INTRODUCTION:Rapid endothelialisation is crucial for developing hemocompatible vascular grafts for coronary artery disease. This bibliometric analysis maps the research landscape of endothelial cells and endothelialisation in tissue-engineered vascular grafts (TEVGs) to identify evolving trends and surgical relevance. METHODS:We analysed 1991 publications (2000-2024) from Web of Science using Bibliometrix, VOSviewer, and CiteSpace. Patent and clinical trial data were obtained from Lens.org and ClinicalTrials.gov. RESULTS:Publication output peaked in 2016 (119 articles), then declined post-2020. The United States led in volume (559 articles; 34,186 citations), while Singapore had the highest citation impact (119.9 average citations). Core themes included endothelialisation, angiogenesis, mesenchymal stem cells, and vascular endothelial growth factor. Early focus on prostheses and in vitro models declined, while 3D bioprinting, gelMA scaffolds, and surface modification emerged. Surface modification was identified as the primary research hotspot, with small-diameter TEVGs remaining the central translational focus. Patent activity decreased notably after 2016, and no clinical trials specifically linking TEVGs with endothelial cells were identified. CONCLUSION:Endothelialisation remains essential in TEVG research but is increasingly integrated into broader scaffold fabrication and validation strategies. The field is shifting toward biofabrication approaches like 3D bioprinting and functional evaluation platforms. However, significant translational gaps persist between laboratory research and clinical implementation.
INTRODUCTION:Calcification morphology is increasingly studied in coronary arteries but remains poorly characterized in the abdominal aorta. Whether morphology provides information beyond total calcium burden is unclear. We used micro-computed tomography (micro-CT) with near-histologic resolution to characterize abdominal aortic calcification morphology and evaluate its relationship with local lumen geometry. METHODS:Abdominal aortic specimens from 19 cadavers were imaged using micro-CT, yielding 26 lesions and 201 cross-sectional slices. Calcification was classified as concentric or eccentric based on circumferential arc. Measurements included calcium thickness, area, and arc, along with lumen area. Associations were assessed using linear mixed-effects models to account for clustering within lesions and specimens (effect estimates reported as β). RESULTS:Lumen area did not differ by morphologic classification. Greater calcium thickness (β [95% CI] = -10.076 [-16.539, -3.613]; p = 0.002), area (β = -0.403 [-0.803, -0.003]; p = 0.049), and arc (β = -0.080 [-0.138, -0.022]; p = 0.007) were each associated with smaller lumen area. In sensitivity analyses, associations for thickness and arc remained significant, whereas the association for area was attenuated. CONCLUSION:Quantitative morphologic features were inversely associated with lumen area, suggesting that calcification morphology may provide structural information beyond total calcium burden.
Introduction: Chronic limb-threatening ischemia (CLTI) carries high morbidity and mortality, yet risk stratification tools after revascularization remain limited. The Systemic Immune-Inflammation Index (SII) and Systemic Inflammatory Response Index (SIRI) have emerged as prognostic markers. This study evaluated their predictive value in CLTI patients undergoing revascularization. Methods: This retrospective single-center cohort study included 122 CLTI patients undergoing endovascular angioplasty (n = 81) or surgical bypass (n = 41) between 2017 and 2023. Pre-procedural SII and SIRI were calculated from blood counts. Outcomes included: overall survival, major adverse cardiovascular and limb events (MACE/MALE), and limb amputation. Kaplan-Meier analysis, Cox regression with Firth’s penalized likelihood adjustment, and C-index analyses were performed. Results: Surgical bypass was associated with longer median survival than angioplasty (48 vs. 27 months, p = 0.012). Patients in the lowest SII quartile (<492) had significantly improved 84-month survival versus higher quartiles (88.4% vs. 55.1%). Elevated SII remained independently associated with mortality on multivariable analysis. SIRI was higher among patients with adverse events (2.7 vs. 2.0, p = 0.024) but was not independently associated with outcomes. SII demonstrated moderate-to-high predictive performance, with C-indices up to 0.921 in the bypass subgroup. Conclusion: Pre-procedural SII is independently associated with survival following CLTI revascularization and may aid risk stratification.
