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 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.
BACKGROUND AND AIMS:Adults with repaired tetralogy of Fallot (TOF) face long-term risks of ventricular tachycardia (VT) and sudden cardiac death (SCD). There is no consensus on arrhythmia management during surgical pulmonary valve replacement (PVR). This study assessed whether pre-operative electrophysiological (EP) testing with targeted intraoperative cryoablation of identified anatomical isthmuses during PVR is associated with a reduction in post-operative VT inducibility and long-term risk of clinical VT/SCD. METHODS:In this prospective multicentre cohort study, consecutive adults with TOF undergoing surgical PVR (2005-22) underwent standardized pre-operative EP studies. Surgical ablation strategy (EP-guided vs empiric) was at the discretion of the treating team. Post-operative EP studies assessed residual inducibility; clinical VT/SCD were evaluated during follow-up. RESULTS:Among 204 patients (age 35.5 ± 13.1 years, 43.1% female), 91 (45.1%) had inducible VT. Among those undergoing surgical ablation, post-operative VT was non-inducible in 74.1% with EP-guided vs 15.0% with empiric ablation [adjusted odds ratio 20.4, 95% confidence interval (CI) 4.5-91.8, P < .0001]. Persistent post-operative inducibility was associated with increased hazard of VT/SCD compared to patients without inducible VT pre-operatively [adjusted hazard ratio (HR) 5.3, 95% CI 1.8-16.0, P = .003], over a median 10.2-year follow-up. Compared to patients without inducible VT pre-operatively, empiric ablation was associated with a significantly higher hazard of VT/SCD (HR 5.2, 95% CI 1.6-16.5, P = .005), whereas EP-guided ablation was not (HR 2.8, 95% CI 0.8-10.3, P = .228). CONCLUSIONS:In adults with repaired TOF undergoing PVR, inducible VT is common. An EP-guided surgical strategy is associated with greater post-operative non-inducibility and improved long-term arrhythmic outcomes compared with empiric ablation.
BACKGROUND AND AIMS:Evidence linking arrhythmias to dementia predominantly focuses on atrial fibrillation/flutter (AF), leaving non-AF subtypes under-researched. This study investigated associations of multiple incident and accumulated arrhythmia exposures with dementia and brain magnetic resonance imaging (MRI) to address these gaps. METHODS:UK Biobank participants without baseline arrhythmias, dementia, or organic central nervous system diseases were included. Cox models estimated associations of incident arrhythmia (AR), AF, bradyarrhythmia/conduction block (Brady/Block), ventricular arrhythmia (VA), and accumulated arrhythmia exposure (types) with all-cause, vascular and Alzheimer's dementia. Specific subtypes-including atrioventricular block (AVB), sinus node dysfunction (SND), and bundle branch block (BBB)-were also evaluated. Arrhythmia-related brain MRI alterations were analysed. RESULTS:Among 391 078 participants (median follow-up 13.35 years), 50 243 (12.85%) developed incident AR (AF, n = 33 182; Brady/Block, n = 21 244; VA, n = 6296), and 10 564 (2.70%) developed all-cause dementia (vascular, n = 2034; Alzheimer, n = 4329). Incident AR, AF, Brady/Block, and VA were independently associated with increased risk of all dementia outcomes (fully adjusted Model 3). Accumulated arrhythmia exposure exhibited a positive dose-response relationship with dementia risk, driven largely by AF+Brady/Block. Concurrent AF and AVB/SND (or BBB) showed higher dementia risk than either exposure alone, whereas pacemaker implantation related to lower risk than AVB/SND without pacing. These associations remained robust to incident stroke or cardiac arrest, genetic dementia risk, baseline cognition, and sensitivity analyses. Non-AF arrhythmias provided incremental predictive value beyond conventional risk factors, similar to AF. Brain MRI analysis revealed arrhythmia-related neurodegenerative changes, including brain atrophy, choroid-plexus enlargement, and white-matter injury. CONCLUSIONS:Incident arrhythmias (both AF and non-AF) exhibit independent and accumulated associations with dementia risk and consistent neurodegeneration. These findings extend the arrhythmia-dementia association beyond AF and suggest multi-arrhythmic framework for dementia risk assessment.
