Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia. In an elderly cohort with acute myocardial infarction (MI), patients with three-vessel CAD were characterized by lower levels of the natural logarithm (Ln) of peripheral blood BPIFB4 (p = 0.0077). The inverse association between Ln BPIFB4 and three-vessel CAD was confirmed by logistic regression adjusting for confounders (Odds Ratio = 0.81, p = 0.0054). Moreover, in infarcted mice, a single administration of LAV-BPIFB4 rescued cardiac function and vascularization. In vitro studies showed that LAV-BPIFB4 protein supplementation exerted chronotropic and inotropic actions on induced pluripotent stem cell (iPSC)-derived cardiomyocytes. In addition, LAV-BPIFB4 inhibited the pro-fibrotic phenotype in human cardiac fibroblasts. These findings provide a strong rationale and proof of concept evidence for treating CAD with the longevity BPIFB4 gene/protein.

长寿个体（LLI）直到生命的最后阶段都可以避免与年龄相关的心血管并发症。先前的研究表明，包含 B 族成员 4 ( BPIFB4 ) 基因的 BPI 折叠的长寿相关变异 (LAV) 与超长寿命相关。此外，LAV-BPIFB4基因的递送在动脉粥样硬化、肢体缺血、糖尿病心肌病和衰老的小鼠模型中发挥了治疗作用。我们假设 BPIFB4 表达的下调标志着人类受试者冠状动脉疾病 (CAD) 的严重程度，而补充 LAV -BPIFB4可以保护心脏免受缺血。在患有急性心肌梗死 (MI) 的老年队列中，三支血管 CAD 患者的特点是外周血 BPIFB4 自然对数 (Ln) 水平较低 ( p  = 0.0077)。通过对混杂因素进行逻辑回归调整，证实了 Ln BPIFB4 与三血管 CAD 之间的负相关性（优势比 = 0.81，p  = 0.0054）。此外，在梗塞小鼠中，单次施用LAV-BPIFB4可以挽救心脏功能和血管化。体外研究表明，LAV-BPIFB4 蛋白补充剂对诱导多能干细胞 (iPSC) 来源的心肌细胞发挥变时性和正性肌力作用。此外，LAV-BPIFB4 抑制人心脏成纤维细胞的促纤维化表型。这些发现为利用长寿 BPIFB4 基因/蛋白治疗 CAD 提供了强有力的理论依据和概念验证证据。