INTRODUCTION:The comprehensive functionality of the cutaneous microcirculation extends beyond its barrier properties, implicating it in thermoregulation, nutrient exchange, and systemic disease pathophysiology. Our study aimed to investigate the sex- and strain-specific differences in cutaneous microvascular function and their relationships with systemic hemodynamics, skin physiology, and sex hormone-related metabolites in BALB/c, C57BL/6J, and KM mice. METHODS:We analyzed sex- and strain-specific cutaneous microhemodynamics to elucidate the impact of genetic and hormonal factors on microvascular function. Our multidimensional approach incorporated body mass, glycemic levels, cardiovascular profiles, along with histological and immunohistochemical analyses, flagging discernible sexual dimorphism and inter-strain variability. RESULTS:Immunohistochemical staining revealed significantly higher estrogen receptor expression within the male cutaneous microcirculation for BALB/c and C57BL/6J strains. Laser Doppler flowmetry and wavelet transform analysis revealed significant sex-specific and inter-strain differences in cutaneous microvascular blood perfusion, RBC concentration, and blood flow velocity. Sexual dimorphism was evident in the KM strain across all examined amplitudes, with males typically displaying greater variability. Similar wavelet statistical analysis results in microhemodynamic indicators suggest the homeostasis of specific frequency contributions. Furthermore, we observed significant correlations between systemic hemodynamics and cutaneous microcirculatory function, with heart rate and blood pressure variably associated with microvascular flow, erythrocyte concentration, and blood perfusion dynamics across strains and sexes. CONCLUSION:These findings indicate the complexities of cutaneous microhemodynamics, emphasizing the interplay between genetic lineage and sex-based differences.
Introduction: We aimed to investigate the effect of different exercise modes on retinal microvascular endothelial function in patients with HF with preserved ejection fraction (HFpEF). Methods: Twenty-eight patients were randomly allocated to either a moderate (MCT) or high-intensity interval training (HIIT) group for 12 weeks. Retinal microvascular structure and function were investigated by analyzing central retinal arteriolar (CRAE) and venular (CRVE) diameter equivalents, the arteriolar-to-venular diameter ratio (AVR), and the dynamic arteriolar (aFID) and venular (vFID) flicker light-induced dilation response. Results: Twenty patients (mean age 70 ± 9 years) were included in the final analysis. After HIIT, AVR increased (0.80 ± 0.03 vs. 0.83 ± 0.04, p = 0.03) due to arteriolar widening. CRAE increased (157 ± 18 µm vs. 164 ± 18 µm, p = 0.05), but CRVE did not change (196 ± 27 µm vs. 197 ± 24 µm, p = 0.56). After MCT, AVR also increased (0.80 ± 0.08 vs. 0.83 ± 0.06, p = 0.02) without significant changes in CRAE (160 ± 19 µm vs. 165 ± 18 µm, p = 0.07) or CRVE (201 ± 14 µm vs. 199 ± 14 µm, p = 0.40). aFID improved after MCT (2.1 ± 1.6% vs. 3.1 ± 1.8%, p = 0.03) but not after the HIIT intervention (2.1 ± 1.7% vs. 2.4 ± 2.1%, p = 0.60). vFID did not statistically significant change neither in the HIIT (4.4 ± 2.2% vs. 3.4 ± 1.9%, p = 0.06) nor in the MCT (4.3 ± 2.2% vs. 5.5 ± 4.1%, p = 0.26) group. Conclusion: MCT and HIIT are both adequate therapy options to improve microvascular health in patients with HFpEF.
BACKGROUND AND AIMS:The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS:In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS:Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS:The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.
