Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A (apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.

Small extracellular vesicles (sEVs) are non-replicating, membrane-derived nanoparticles secreted by cells into the extracellular space.^1,2 They carry bioactive molecules that can modulate recipient cell functions. When derived from human cardiac progenitor cells (CPCs) or cardiosphere-derived cells (CDCs), sEVs are hypoimmunogenic and cardioprotective and exhibit pro-angiogenic capacity, making them attractive candidates for the treatment of acute myocardial infarction (AMI). We and others have shown that sEVs secreted by human CPCs or CDCs reduce infarct size and improve cardiac function in AMI models^3–6; however, benefits have only been demonstrated after their intramyocardial (IM) injection in open-chest AMI models. Since most AMI patients undergo emergency percutaneous coronary intervention (PCI), clinical translation of sEV-based therapies will require percutaneous delivery modalities. While intracoronary (IC) delivery of sEVs during PCI would be suitable for AMI patients, a previous study in porcine AMI showed a lack of efficacy.⁵ In contrast, percutaneous, catheter-based IM delivery of CDC-sEVs using the NOGA cardiac navigation system showed promise in a porcine model of convalescent myocardial infarction.⁵

Despite the success of coronary artery bypass graft (CABG) surgery using autologous saphenous vein grafts (SVGs), nearly 50% of patients experience vein graft disease within 10 years of surgery. One contributing factor to early vein graft disease is endothelial damage during short-term storage of SVGs in inappropriate solutions. Our aim was to evaluate the effects of a novel endothelial damage inhibitor (EDI) solution, DuraGraft^®, on SVGs from patients undergoing elective CABG surgery and on venous endothelial cells (VECs) derived from these SVGs. SVGs from 11 patients from an ongoing clinical registry (NCT02922088) were included in this study, and incubated with both full electrolyte solution (FES) or EDI for 1 h and then examined histologically. In 8 of 11 patients, VECs were isolated from untreated grafts, incubated with both FES and EDI for 2 h under hypothermic stress conditions, and then analyzed for activation of an inflammatory phenotype, cell damage and cytotoxicity, as well as endothelial integrity and barrier function. EDI was superior to FES in protecting the endothelium in SVGs (74 ± 8% versus 56 ± 8%, p < 0.001). Besides confirming that EDI prevents apoptosis in SVG-derived VECs, we also showed that EDI temporarily reduces adherens junctions in VECs while protecting focal adhesions compared to FES. EDI protects the connectivity and function of the SVG endothelium. Our data suggest that EDI can preserve focal adhesions in VECs during short-term storage after graft harvesting. This might explain the superiority of EDI in maintaining most of the endothelium in venous CABG surgery conduits.

Cell-based therapy has long been considered a promising strategy for the treatment of heart failure (HF). However, its effectiveness in the clinical setting is now doubted. Because previous meta-analyses provided conflicting results, we sought to review all available data focusing on cell type and trial design. The electronic databases PubMed, Cochrane library, ClinicalTrials.gov, and EudraCT were searched for randomized controlled trials (RCTs) utilizing cell therapy for HF patients from January 1, 2000 to December 31, 2020. Forty-three RCTs with 2855 participants were identified. The quality of the reported study design was assessed by evaluating the risk-of-bias (ROB). Primary outcomes were defined as mortality rate and left ventricular ejection fraction (LVEF) change from baseline. Secondary outcomes included both heart function data and clinical symptoms/events. Between-study heterogeneity was assessed using the I2 index. Subgroup analysis was performed based on HF type, cell source, cell origin, cell type, cell processing, type of surgical intervention, cell delivery routes, cell dose, and follow-up duration. Only 10 of the 43 studies had a low ROB for all method- and outcome parameters. A higher ROB was associated with a greater increase in LVEF. Overall, there was no impact on mortality for up to 12 months follow-up, and a clinically irrelevant average LVEF increase by LVEF (2.4%, 95% CI = 0.75−4.05, p = 0.004). Freshly isolated, primary cells tended to produce better outcomes than cultured cell products, but there was no clear impact of the cell source tissue, bone marrow cell phenotype or cell chricdose (raw or normalized for CD34+ cells). A meaningful increase in LVEF was only observed when cell therapy was combined with myocardial revascularization. The published results suggest a small increase in LVEF following cell therapy for heart failure, but publication bias and methodologic shortcomings need to be taken into account. Given that cardiac cell therapy has now been pursued for 20 years without real progress, further efforts should not be made. This meta-analysis is registered at the international prospective register of systematic reviews, number CRD42019118872.

Heart failure is the leading cause of morbidity and mortality and currently affects more than 60 million people worldwide. A key feature in the pathogenesis of almost all forms of heart failure is cardiac fibrosis, which is characterized by excessive accumulation of extracellular matrix components in the heart. Although cardiac fibrosis is beneficial in the short term after acute myocardial injury to preserve the structural and functional integrity of the heart, persistent cardiac fibrosis contributes to pathological cardiac remodeling, leading to mechanical and electrical dysfunction of the heart. Despite its high prevalence, standard therapies specifically targeting cardiac fibrosis are not yet available. Cell-based approaches have been extensively studied as potential treatments for cardiac fibrosis, but several challenges have been identified during clinical translation. The observation that extracellular vesicles (EVs) derived from stem and progenitor cells exhibit some of the therapeutic effects of the parent cells has paved the way to overcome limitations associated with cell therapy. However, to make EV-based products a reality, standardized methods for EV production, isolation, characterization, and storage must be established, along with concrete evidence of their safety and efficacy in clinical trials. This article discusses EVs as novel therapeutics for cardiac fibrosis from a translational perspective.