留的心力衰竭（HFpEF）
HF with LVEF ≥50%. 左室射血分数≥50%的心力衰竭。
Left ventricular (LV) ejection fraction (LVEF) 左心室（LV）射血分数（LVEF）
a clinical indicator of LV systolic function of the heart, calculated by the following formula: 左心室收缩功能的临床指标，通过以下公式计算：
LVEF = [(LV end diastolic volume − LV end systolic volume) /LV end diastolic volume] × 100 (%). 左室射血分数 = [(左室舒张末期容积 - 左室收缩末期容积) / 左室舒张末期容积] × 100 (%)。
microRNAs (miRNAs) 微小 RNA（miRNAs）
small noncoding RNAs involved in the post-transcriptional regulation of gene expression. 参与基因表达转录后调控的小型非编码 RNA。
Obesity paradox 肥胖悖论
the observation that although obesity is a major risk factor in the development of several diseases, when such diseases occur, obesity is associated with improved survival. 观察到尽管肥胖是多种疾病发展的主要风险因素，但当这些疾病发生时，肥胖却与改善的生存率相关。
Paracrine effects 旁分泌效应
the effects of factors secreted from one cell on neighboring cells, which alter the functioning of those cells. In contrast to endocrine factors, which travel long distances through the circulatory system, paracrine factors travel to nearby cells and act locally. 一个细胞分泌的因子对邻近细胞的影响，这些因子改变了这些细胞的功能。与通过循环系统长距离传输的内分泌因子不同，旁分泌因子传输到附近的细胞并在局部起作用。
Preconditioning 预处理
a technique of exposing the target to stimuli to confer some effect on a subsequent event. 一种通过向目标施加刺激以对后续事件产生某种影响的技术。
Renin–angiotensin system (RAS) 肾素-血管紧张素系统（RAS）
a key hormonal system in the physiological regulation of blood pressure and fluid balance, which plays a pivotal role in the pathophysiology of HF. 一个在血压和体液平衡生理调节中起关键作用的激素系统，在心力衰竭的病理生理学中发挥着核心作用。