BACKGROUND AND AIMS:Low-dose mineralocorticoid receptor antagonists (MRAs) are guideline-recommended heart failure (HF) therapies. However, MRAs increase aldosterone production, and the sub-saturating doses utilized may allow continued mineralocorticoid receptor (MR) stimulation. The aim of the current analysis was to understand how baseline and change in aldosterone concentrations during MRA therapy impacts MR activity and clinical outcomes. METHODS:HF cohorts with MRA exposure and plasma aldosterone concentrations available were included in patient-level, pooled cohort analyses [DOSE, CARRESS-HF, MDR, and TOPCAT (n = 1019)]. In the MDR cohort (n = 136), urine sodium to potassium ratio was utilized to quantitate MR activity. The relationship of pre-MRA aldosterone concentration, MRA use, and clinical outcomes were meta-analysed utilizing the above pooled cohorts in addition to the EARLIER (n = 300) and EPHESUS (n = 453) trials. RESULTS:MRA use was associated with significantly higher median aldosterone concentrations [MRA = 310 (interquartile range, IQR 180, 533) pg/mL vs no MRA = 174 (IQR 106, 299) pg/mL, P < .001] in the pooled cohort. In the MDR cohort, higher aldosterone was correlated with higher MR activity, with a similar relationship on MRA (r = -.52, P < .001) vs off MRA (r = -.44, P < .001, P interaction = .65), differing only in that higher aldosterone concentrations were required on MRA to achieve the same level of MR activity. In patients with high pre-MRA aldosterone, new MRA initiation reduced MR activity, but MRA initiation increased MR activity in patients with low pre-MRA aldosterone [median change in urine Na/K with high aldosterone =1.4 (IQR 1.1, 2.9) vs low aldosterone = -.9 (IQR -2.1, -.1), P < .001]. In the pooled cohort, the association between MRA use and clinical outcomes was dependent on pre-MRA aldosterone concentration (P interaction = .005). In patients with high pre-MRA aldosterone, MRA was associated with substantially improved clinical outcomes [hazard ratio (HR) .63, 95% confidence interval (CI) .42-.92, P = .02]. However, in patients with low pre-MRA aldosterone, MRA use was associated with worse clinical outcomes (HR 1.66, 95% CI 1.12-2.45, P = .01). CONCLUSIONS:Low-dose MRAs significantly increase aldosterone but inadequately block MR activity (measured by urine Na/K) at these new higher aldosterone concentrations. In patients with high pre-MRA aldosterone, MRA use is associated with improved MR activity and clinical outcomes. However, in patients with lower pre-MRA aldosterone concentrations, MRA use is associated with worsened MR activity and clinical outcomes. MRAs remain guideline-directed HF medications with established population level benefit, but these hypothesis-generating findings indicate additional research is warranted to understand if outcomes can be further improved.
BACKGROUND AND AIMS:Familial hypercholesterolaemia (FH) leads to life-long exposure to high low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease. Evidence supporting initiation of cholesterol-lowering medication (CLM) in childhood to lower this cumulative cholesterol burden and cardiovascular sequelae is sparse. This study assessed the long-term impact of contemporary management of FH on LDL-C and cardiovascular events. METHODS:Observational prospective cohort study (SAFEHEART) including children/adolescents (age <18 years) with genetically confirmed heterozygous FH (FH-Ch), their non-affected children and adolescents' relatives (non-FH-Ch), and FH parents (FH-P). Impact of CLM, LDL-C burden, and cardiovascular events were assessed. RESULTS:Overall, 348 FH-Ch, 165 non-FH-Ch and 288 FH-P were included (49.8% female; median untreated LDL-C: 5.46, 2.63, and 7.19 mmol/L, respectively). Median follow-up was 12.4 years (interquartile range 9.6-15.3). At follow-up, 84.5% FH-Ch, 4.2% non-FH-Ch, and 95.1% FH-P were receiving CLM. FH-Ch started therapy at a median age of 14.5, vs. 36.1 years in their FH-P. Latest on-treatment LDL-C was 3.00 mmol/L in FH-Ch (median change: -2.60 mmol/L, -47.4%) and 2.44 mmol/L in FH-P (-4.72 mmol/L, -67.6%); LDL-C among non-FH-Ch (not on CLM) was 2.72 mmol/L. By age 30-40 years, median LDL-C burden over life was 5909.0 and 10 206.8 mg/dL*years among FH-Ch and FH-P, respectively. By age 39 years, rate of cardiovascular events was 0.0%, 0.3% and 5.2% among non-FH-Ch, FH-Ch, and FH-P, respectively. CONCLUSIONS:Treatment of FH from childhood/adolescence reduces the cumulative LDL-C burden compared with later onset treatment from adulthood in affected parents and permits attainment of LDL-C levels close to non-FH individuals; this finding was associated with the observation of a reduction in the cardiovascular risk of young FH patients. These findings support FH as a paediatric condition requiring early-life detection and treatment. STUDY REGISTRATION NUMBER:ClinicalTrials.gov, NCT02693548.
