Aims: Familial hypercholesterolemia (FH) significantly increases cardiovascular risk from childhood yet remains widely underdiagnosed. This cross-sectional study aimed to evaluate existing paediatric FH diagnostic criteria in real-world cohorts and to develop two novel diagnostic tools: a semi-quantitative scoring system (FH-PeDS) and a machine learning model (ML-FH-PeDS) to enhance early FH detection. Methods and results: Five established FH diagnostic criteria were assessed (Dutch Lipid Clinics Network [DLCN], Simon Broome, EAS, Simplified Canadian, and Japanese Atherosclerosis Society) in Slovenian (N = 1360) and Portuguese (N = 340) paediatric hypercholesterolemia cohorts, using FH-causing variants as the reference standard. FH-PeDS was developed from the Slovenian cohort, and ML-FH-PeDS was trained and tested using a 60%/40% split before external validation in the Portuguese cohort. Only 47.4% of genetically confirmed FH cases were identified by all established criteria, while 10.9% were missed entirely. FH-PeDS outperformed DLCN in the combined cohort (AUC 0.897 vs. 0.857; P < 0.01). ML-FH-PeDS showed superior predictive power (AUC 0.932 in training, 0.904 in testing vs. 0.852 for DLCN; P < 0.01) and performed best as a confirmatory test in the testing subgroup (39.7% sensitivity, 87.7% PPV at 98% specificity). In the Portuguese cohort, ML-FH-PeDS maintained strong predictive performance (AUC 0.867 vs. 0.815 for DLCN; P < 0.01) despite population differences. Conclusion: Current FH diagnostic criteria perform sub-optimally in children. FH-PeDS and ML-FH-PeDS provide tools to improve FH detection, particularly where genetic testing is limited. They also help guide genetic testing decisions for hypercholesterolemic children. By enabling earlier diagnosis and intervention, these tools may reduce long-term cardiovascular risk and improve outcomes.

Cascade familial hypercholesterolemia (FH) screening of parents could reduce the burden cardiovascular disease (CVD) in relatives of index cases by enabling timely diagnosis of FH. Here, we present the positive outcomes of the pilot child-parent cascade screening program in Slovenia. One hundred and thirty-eight parents from 123 families of an index child with genetically confirmed FH were randomly included in the pilot child-parent cascade screening program. Index children were identified through the universal FH screening program in preschool children. Genetic testing using Sanger sequencing was performed for cascade screening to detect (likely) pathogenic variants, previously confirmed in the index child. The success rate of confirming a (likely) pathogenic variant was 77.2 % when the first parent, preferably with higher total cholesterol levels, was tested, and reached 99.1 % when the variant was identified in the first tested parent or when both parents were tested. In the minority of cases (13.8 %), parents had had a clinical diagnosis of FH prior to their child and these had somewhat higher prevalence of CVD compared to parents that were diagnosed after their index child through the pilot program (12.5 % vs. 4.3 %; p = 0.382). In conclusion, the presented pilot child-parent cascade screening program is feasible in clinical practice and shows a high success rate in identifying parents with FH. Parents diagnosed through the program appeared to have a lower prevalence of CVD. However, larger cohorts are needed to confirm these findings.

Aims: Lipoprotein(a) [Lp(a)] is a significant genetic risk factor for cardiovascular disease (CVD). Extremely high Lp(a) levels (153 mg/dL), affecting about 1 in 100 individuals, can elevate LDL cholesterol (LDL-C) due to structural similarities between Lp(a) and LDL-C particles. This study assessed the role and impact of Lp(a) on LDL-C in children with hypercholesterolaemia, a relationship that remains poorly understood. Methods and results: The study included 1418 children (median age: 6.34 years) with hypercholesterolaemia, identified by universal or cascade familial hypercholesterolaemia (FH) screening in Slovenia. Participants were categorized as 363 (25.6%) with definite FH (pathogenic variants in LDLR/APOB/PCSK9), 1014 (71.5%) with possible FH (no FH pathogenic variant), and 41 (2.9%) definite non-FH (siblings of definite FH cases without FH pathogenic variant). Elevated Lp(a) levels (>30 mg/dL) were found in 25.1% of definite FH and 34.9% of possible FH cases (P = 0.003). In definite FH, 32.7% of Lp(a) levels contributed to LDL-C levels, and 18.6% of Lp(a) levels contributed to apolipoprotein B (ApoB). The Lp(a) component of LDL-C varied widely (0–49.6%) and accounted for 10.3% of LDL-C variability. After adjusting for Lp(a), elevated LDL-C (>3.5 mmol/L) still persisted in 88.4% of definite FH and 30.4% of possible FH children. Conclusion: One in four children with FH and one in three children with polygenic hypercholesterolaemia have elevated Lp(a) levels, contributing notably to LDL-C levels and ApoB. Modifiable CVD risk factors (elevated LDL-C and obesity) are already present in those children, highlighting the need for early, targeted evaluation and management.

