Toward precision cardiovascular medicine: progressing basic and translational science

In their excellent lead article "Precision cardiovascular medicine: shifting the innovation paradigm" Aikawa and coworkers (Aikawa et al. 2025) highlight that, in addition to cardiovascular risk management, new and more effective therapies are needed to treat complex and heterogenous cardiovascular diseases to reduce overall morbidity and mortality among patients. There is no doubt that "precision medicine" has the potential to achieve such a goal in the near future. However, this will require progress in several aspects of basic and translational science (Figure 1); i.e. creation of adequate animal models mimicking the complexity of human diseases, better definition of the time course and the specific cells involved in disease development or progression and finally improvement of cell type specific targeting of therapeutic approaches and understanding of potential off-target effects,While "big" clinical data are required to discover and test novel preventive and curative therapies for cardiovascular diseases, just as important are new experimental models that better recapitulate human diseases. Translating basic science into clinical practice is challenging, especially for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. In coming years, animal models need to be further refined and made more "human-like" based on big datasets from human studies (van der Velde et al., 2022;Heusch et al., 2023). As well predicting efficacy, this is also important to identify uncommon or "hidden" cardiotoxic effects of treatment modalities, which currently are often detected only after market launch when large numbers of patients are exposed to treatment (Ferdinandy et al, 2019). As cardiovascular disease mechanisms and treatment responses potentially differ between male and females, the effect of sex should also be taken into account in the design of experimental studies (Perrino et al., 2021). Novel in vitro technologies such as inducible pluripotent stem cells in two-or three-dimensional (so called organoids) culture or human slices, and advanced computational analyses, will affect our experimental design to better capture human pathophysiology-thereby reducing the number of laboratory animals required.Different cell typesmight behave differently during disease development. This can be because a certain protein might have different functions: a) within or outside the cell: for example, intracellular deletion of proprotein convertase subtilisin kexin type 9 (PCSK9) using genetic approaches, but not inhibition of extracellular PCSK9 using antibodies, reduced infarct sizes ex vivo (Schreckenberg et al., 2022). Thus, exact understanding of the intra-and extracellular function of a protein is required before target definition. b) in different cell types: for example, the uncoupling protein 2 contributes to the formation of reactive oxygen species (ROS) in many cell types, potentially causing harm under pathophysiological conditions. However, this is not the case in cardiomyocytes (Schulz & Schlüter, 2023) Lipid nanoparticles (LNP) have been synthesized to protect messenger (m)RNA therapeutic agents from degradation and, with adequate composition of the bilayer membrane, facilitate uptake into specific cellular compartments. However, even though there might be a certain cell type specificity, LNPs are taken up to a small extent by almost every cell, raising the potential for adverse effects of the mRNA-encoded protein and/or protein inhibition (Schreckenberg et al., 2024). Moreover, LNPs might induce immune responses and local inflammation due to their synthetic components. Extracellular vesicles, which play an essential role in intercellular communication by facilitating the transport of bioactive molecules, may offer advantages over LNPs as delivery vehicles-being naturally derived and thus less likely to elicit immune responses. However, far more research is needed to develop standardized techniques for their isolation and purification, and to explore their therapeutic use (Wang et al., 2025).Small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs) offer advantages over small-molecule drugs. These small RNAs can target any gene product, offering new, effective, and safe therapeutic approaches for a wide range of diseases. However, these agents face important challenges. Hybridization-dependent off-target effects remain a major hurdle, for example, as no established, standard methodology exists to minimize these and the various proposed methods have limitations.Here, the inclusion of new techniques (including network theoretical algorithms and artificial intelligence) in the development process would enable examination of the entire, complex regulatory network-allowing more accurate prediction of potential off-target effects and more precise sequence design (Bereczki et al., 2025).Taken together, precision medicine has enormous potential to improve therapy for cardiovascular diseases and reduce patients' morbidity and mortality. However, further research using a new generation of adequate experimental models if we are to develop and deliver new cell type-specific therapies that are effective and safe.Each author must be listed under at least one of the Writing rows to qualify for authorship.