BACKGROUND:Intracranial aneurysms, spontaneous coronary artery dissection, and fibromuscular dysplasia are significantly more common in women than in men, but the cause of these diseases and the cause of the predominance in women are unknown. It is also unclear whether and how genetic factors (genetic disposition or genetic pleiotropy) can influence the development of these diseases. A literature search in PubMed was conducted to identify the causes of the three arterial diseases. Particular attention was paid to the hemodynamic load on the arteries. SUMMARY:The imbalance of body fluids in pregnancy, menstruation, and premenstrual syndrome contributes to structural changes in the arterial wall and can promote arterial diseases. KEY MESSAGES:Increase in blood volume, high blood flow velocity, and edema of the vessel wall are factors that contribute to arterial diseases and can explain the predominance of some arterial diseases in women. These hemodynamic factors are to be distinguished from genetic causes, arteriosclerosis, or inflammatory diseases.
INTRODUCTION:Chronic venous disease (CVD) is characterized by progressive venous wall remodeling, extracellular matrix dysregulation, and chronic inflammation. MicroRNAs (miRNAs) regulate vascular processes, but their expression in human venous tissue across disease stages remains incompletely defined. We evaluated global miRNA expression in great saphenous veins across CVD severity. METHODS:In this cross-sectional pilot study, paraffin-embedded vein samples were obtained from patients with CVD and classified according to CEAP criteria into early-stage (C2-C3; G1) and advanced-stage (C4-C5; G2). Vein segments from patients without venous reflux undergoing arterial revascularization served as controls. Global miRNA expression profiling was performed using the GeneChip® miRNA 4.0 Array with multiple-testing correction. Direct statistical comparison between G1 and G2 was not performed. RESULTS:Twenty-seven samples were analyzed (6 controls, 12 G1, 9 G2). A total of 155 miRNAs were significantly dysregulated in CVD compared with controls. Most miRNAs were detected in both G1 and G2 comparisons, whereas 36 were identified only in the G1 vs. control comparison and two (hsa-miR-7977 and hsa-miR-23a-5p) only in the G2 vs. control comparison. CONCLUSION:miRNA profiling suggests stage-associated expression patterns in human saphenous veins, indicating early molecular remodeling during CVD progression. These findings are exploratory and require independent validation.
BACKGROUND AND AIMS:Adults with congenital heart disease tend to develop both cardiac and noncardiac age-related comorbidities earlier in life than the general population, suggesting accelerated biological ageing. Epigenetic clocks estimate biological age based on DNA methylation profiles. This study investigated whether adults with congenital heart disease display accelerated epigenetic ageing and whether the degree of age acceleration relates to disease complexity. METHODS:A total of 120 patients with congenital heart disease (age 29-50 years, 58 females) and 120 age- and sex-matched healthy controls were included. Patients were divided into simple, moderate, and complex disease complexity groups (n = 40 per group). Epigenetic age was estimated using the Horvath, Hannum, Zhang, GrimAge2, and PhenoAge clocks, whereas the pace of ageing was assessed using DunedinPACE. RESULTS:Compared to healthy controls, patients with moderate and complex congenital heart disease exhibit significant age acceleration with PhenoAge (+3.0 years, P = .019; +5.5 years, P < .001) and GrimAge2 (+2.1 years, P = .045; +2.3 years, P = .022) and a higher pace of ageing (P = .008 and P = .016, respectively). No significant differences were detected between healthy controls and patients with simple disease. CONCLUSIONS:Accelerated epigenetic ageing is observed in adults with moderate and complex congenital heart disease, while individuals with simple disease show ageing patterns comparable to healthy peers. These findings provide biological evidence of premature ageing in congenital heart disease and suggest a lifelong systemic vulnerability. Integrating biological ageing metrics into follow-up strategies may enable earlier detection of age-related complications and support interventions to preserve long-term healthspan.