Cardiac rehabilitation (CR) plays a crucial role in managing patients who have undergone coronary intervention (CI) following acute myocardial infarction. While water-based exercise is gaining recognition as an exercise modality in this patient population, its impact on the subgroup of older adults remains unexplored. In this post hoc analysis, we investigated the effects of water-based exercise on adults older than 60 years undergoing CR after CI, comparing it to land-based exercise and a control group. In total, 45 patients aged over 60 participated in 14-day exercise programs, featuring two daily 30-min sessions. We assessed exercise capacity (VO_2peak), vascular function (flow-mediated vasodilation (FMD)), heart rate variability (HRV), and blood markers (Interleukins 6, 8, and 10, P-Selectin, ICAM, and High-sensitivity CRP) before and after CR. VO_2peak in the water-based group improved significantly after CR in comparison with the land-based group: 1.35 kg/mL/min (95% CI [0.20–2.50], p = 0.022). The significant difference between water-based and land-based groups was observed in several HRV parameters: Total power −1129.20 ms² (95% CI [−1951.92–−306.49], p = 0.008); peak LF 0.04 Hz (95% CI [0.00–0.08], p = 0.036); SD1 −9.02 millisecond (95% CI [−16.86–−1.18], p = 0.025); and SD2 −19.71 ms (95% CI [−35.08–−4.34], p = 0.013). FMD and blood markers did not vary significantly based on the exercise group. These findings suggest that short-term water-based CR may have potential as an alternative to traditional land-based CR, improving VO_2peak and cardiorespiratory fitness among adults over 60 years undergoing CR after CI.

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients’ lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.

Background and Objectives: Postoperative atrial fibrillation (AF) is a frequent complication after coronary artery bypass grafting (CABG), and is particularly associated with poor outcomes. Heart rate variability (HRV), a non-invasive marker of autonomic function, has been proposed as a tool to predict AF risk, but its utility in off-pump CABG remains unclear. This study aimed to evaluate the predictive value of preoperative HRV parameters, including nonlinear metrics, for postoperative AF in patients undergoing off-pump CABG. Materials and Methods: We prospectively enrolled 67 patients undergoing elective off-pump CABG. HRV was assessed using 15 min high-resolution ECGs. Linear and nonlinear HRV parameters were analyzed. Postoperative AF was monitored through continuous ECG (days 0–4), daily 12-lead ECGs (days 5–7), and a 24 h Holter ECG on day 7. Statistical comparisons between AF and non-AF groups were performed, and the predictive accuracy was evaluated using ROC analysis. Results: Postoperative AF occurred in 40.3% (n = 27) of patients. Standard HRV measures (total power, frequency components, LF/HF ratio) did not differ significantly between groups. However, preoperative DFA Alpha 1 was significantly lower in patients who developed AF (p = 0.010) and showed the highest predictive value (AUC = 0.725, specificity = 80%). Alpha 1 also remained significantly reduced postoperatively in the AF group. Other nonlinear parameters, such as low and average fractal dimension, were also lower postoperatively in the AF group. Conclusions: Traditional HRV parameters showed limited predictive value for postoperative AF following off-pump CABG. The nonlinear DFA Alpha 1 index demonstrated a moderate predictive performance and may serve as a useful marker of autonomic dysregulation. Incorporating nonlinear HRV measures into preoperative assessment may improve AF risk stratification.