Treatment for heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) has evolved significantly in recent years. This period of therapeutic progress follows a span of over two decades during which randomized controlled trials (RCTs) of neurohormonal blockade and other therapies failed to definitively demonstrate clinical benefits. As such, traditionally, management guidelines for HFmrEF and HFpEF were limited to recommendations focused on optimization of volume status with diuretics, management of comorbidities, and consideration of certain medications such as angiotensin receptor-neprilysin inhibitor (ARNi) or steroidal mineralocorticoid receptor antagonists (MRA) to subsets of patients. After definitive results from multiple RCTs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently a main pillar in treating HFmrEF and HFpEF in European and American guidelines. However, other therapies, including non-steroidal mineralocorticoid receptor antagonists (nsMRA) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), are proving to be additional effective treatments for HFmrEF and HFpEF and preventing the progression of cardiovascular-kidney-metabolic (CKM) syndrome. There is now increasing justification for combining multiple proven treatments for HFmrEF and HFpEF to maximize potential benefits. Treatment for different types of heart failure has improved significantly in recent years. For many years, there were few treatments that clearly helped people with heart failure whose heart still pumps normally or nearly normally. Care mainly focused on treating symptoms, helping the body remove excess fluid, and managing related health conditions such as high blood pressure, diabetes, and obesity. Today, research has expanded the available treatment options. One important group of medicines helps the body remove excess sugar and salt through the urine, which also reduces excess fluid and lowers the strain on the heart. Newer studies have shown that medicines that block the effects of a hormone called mineralocorticoid can improve outcomes while causing fewer side effects than older steroid-based treatments. For people who also have obesity, another newer group of medicines that acts on natural gut hormones has been shown to improve symptoms, physical activity, and quality of life. Overall, using a combination of these newer treatments may help people with heart failure whose heart still pumps normally or nearly normally feel better, improve their quality of life, and achieve better long-term health outcomes.
In recent years, establishing multidisciplinary pulmonary embolism response teams (PERTs/EXPERT-PE) has become more prevalent. A survey was conducted to assess the availability and structure of PERTs in German and European hospitals. A survey was circulated among German hospital centers with cardiovascular expertise to obtain data on their current PE treatment approaches, the existence and features of PERTs, their activation methods, and their structural organization. Additionally, data regarding PE treatment priority relative to acute coronary syndrome and the availability of outpatient PE follow-up programs was gathered. Results were compared with those of European PE reference centers. Overall, 65 hospitals participated at this German survey with most PERTs available at university hospitals (63%), especially in West (63%) and Southern (62%). Although 61.5% of the German centers handle over 40 PE cases annually, only 52.3% of those hospitals already implemented a PERT, which is low in comparison to a European Survey among PE reference centers (80.8%). In 86% cases, PERT is led by Cardiology, followed by Angiology (6.9%), Pulmonology (4.6%), and Critical Care Medicine (2.3%). Regarding advanced treatment the majority of hospitals performed catheter-directed thrombolysis (72.2%) and catheter-based thrombectomy/aspiration (74.1%). A follow-up program for patients with PE is considerable higher in European reference centers opposed to German hospitals. This survey demonstrated that among large German cardiovascular centers PERTs are markedly less often present compared to European PE reference centers. Additionally, in German centers, PE follow-up programs are not widely implemented. This emphasizes the pressing need for awareness campaigns for acute and chronic PE.
Stereotactic arrhythmia radioablation (STAR) has been proposed to treat refractory ventricular tachycardia (VT) in patients with structural heart disease (SHD). The aim of the STAR-VT-2020 (Stereotactic Ablative Radiosurgery of Recurrent Ventricular Tachycardia in Structural Heart Disease) randomized trial was to compare the efficacy of STAR and catheter ablation (CA) after a failure of previous CA. Patients with VT recurrences were randomized at 2 centers (June 2020 to January 2024) to the STAR or CA group in a 1:1 fashion using a covariate-adaptive algorithm. In the STAR group, the arrhythmogenic substrate was irradiated by a single dose of 25 Gy delivered by a robotic system (CyberKnife). The planning target volume was delineated by coregistering the electroanatomical substrate map (CARTO 3) with the planning computed tomographic scan. In the CA group, CA was performed using substrate modification strategies. The primary endpoint was VT recurrence, while repeated CA was one of the secondary endpoints. A total of 22 patients (68% men, mean age 67 ± 11 years, 27% with ischemic cardiomyopathy, mean left ventricular ejection fraction 31% ± 9%, 3.0 ± 1.3 previous CAs) were enrolled (11 in each group) and followed for 28 ± 17 months. The STAR patients exhibited a nonsignificantly higher risk for VT recurrence (HR: 2.5; 95% CI: 0.97-6.6) than those who underwent CA, and a significantly higher risk of repeated CA for VT (HR: 4.0; 95% CI: 1.2-13.8). Throughout the trial, 13 patients died, 3 underwent heart transplantation, and 3 received left ventricular assist devices, with no significant differences between the 2 groups. The STAR-VT-2020 trial suggests a potential clinical benefit of repeated CA over STAR in patients with SHD, despite prior failed CA at specialized centers. Because of the small study cohort of highly selected patients and several methodological limitations, the results of the prematurely terminated trial should be considered exploratory and interpreted strictly as hypothesis generating. Larger trials with optimized design are warranted. (Stereotactic Ablative Radiosurgery of Recurrent Ventricular Tachycardia in Structural Heart Disease; NCT04612140).