BACKGROUND AND AIMS:Frailty is associated with cardiovascular disease (CVD) through shared pathophysiology and risk factors, and frailty is a known modifiable risk factor for CVD. Statins reduce CVD risk and have anti-inflammatory properties that may lower the risk of frailty, though this has not been comprehensively examined. METHODS:Older US veterans (aged ≥67 years) who were statin naïve and received regular care in the Veteran Affairs (VA) medical system from 2002 to 2018 were included. Veterans who were frail at baseline based on a validated 31-item VA-Frailty Index (VA-FI) were excluded (scores >0.2). Data were linked to Medicare and Medicaid. Overlap propensity score weighting (PSW) was used to address confounding by indication. Cox regression models were fit to examine the association of statin use with the composite outcome of incident frailty with censoring at death. Similar analyses were conducted on pre-frail veterans (VA-FI score of 0.1-0.2). RESULTS:Of 987 301 veterans included in the study population (age 72 ± 6 years; 98% men; 87% white), 290 729 initiated statins during the study period. During a mean follow-up of 5.3 (SD 4.1) years, 636 195 incident frailty events occurred, representing unadjusted event rates of 153.1 events per 1000 person-years among statin initiators and 111.4 events per 1000 person-years in non-initiators. After PSW, new statin initiators were less likely to experience incident frailty (hazard ratio 0.76, 95% confidence interval 0.75-0.76) compared to non-initiators. Similar results were seen in pre-frail veterans. CONCLUSIONS:Statin initiation was associated with a significantly lower risk of incident frailty or death among older US veterans including those who were pre-frail at baseline.
BACKGROUND AND AIMS:The 2021 ESC guidelines on cardiovascular (CV) disease prevention recommend the SMART-REACH lifetime risk model to guide treatment decisions in patients with established atherosclerotic CV disease. The aim was to develop the SMART-REACH2 model for estimating lifetime risk of recurrent CV events and treatment benefits in patients with established atherosclerotic CV disease, with systematic recalibration to the four European and other global risk regions. METHODS:SMART-REACH2 was derived in 8708 individuals aged 40-90 years with coronary, cerebrovascular, peripheral artery disease and/or abdominal aortic aneurysm from the UCC-SMART cohort. Sex-stratified, cause-specific Cox models for recurrent CV events and non-CV death were fitted using age as timescale and routinely available predictors. Recurrent CV events were defined as a composite of myocardial infarction, stroke, or CV death. Recalibration was based on representative cohorts per risk region. External validation was performed in 2 085 780 patients from 54 countries; model performance was assessed by calibration plots and Harrell's C-statistic. RESULTS:In the derivation cohort, 2057 recurrent CV events occurred over a median follow-up of 8.5 years (25th-75th: 4.3-13.0). In external validation, 307 706 events occurred. The pooled C-statistic was 0.68 (95% confidence interval 0.66-0.69) and ranged from 0.66 (0.64-0.69) for European low-risk region up to 0.72 (0.66-0.78) for Latin America, with adequate calibration across risk regions. Performance was consistent across sexes and CV disease subtypes. Using SMART-REACH2, estimated potential gains in CV disease-free life expectancy for a 50-year-old example patient receiving intensified preventive treatment (15 mmHg systolic blood pressure and 1.0 mmol/L low-density lipoprotein cholesterol reduction) ranged from 2 years in the low-risk region to 4.4 years in the very-high-risk region. CONCLUSIONS:The updated SMART-REACH2 model accounts for geographical and sex-specific variations and allows estimation of short-term and lifetime risk of recurrent CV events and treatment benefits, facilitating shared decision-making as recommended by guidelines.