Background and Aims Chimeric antigen receptor T-cell (CAR-T) therapies are cellular immunotherapies that improve survival in patients with relapsed haematologic malignancies. However, their association with major adverse cardiovascular events (MACE) has received limited study, particularly in older adults. This study investigated the incidence of MACE, associated risk factors, and their impact on survival among older patients undergoing CAR-T in the USA.Methods Medicare fee-for-service beneficiaries over 65 who received inpatient CAR-T therapy between 2018 and 2023 were included. Baseline characteristics were assessed during the 12 months preceding CAR-T. MACE were defined as a composite of acute heart failure (HF), cardiogenic shock, myocardial infarction, cardiac tamponade, ventricular arrhythmia, complete heart block, or stroke. Multivariable models were adjusted for demographics, malignancy type, and baseline cardiovascular comorbidities.Results Among 3292 patients receiving CAR-T, 191 (5.8%) had MACE. Most common events were acute HF (3.1%), followed by ischaemic (1.3%) and haemorrhagic stroke (1%). Pre-treatment atrial fibrillation/flutter [adjusted odds ratio (aOR) 1.52 (1.08-2.16)], cardiomyopathy [aOR 2.49 (1.75-3.54)], and cerebrovascular disease [aOR 2.40 (1.30-4.43)] were independently associated with MACE. In 2021-23, MACE were also associated with immune effector cell-associated neurotoxicity syndrome and higher-grade cytokine release syndrome. MACE were associated with higher in-hospital mortality [aOR 16.9 (11.0-26.1)] and 1-year mortality after discharge [adjusted hazard ratio 1.91 (1.46-2.49)].Conclusions In the largest national sample of older adults receiving CAR-T, MACE occurred in 5.8% of patients and were associated with increased in-hospital and 1-year mortality. Further investigation into preventive and mitigating measures is needed.
BACKGROUND AND AIMS:After acute coronary syndrome (ACS), high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) levels have been associated with risk of major adverse cardiovascular events (MACE). Whether the prognostic information provided by hsCRP and IL-6 is independent and complementary after ACS is unclear. METHODS:The ODYSSEY OUTCOMES trial compared alirocumab with placebo in post-ACS patients on optimized statin therapy. In post hoc analyses, the relation between log-transformed hsCRP and IL-6 levels and risk of MACE and all-cause death was assessed in proportional hazards models. RESULTS:A total of 11 817 patients had baseline hsCRP and IL-6 data; 1306 had a MACE primary endpoint and 458 died. Median hsCRP, IL-6, and low-density lipoprotein cholesterol (LDL-C) were 1.54 mg/L, 5.00 pg/ml, and 86 mg/dl, respectively. hsCRP and IL-6 had moderate correlation (r = 0.52). In models for one biomarker adjusted for the other biomarker, treatment assignment, age, sex, diabetes, LDL-C, and time since index ACS, hsCRP was a significant independent predictor of MACE (P < .0001) and IL-6 was not (P = .21); both independently predicted death (P < .0001 for hsCRP and P = .0003 for IL-6). Relationships did not depend on treatment (all Pinteraction > .25). When dichotomized at 2 mg/L (hsCRP) and 5 pg/ml (IL-6), risks of MACE and death were significantly elevated when both, but not when one marker was elevated. CONCLUSIONS:In patients with recent ACS, hsCRP independently predicted MACE, while both hsCRP and IL-6 predicted death. Together, the two markers provided complementary prognostic information. hsCRP conveys independent information on inflammatory risk beyond that provided by IL-6.
BACKGROUND AND AIMS:In patients with myocardial infarction (MI), no heart failure, and left ventricular ejection fraction (LVEF) ≥ 40%, the combined BETAMI-DANBLOCK trial showed that beta-blockers reduced the risk of all-cause mortality or major adverse cardiovascular events. This study evaluated the representativeness of the trial. METHODS:Participants in BETAMI (n = 2867) and DANBLOCK (n = 2707) were compared with a cohort of revascularized MI patients with LVEF ≥40%, and no heart failure from the Norwegian Myocardial Infarction Registry (the NORMI cohort)(n = 20 804). Baseline characteristics were evaluated, and absolute risks of all-cause mortality and/or MI were estimated. A transportability analysis was conducted by weighting the BETAMI-DANBLOCK population according to the NORMI cohort. RESULTS:Median age was 66 years (interquartile range [IQR]: 57-74) in the NORMI cohort and 63 years (IQR: 55-70) in BETAMI and DANBLOCK. Patients in the NORMI cohort had a higher prevalence of diabetes, previous coronary artery disease, and LVEF 40-49%, compared with trial participants. At 3-year follow-up, the absolute risk of all-cause mortality or MI was 12.0% in the NORMI cohort, 7.7% in BETAMI, and 7.8% in DANBLOCK. Corresponding risks of MI were 6.3%, 5.6%, and 4.3%, respectively. The treatment effects of beta-blockers were similar when the trial population was weighted according to the characteristics of the NORMI cohort. CONCLUSIONS:Compared with the NORMI cohort, participants in BETAMI and DANBLOCK were younger, had a lower proportion of certain comorbidities, and experienced a lower risk of all-cause mortality and MI. Despite these differences, the effect of beta-blockers remained consistent when the trial population was weighted according to the NORMI cohort.