Whether type 2 diabetes (T2DM) accelerates age-related disease uniformly across organ systems or selectively in specific domains remains unresolved, as prior evidence comes largely from single-outcome studies. Using SHARE (27 European countries, 2004-2020), we matched incident T2DM cases 1:1 to diabetes-free controls on age, sex, and survey wave, yielding six outcome-specific cohorts (n = 1,589-5,781). We fitted Cox proportional-hazards and Fine-Gray competing-risk models with pre-specified subgroup analyses by age at diagnosis (50-59, 60-69, ≥70 years). Fully adjusted hazard ratios ranged from 1.41 (95% CI 1.23-1.62) for arthritis to 2.34 (1.84-2.97) for stroke. Age at diagnosis modified the associations for heart disease, stroke, cataract, and cancer (P-interaction < 0.05) but not for hypertension (P = 0.071) or arthritis (P = 0.154). The age gradient was steepest for cataract (HR 4.66 at age 50-59 vs. 1.39 at ≥ 70); the diabetes-cancer association disappeared after age 70 (HR 1.01, 95% CI 0.69-1.49). T2DM accelerates age-related disease selectively; excess risk magnitude and its dependence on age at diagnosis differ substantially by outcome. These findings support risk stratification by organ system and diagnosis age rather than uniform comorbidity prevention strategies.
Kayak marathon competitions entail several laps and frequent portages in all boat classes. Race demands related to modern elite kayak marathon competition rules have not been evaluated. This investigation characterized mean race speed, lap and portage speeds, frequency of speed changes, and heart rate (HR) responses in elite paddlers of both sexes. During the 2022 European Marathon Championships, national team marathon paddlers in the K1 and K2 classes (N = 30, 15 women) wore a chest belt with integrated global positioning system and HR sensors. Elite kayak marathon paddlers maintain an exercise intensity of 85% to 91% HRmax irrespective of sex and boat type. Mean and peak paddling speeds were lower for women compared to men (P values ranging: .001-.001). In K1, men had more relative speed shifts of both 5% to 10% (35.6 [16.3] vs 25.5 [10.6]; P = .0283) and above 10% (P values ranging .0283-.0003). In K2, there were no statistical differences in speed shifts. In all boat classes, mean boat speed of the final 100 m was always significantly faster than the mean speed of the first part of the lap (P values ranging: .0105-.00000001). Portage running speed varied by 9.4% between sexes. During marathon races, world-class kayak paddlers sustain a mean of 85% to 91% HRmax for a prolonged period (121-129 min), with men in K1 having more speed shifts of 5% to 10% compared to women. To handle race demands, we therefore suggest that on-water training for both sexes include high-intensity steady-state exercise interspersed by frequent, more intense speed bouts.
The Brain-Heart axis regulates cardiovascular and cerebral function through bidirectional neural communication, integrating autonomic reflexes such as respiratory sinus arrhythmia and postural blood pressure regulation. Despite a growing body of literature, the quantitative dynamics of Brain-Heart interplay (BHI) underlying respiratory and baroreflex-mediated changes to postural challenges remain incompletely understood. This study aims to elucidate this relationship by investigating postural and controlled respiratory changes. Seventeen healthy volunteers (average age: 22 ± 1.83 years) participated in the study, performing a 5-minute resting state in both supine and upright positions, with breathing patterns categorized as either spontaneous or slow-paced (6 cycles/min). Throughout the experiment, we recorded high-density electroencephalography (EEG), arterial blood pressure, and electrocardiogram signals to derive RR interval series and calculate baroreflex sensitivity (BRS). Results indicate that postural changes reduced the power of EEG delta (δ) oscillations and cardiac vagal activity while enhancing EEG beta (β) and gamma (γ) oscillations and increasing diastolic blood pressure. Slow-paced breathing amplified EEG beta (β) and gamma (γ) oscillations but reduced sympathovagal activity. Finally, the upright position enhanced bidirectional BHI information transfer while weakening the functional coupling between BRS and BHI. In contrast to slow-paced breathing, spontaneous breathing is characterized by negative heart-brain correlations in both the high- and low-frequency bands across all EEG spectral bands. These findings underscore the contributions of respiratory sinus arrhythmia and baroreflex-mediated cardiovascular regulation to BHI, demonstrating that both postural and respiratory changes influence BHI directionality and autonomic cardiovascular regulation.