BACKGROUND AND AIMS:Atherosclerosis (AS) and abdominal aortic aneurysm (AAA) are both metabolism-associated vascular diseases, yet the role of lipid metabolic disturbances in their pathogenesis remains largely unknown. This study aimed to clarify the differential impact of lipid metabolic disturbances and their underlying mechanisms in AS and AAA. METHODS:Lipidomic analysis was performed to identify lipid metabolic differences between AS and AAA in various mouse models and different human cohorts. A multi-omics approach, integrated with functional assays, was utilized to elucidate the downstream mechanisms underlying disease-specific lipid metabolic features. Machine learning models were developed based on lipidomic features to differentiate AS from AAA. RESULTS:Lipidomic analysis of mouse models and human samples revealed a predominant enrichment of neutral lipids (e.g. triglycerides and cholesterol esters) in AS, in contrast to phosphoglycerides in AAA. Consistently, large-scale longitudinal data from the UK Biobank showed strong positive associations of triglycerides, cholesterol, and fatty acid with the future risk of coronary atherosclerotic disease, while phosphoglycerides were negatively associated with the risk of AAA. Integrated transcriptomic and metabolomic analyses identified fatty acid metabolism, particularly Acadm-mediated fatty acid β-oxidation (FAO) pathway, as the most significantly altered lipid metabolic pathway contributing to the lipid metabolic differences between AS and AAA. Consistently, targeted restoration of the Acadm-mediated FAO pathway inhibited AS by reducing lipotoxic metabolites and preserving mitochondrial homeostasis but had little impact on AAA. Further validation with lipid droplets autophagy-tethering compound (LD·ATTEC), which selectively eliminates intracellular lipid droplets, significantly alleviated AS progression and improved FAO with no significant change observed in AAA. Finally, predictive models were developed based on lipidomic features using machine learning algorithms, facilitating accurate differentiation between these two vascular diseases. CONCLUSIONS:These findings define previously unrecognized distinct lipid metabolic characteristics in the pathogenesis of AS vs AAA, providing a basis for differential diagnosis and targeted treatments.
BACKGROUND AND AIMS:Lipoprotein(a) (Lp(a)) is considered a causal risk factor for atherogenesis. A higher prevalence of certain adverse events, including diabetes mellitus (DM), has been reported for patients with low Lp(a) concentrations. Therapeutics that lower Lp(a) are now in clinical testing. Thus, the association between lower Lp(a) concentration and safety outcomes is of clinical importance. METHODS:The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized 27 564 patients with stable atherosclerotic cardiovascular disease (ASCVD) to evolocumab versus placebo on a background of statin therapy. The relationship between Lp(a) and the risk of prevalent and incident adverse outcomes of interest was examined, adjusting for relevant predictors. RESULTS:Lp(a) was assessed in 25 090 participants at baseline (median 37 nmol/L, interquartile range 13-165). There was no association between Lp(a) concentration and incident risk of haemorrhagic stroke, serious bleeding, neurocognitive events, malignancy, or atrial fibrillation, including those with Lp(a) levels ≤13 nmol/L. There was an inverse association between lower baseline Lp(a) levels and prevalent DM at baseline (adjusted odds ratio 1.03, 95% confidence interval [CI] 1.02-1.04, P < .001; for every 50 nmol/L lower Lp(a)), as well as the incident risk of developing DM during follow-up (adjusted hazard ratio [HR] 1.05, 95% CI 1.02-1.08, P = .002; for every 50 nmol/L lower Lp(a)), with consistent results by treatment arm. Evolocumab did not increase the risk of DM irrespective of baseline Lp(a), even in participants in the top decile of baseline Lp(a) (adjusted HR .72, 95% CI .38-1.35) in whom evolocumab reduced Lp(a) by a median of 71 nmol/L. CONCLUSIONS:In patients with ASCVD, low Lp(a) concentration was not associated with an increased risk of most adverse safety outcomes, but lower Lp(a) was associated with an increased risk of prevalent and incident DM.
BACKGROUND AND AIMS:Calcific aortic valve disease (CAVD) culminates in severe aortic stenosis, currently lacking pharmacological treatment. Intra-leaflet haemorrhage-induced iron overload promotes valvular ferroptosis. This study identifies a druggable ferroptosis pathway and validates its translational relevance across large-scale population cohorts. METHODS:Bulk- and single-cell transcriptomics, whole-mount histology, immunohistochemistry, and primary human valvular interstitial cell (VIC) models of 212 aortic valves from surgical patients were integrated for mechanistic insights. In vivo, valvular ferroptosis and thickness were assessed in a doxorubicin-induced ferroptosis mice model, and a wire injury model with ferroptosis inhibition was utilized to evaluate remodelling and haemodynamic obstruction. A total of 4874 participants of the Swedish CArdioPulmonary bioImage Study (SCAPIS) underwent cardiac computed tomography for aortic valve calcification determination and 273 550 individuals from the UK Biobank were followed for aortic stenosis incidence. RESULTS:Intra-leaflet haemorrhage was prevalent in calcified aortic valves and correlated positively with calcification and circulating ferroptosis biomarker. Bulk transcriptomics and single-cell RNA sequencing identified lipid peroxidation as the dominating valvular ferroptosis pathway centred on arachidonate 5-lipoxygenase (ALOX5). Inducing ferroptosis in VIC triggered lipid peroxidation and calcification while reducing viability, which were reversed by targeting the ALOX5-ACSL4 axis. In vivo, doxorubicin-induced valvular ferroptosis exacerbated valvular thickening in apoE-/- mice through ALOX5-ACSL4 upregulation. ALOX5 inhibition reduced valve thickness and haemodynamically improved valve function in the wire injury model. Arachidonic acid levels independently predicted aortic valve calcification and incident aortic stenosis in SCAPIS and UK Biobank, respectively, and positively correlated with circulating ferroptotic marker. CONCLUSIONS:These findings establish the ALOX5-ACSL4 axis as a critical mediator of ferroptosis in CAVD and promising repurposing target for clinical intervention.