BACKGROUND AND AIMS:There is interest in developing lipoprotein(a) [Lp(a)] lowering therapies. Cholesteryl ester transfer protein inhibitors lower Lp(a), however the effects of the selective inhibitor obicetrapib on Lp(a) levels in high cardiovascular risk patients have not been fully elucidated. This analysis investigated the effect of obicetrapib on Lp(a). METHODS:A pooled analysis of trials evaluating the 12-week lipid effects of daily obicetrapib 10 mg compared with placebo in patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) investigated the effect of obicetrapib on Lp(a) levels. RESULTS:In 2356 patients, the pooled cohort had a median age of 66 years, 36% were female with a history of ASCVD in 82%, HeFH in 27% and statin use in 91%. Median baseline lipid levels included low-density lipoprotein cholesterol (LDL-C) of 92 mg/dL, apolipoprotein B (apoB) of 87 mg/dL and Lp(a) of 42.9 nmol/L. Obicetrapib produced placebo-adjusted reductions in LDL-C of 37.0% and 35 mg/dL, in apoB of 21.3% and 20 mg/dL, and in Lp(a) of 37.3% and 14.9 nmol/L. In patients with baseline Lp(a) levels ≥50-<150 nmol/L, obicetrapib produced placebo-adjusted reductions in Lp(a) of 43.3% and 36.3 nmol/L. While patients with baseline Lp(a) ≥150 nmol/L demonstrated a lower percentage reduction in Lp(a) with obicetrapib than those with baseline levels ≥50-<150 nmol/L, the absolute reduction in Lp(a) was similar in both groups (-32.3 vs -36.3 nmol/L). CONCLUSIONS:Obicetrapib lowered LDL-C, apoB and Lp(a). The absolute reduction in Lp(a) with obicetrapib was similar in patients with mildly elevated Lp(a) levels, who are unlikely to qualify for administration of RNA-targeted Lp(a) lowering agents.
BACKGROUND AND AIMS:Evidence on the association between female-specific factors and heart failure (HF) remains limited. This study examined their associations with HF and subsequent mortality. METHODS:Using the Korean National Health Insurance Service database, 3 692 157 postmenopausal women without prior HF or structural heart disease and with intact ovaries and uterus were identified. Associations between reproductive factors, including parity, breastfeeding duration, oral contraceptive (OC) and menopausal hormone therapy (MHT) use, age at menarche, age at menopause, and total reproductive period, and HF risk were assessed using Fine-Gray competing risk models, with death treated as a competing event. Among women with HF hospitalization, associations between reproductive factors and mortality were evaluated using multivariable Cox regression. RESULTS:During a median follow-up of 120 months, 48 640 women were hospitalized for HF. OC (sub-distribution hazard ratios [SHRs]≥1y vs non-user: 0.942, 99.3% confidence interval [CI] 0.896-0.990) or MHT (SHR≥5y vs non-user: 0.782 [99.3% CI 0.708-0.863]) use was associated with a lower HF risk. Later menarche (SHRage≥17 vs 13-16y: 1.099 [99.3% CI 1.071-1.128]), earlier menopause (SHRage 40-44y vs 50-54y: 1.229 [99.3% CI 1.173-1.288]), and shorter reproductive period (SHRage <30y vs ≥40y: 1.284 [99.3% CI 1.213-1.361]) were linked to higher HF risk (all P for trend <.001). Among women with HF, OC, and MHT use were associated with lower mortality, while earlier menarche, earlier menopause, and shorter reproductive period were linked to increased mortality. CONCLUSIONS:Prolonged lifetime exposure to both endogenous and exogenous female sex hormones is associated with lower HF incidence and subsequent mortality.
