Background: There is limited data on the genetic characteristics of patients with familial hypercholesterolemia (FH) in Latvia. We aim to describe monogenic variants in patients from the Latvian Registry of FH (LRFH). Methods: Whole genome sequencing with 30× coverage was performed in unrelated index cases from the LRFH and the Genome Database of Latvian Population. LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, LIPA, LPA, CYP27A1, and APOE genes were analyzed. Only variants annotated as pathogenic (P) or likely pathogenic (LP) using the FH Variant Curation Expert Panel guidelines for LDLR and adaptations for APOB and PCSK9 were reported. Results: Among 163 patients, the mean highest documented LDL-cholesterol level was 7.47 ± 1.60 mmol/L, and 79.1% of patients had LDL-cholesterol ≥6.50 mmol/L. A total of 15 P/LP variants were found in 34 patients (diagnostic yield: 20.9%): 14 in the LDLR gene and 1 in the APOB gene. Additionally, 24, 54, and 13 VUS were detected in LDLR, APOB, and PCSK9, respectively. No P/LP variants were identified in the other tested genes. Conclusions: Despite the high clinical likelihood of FH, confirmed P/LP variants were detected in only 20.9% of patients in the Latvian cohort when assessed with genome-wide next generation sequencing.

Despite the implementation of next-generation sequencing-based genetic testing on patients with clinical familial hypercholesterolemia (FH), most cases lack complete genetic characterization. We aim to investigate the utility of the polygenic risk score (PRS) in specifying the genetic background of patients from the Latvian Registry of FH (LRFH). We analyzed the whole-genome sequencing (WGS) data of the clinically diagnosed FH patients (n = 339) and controls selected from the Latvian reference population (n = 515). Variant pathogenicity in FH patients was classified according to the ACMG/AMP guidelines. The low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (LPA) PRS were calculated based on the WGS data. We identified unique causative variants in 80 (23.6%) of the tested individuals (39 variants in FH genes and 4 variants in phenocopy genes, with 6 variants being novel). The LDL-C PRS was highly discriminative compared to the LPA PRS. Nevertheless, both PRS were able to explain the genetic cause of hypercholesterolemia in 26.3% of the remaining non-monogenic patients. The combined genetic analysis of monogenic and polygenic hypercholesterolemia resulted in 43.7% genetically explained hypercholesterolemia cases. Even though the application of PRS alone does not exclude monogenic testing in clinical FH patients, it is a valuable tool for diagnosis specification.

Background and Objectives: Pulmonary vein isolation (PVI) is an established rhythm control strategy for atrial fibrillation (AF). In many healthcare systems, increasing demand and limited procedural capacity have resulted in prolonged waiting times. The primary aim of this study was to evaluate the association between waiting time for PVI and AF progression. Secondary aims were to assess the relationship between waiting time and AF-related complications, healthcare utilization, and clinical factors associated with higher risk of progression. Materials and Methods: We performed a single-center observational cohort study of patients on the waiting list for PVI at Pauls Stradiņš Clinical University Hospital between 2016 and 2023. Results: A total of 341 patients completed structured ambulatory follow-up to assess the complication and progression rates of AF. The mean age was 64.8 ± 10.5 years, 50.9% were male, and the median waiting time was 37.2 months (IQR 15.0–61.3). AF progression occurred in 25.7% (n = 88) of patients, with longer waiting time independently associated with progression (OR, 1.017 per month; 95% CI, 1.006–1.028; p < 0.05). Electrical cardioversion during the waiting period was associated with a lower likelihood of progression (OR, 0.32; p = 0.029), and Class IC antiarrhythmic therapy was associated with reduced risk of AF progression (HR 0.78; p = 0.013). During follow-up, 45.2% of patients were hospitalized for AF paroxysms, 29.6% underwent electrical cardioversion, and 13.5% experienced complications including stroke and heart failure decompensation. Left atrial volume index and left ventricular ejection fraction were inversely correlated (ρ = −0.355, p < 0.05), but neither was associated with waiting time. Conclusions: Longer waiting times for PVI are associated with AF progression and substantial interim healthcare utilization due to complications. Strategies to prioritize higher-risk patients may help prevent disease progression and reduce complication burden.