BACKGROUND AND AIMS:Standard modifiable risk factors (SMuRFs), including hypertension, diabetes, hyperlipidaemia, and smoking, are prevalent among patients undergoing percutaneous coronary intervention (PCI). This study aimed to assess the prevalence and impact of controlled SMuRFs in patients undergoing PCI. METHODS:Data of patients who underwent PCI at a single tertiary-care centre between 2012 and 2023 were analysed. SMuRF control was assessed using pre-procedural measurements: systolic blood pressure <140 mmHg, fasting glucose <126 mg/dL or a haemoglobin A1c < 7%, low-density lipoprotein <100 mg/dL, and smoking status (non-smoker). Patients were stratified by the number of controlled risk factors (CRF): 4, 3, 2, and ≤1. The primary outcome was major adverse cardiovascular events (MACE), a composite of all-cause mortality, myocardial infarction, and stroke, at one-year post-PCI. RESULTS:Among 19 651 patients, 5876 (29.9%) had 4-CRF, 8199 (41.7%) had 3-CRF, 4415 (22.5%) had 2-CRF, and 1161 (5.9%) had ≤1-CRF. Compared with 4-CRF, the risk for MACE increased progressively with fewer controlled risk factors (3-CRF: adjHR 1.17, 95% CI 0.98-1.40; 2-CRF: adjHR 1.39, 95% CI 1.14-1.69; ≤1-CRF: adjHR 1.48, 95% CI 1.10-2.00). Glycaemic control had the most significant association with lower MACE (adjHR 0.56, 95% CI 0.49-0.65). CONCLUSIONS:Comprehensive SMuRF control before PCI remains infrequent, though it is associated with lower MACE rates. Prioritizing glycaemic control may yield the greatest benefit in improving post-PCI prognosis.
Background and Aims Cardiac fibroblast (CF) activation in response to injury or inflammation is a central driver of pathological cardiac fibrosis, contributing to arrhythmias and heart failure. As previously demonstrated, intermittent hypoxia (IH), the hallmark pathophysiological feature of obstructive sleep apnoea (OSA), induces cardiac fibrosis. However, the mechanisms by which IH promotes CF activation and the key molecular mediators involved remain unclear.Methods Single-cell RNA sequencing (scRNA-seq) was performed on heart tissue from IH-exposed mice to characterize CF populations. Mice with myofibroblast-specific GLI1 overexpression or knockout were generated to evaluate the role of GLI1 in cardiac fibrosis under normoxic and IH conditions. Integrated RNA sequencing and ChIP sequencing were used to identify potential GLI1 target genes. The therapeutic effects of pharmacological GLI1 inhibition on CF activation and cardiac fibrosis were assessed.Results scRNA-seq revealed that Hedgehog signalling is activated in CFs during IH-induced cardiac fibrosis. IH promoted GLI1 nuclear translocation and increased its expression in CFs. GLI1 overexpression recapitulated the effects of IH, inducing CF activation and spontaneous cardiac fibrosis. Conversely, both genetic deletion and pharmacological inhibition of GLI1 attenuated IH-induced CF activation and cardiac dysfunction. Mechanistically, enhanced glycolysis was identified as a downstream effector of GLI1- and IH-induced fibrosis, with PKM2 identified as a direct transcriptional target of GLI1. Finally, a positive association of elevated plasma lactate concentration with a higher cumulative incidence of heart failure events was observed in 1509 patients with OSA.Conclusions GLI1 is a critical pro-fibrotic transcription factor mediating IH-induced CF activation and cardiac fibrosis. Targeting GLI1 may offer a promising therapeutic strategy for the treatment of cardiac fibrosis, particularly in patients with OSA.
