Sava Ruxandra I, Pepine Carl J, March Keith L
Center for Regenerative Medicine, University of Florida, Gainesville, FL 32610, USA.
Cardiology Department, Elias Emergency University Hospital, Bucharest 011461, Romania.
J Clin Med. 2020 Jan 16;9(1):241. doi: 10.3390/jcm9010241.
Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF is strongly associated with aging, inflammation, and comorbid burden, which are thought to play causal roles in disease development. Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory actions and promote tissue healing, thus representing an attractive therapeutic option in HFpEF. In this review, we summarize recent data suggesting that a two-hit model of immune dysregulation lies at the heart of the HFpEF. A first hit is represented by genetic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), which skew immune cells toward a pro-inflammatory phenotype, are associated with HFpEF development in animal models, and with immune dysregulation and risk of HF hospitalization in patients. A second hit is induced by cardiovascular risk factors, which cause subclinical cardiac dysfunction and production of danger signals. In mice, these attract proinflammatory macrophages, Th1 and Th17 cells into the myocardium, where they are required for the development of HFpEF. MSCs have been shown to reduce the pro-inflammatory activity of immune cell types involved in murine HFpEF in vitro, and to reduce myocardial fibrosis and improve diastolic function in vivo thus they may efficiently target immune dysregulation in HFpEF and stop disease progression.
全球超过2600万人患有心力衰竭，这是一种1年死亡率为22%的疾病。其中一半患者表现为射血分数保留的心力衰竭（HFpEF），对此目前尚无改善预后的有效治疗方法。HFpEF与衰老、炎症和共病负担密切相关，这些因素被认为在疾病发展中起因果作用。间充质基质/干细胞（MSCs）具有强大的免疫调节作用并促进组织愈合，因此是HFpEF中一种有吸引力的治疗选择。在这篇综述中，我们总结了最近的数据，表明免疫失调的双打击模型是HFpEF的核心。第一次打击表现为与不确定潜能的克隆性造血（CHIP）相关的基因突变，这些突变使免疫细胞倾向于促炎表型，与动物模型中的HFpEF发展以及患者的免疫失调和HF住院风险相关。第二次打击由心血管危险因素诱导，这些因素导致亚临床心脏功能障碍和危险信号的产生。在小鼠中，这些因素吸引促炎巨噬细胞、Th1和Th17细胞进入心肌，而它们是HFpEF发展所必需的。已证明MSCs在体外可降低参与小鼠HFpEF的免疫细胞类型的促炎活性，并在体内减少心肌纤维化并改善舒张功能，因此它们可能有效地针对HFpEF中的免疫失调并阻止疾病进展。
