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.

Mesenchymal stromal cells (MSCs) offer great potential for the treatment of cardiovascular diseases (CVDs) such as myocardial infarction and heart failure. Studies have revealed that the efficacy of MSCs is mainly attributed to their capacity to secrete numerous trophic factors that promote angiogenesis, inhibit apoptosis, and modulate the immune response. There is growing evidence that MSC-derived extracellular vesicles (EVs) containing a cargo of lipids, proteins, metabolites, and RNAs play a key role in this paracrine mechanism. In particular, encapsulated microRNAs have been identified as important positive regulators of angiogenesis in pathological settings of insufficient blood supply to the heart, thus opening a new path for the treatment of CVD. In the present review, we discuss the current knowledge related to the proangiogenic potential of MSCs and MSC-derived EVs as well as methods to enhance their biological activities for improved cardiac tissue repair. Increasing our understanding of mechanisms supporting angiogenesis will help optimize future approaches to CVD intervention.Significance statement Mesenchymal stromal cells (MSCs) are currently being evaluated in clinical trials for the treatment of numerous diseases. Their therapeutic potential is mainly due to the factors they secrete. Studies have demonstrated that MSCs also produce extracellular vesicles that carry proteins, metabolites, lipids, and various RNAs. Based on their multifunctional properties, extracelullar vesicles are of great importance and interest in the development of future medicine. This study provides an overview of the current knowledge on the therapeutic potential of MSCs and MSC-derived extracelullar vesicles, as well as methods for improving their biological activities to promote angiogenesis and tissue repair.

The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.

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

In the early 2000s, the concept of cell transplantation for myocardial regeneration moved from bench to bedside within just 1 year.^1,2 Almost 20 years later, we are facing a large number of clinical trials that utilized various stem and progenitor cell preparations with widely contradictory results.³ Furthermore, a meta-analysis revealed that the study outcomes were heavily biased towards more positive outcomes by inferior methodological quality of study design and absent quality controls for the cells used.⁴ Based on the posted results, it remains questionable that currently available cell-based therapies result in true myocardial regeneration.⁵

Excessive cardiac fibrosis plays a crucial role in almost all types of heart disease. Generally, cardiac fibrosis is a scarring process triggered in response to stress, injury, or aging and is characterized by the accumulation of activated myofibroblasts that deposit high levels of extracellular matrix proteins in the myocardium. While it is beneficial for cardiac repair in the short term, it can also result in pathological remodeling, tissue stiffening, and cardiac dysfunction, contributing to the progression of heart failure, arrhythmia, and sudden cardiac death. Despite its high prevalence, there is a lack of effective and safe therapies that specifically target myofibroblasts to inhibit or even reverse pathological cardiac fibrosis. In the past few decades, cell therapy has been under continuous evaluation as a potential treatment strategy, and several studies have shown that transplantation of mesenchymal stromal cells (MSCs) can reduce cardiac fibrosis and improve heart function. Mechanistically, it is believed that the heart benefits from MSC therapy by stimulating innate anti-fibrotic and regenerative reactions. The mechanisms of action include paracrine signaling and cell-to-cell interactions. In this review, we provide an overview of the anti-fibrotic properties of MSCs and approaches to enhance them and discuss future directions of MSCs for the treatment of cardiac fibrosis.