BACKGROUND AND AIMS:Introduction of the three-vessel trachea view to the second trimester foetal anomaly screening programme increased detection of right (RAA) and double (DAA) aortic arch. Aim was to investigate incidence, associations, and medium-term outcome of RAA/DAA. METHODS:Retrospective, population-based, multicentre, observational study of foetuses diagnosed with RAA/DAA between 1 April 2015 and 31 March 2019. All cardiology units in England, Scotland and Wales participated. Foetuses with major congenital heart disease were excluded. RESULTS:Overall, 1046 foetuses were diagnosed with RAA (n = 898, 85.9%) or DAA (n = 141, 13.5%), uncategorized in seven (0.6%). Estimated incidence of RAA and DAA was 17.98 and 4.58 per 10 000 pregnancies screened/year (0.23%). Nine hundred forty cases (89.9%) were isolated, with prenatal extracardiac anomaly (ECA) and/or minor cardiac difference in the remainder. Genetic results were abnormal in 80 of 1046 (7.6%): 22q11.2 microdeletion (n = 28, 35%). Prenatal ECAs increased the risk of genetic anomaly (risk ratio 3.39, 95% confidence interval 1.89-5.73, P < .0001). Nine hundred eighty six (94.3%) were liveborn, while five died postnatally from unrelated problems. Mean follow-up is 4.1 years (standard deviation 1.4), and symptoms of tracheoesophageal compression were found in 278 of 986 (28.2%). Vascular ring relief was performed in 234 of 986 liveborn (23.7%) with no deaths. There was variation in management pathways. Surgery was performed in 74.6% with DAA, 24.4% with RAA-left arterial duct (LAD)-aberrant left subclavian artery (ALSA); median age at surgery was 5.29 months [interquartile range (IQR): 2.99-11.26 months] and 12.62 months (IQR: 8.68-17.32 months), respectively (P < .0001). CONCLUSION:Incidence of RAA/DAA is higher than previously reported. Genetic anomaly is identified in at least 7.6%, particularly in the presence of ECA. Liveborn with DAA have earlier and more surgical intervention compared to those with RAA-LAD-ALSA.
BACKGROUND AND AIMS:It remains unclear what the safe serum potassium range is in heart failure (HF) and whether it is the same in HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). METHODS:A patient-level pooled analysis from 12 randomized controlled trials including 32 346 HFrEF and 13 723 HFpEF patients was performed. Baseline serum potassium level was categorized into six groups (<3.5, ≥3.5-<4.0, ≥4.0-<4.5, ≥4.5-<5.0, ≥5.0-<5.5, and ≥5.5 mmol/L) and serum potassium level at baseline was also analysed as a continuous variable using restricted cubic splines. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, sudden death, pump failure death, first HF hospitalization, and composites of HF hospitalization and cardiovascular or all-cause death. RESULTS:The median follow-up was 24.2 and 36.8 months in HFrEF and HFpEF trials, respectively. In HFrEF, serum potassium levels showed a reverse J-shaped association with outcomes. Compared with ≥4.0-4.5 mmol/L (reference), potassium <3.5 mmol/L was associated with higher risks of all-cause mortality (adjusted hazard ratio 1.49; 95% confidence interval, 1.27-1.76), as well as cardiovascular, sudden, and pump failure death. The lowest risk for all outcomes was observed within the baseline serum potassium range of 4.2-5.0 mmol/L, but even 'mild hyperkalaemia' (5.0-5.5 mmol/L) was not associated with worse outcomes in HFrEF. Although the risk curve was U-shaped and flatter in HFpEF, the lowest incidence of all outcomes was observed over the same potassium range as HFrEF. CONCLUSION:In HFrEF, hypokalaemia is strongly associated with worse outcomes and should be avoided. In terms of safety, the optimal serum potassium concentration in both HFrEF and HFpEF appears to be in the range 4.2-5.0 mmol/L.