The incidence of cancer in people with cardiovascular disease (CVD) is poorly understood. This study aimed to understand the sex differences in incident cancer and cancer-related mortality in people with and without CVD. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk study and followed up for a median of 26.2 years. Participants were stratified by sex and incident CVD during follow-up. Cumulative cancer incidence was calculated for each group. Sex-specific lifetime risks of cancer were determined, accounting for competing risks of death. Cause-specific hazard ratios (HRs) were determined using Royston-Parmar models, adjusted for ethnicity and time-updated covariates, including deprivation index, cardiovascular risk factors, comorbidities, and medication. Participants' CVD status was updated throughout follow-up. A total of 22 534 participants were cancer-free at baseline (57% women; mean age 58.6 ± 9.3 and 59.5 ± 9.3 for women and men, respectively); 10 889 participants either had prevalent CVD at baseline or developed CVD during follow-up. Men had more comorbidities. The adjusted lifetime risk of incident cancer in CVD participants at age 75 was higher in men (17.3%) than in women (12.8%), with a significant cause-specific HR of 1.39 (99% confidence interval [CI] 1.25-1.53, P < .0001). Corresponding data for participants with no CVD were 10.2% for men and 8.2% for women, with an HR of 1.27 (99% CI 1.15-1.41, P < .0001 for men vs women). A similar trend exists for cancer-related mortality (HR 1.51, 99% CI 1.31-1.75, P < .0001 for men with CVD and HR 1.31, 99% CI 1.14-1.50, P < .0001 for men without CVD). This study showed an increased lifetime cancer risk and mortality in men compared with women, which was mediated by comorbid CVD.
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Cardiac computed tomography (CCT) plays an established role in the assessment of cardiac patients. In this document, the aim is to demonstrate and clarify the role of CCT in the clinical management of heart disease. This document will cover the clinical indications, prognostic values, and limitations of CCT in the diagnosis and follow-up of heart disease, including ischaemic heart disease, valvular heart disease, cardiomyopathies, cardiac masses, large vessel disease, and adult congenital heart disease. It will provide a basic knowledge of CCT technology and scan protocols. Continuous improvements in CCT technology and reduced radiation exposure will further enhance its clinical utility. Therefore, this document outlines the technical principles of CCT and its use in everyday clinical practice for cardiologists who are not experts in CCT.
The optimal initial intravenous atropine dose for unstable bradycardia remains uncertain. While American Heart Association guidelines recommend 1.0 mg, European Resuscitation Council algorithms recommend 0.5 mg. We compared the effectiveness of these two doses in emergency department patients with unstable bradycardia. In this single-center retrospective cohort study, adults receiving intravenous atropine as first-line treatment for unstable bradycardia (heart rate < 50 beats/min with hypoperfusion signs) were grouped by initial dose (0.5 mg or 1.0 mg). Propensity score matching (1,1) was performed. The primary outcome was first-dose success, defined as heart rate > 50 beats/min within 3 min without additional atropine or rescue therapy. Secondary outcomes included additional atropine use, rescue therapy, intensive care unit admission, and in-hospital mortality. Of 355 screened patients, 242 were included; 174 remained after matching (87 per group). First-dose success was higher with 1.0 mg than with 0.5 mg (44.8% vs. 25.3%; p = 0.007). The 1.0 mg group required less additional atropine (26.4% vs. 48.3%; p = 0.003), less rescue therapy (50.6% vs. 73.6%; p = 0.002), and had fewer intensive care unit admissions (52.9% vs. 73.6%; p = 0.005). Mortality was similar (3.4% vs. 4.6%, p = 1.000). In multivariable analysis, a 1.0 mg dose (aOR 2.42, 95% CI 1.25-4.68; p = 0.008) and sinus node dysfunction (aOR 3.85, 95% CI 1.95-7.60; p < 0.001) independently predicted first-dose success. An initial atropine dose of 1.0 mg was associated with higher first-dose success and less treatment escalation than 0.5 mg in adults with unstable bradycardia. Prospective multicenter studies are needed to confirm these findings.
Atrial fibrillation (AF) affects over 37 million people internationally and confers increased risk of cardiovascular conditions. Prediction algorithms have attempted to predict incident AF, but other cardio-renal diseases could also provide targets for earlier intervention. We derived a random forest classified for incident AF within 5 years (Future Innovations in Novel Detection of Atrial Fibrillation [FIND-AF] Taiwan) using routinely collected data from the National Taiwan University Hospital database. We compared this to congestive heart failure, hypertension, age >75 years (two points), diabetes mellitus, stroke/transient ischaemic attack/thromboembolism (two points), vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) and coronary artery disease/chronic obstructive pulmonary disease (one point each), hypertension, elderly (age ≥75 years, two points), systolic heart failure, thyroid disease (hyperthyroidism) (C2HEST). Youden's Index was calculated to determine optimal threshold for higher versus lower predicted AF risk. We calculated cumulative incident curves and hazard ratios for incident AF, heart failure hospitalisation, or development of moderate-to-severe renal impairment, stroke or transient ischaemic attack and cardiovascular and all-cause mortality. Overall, 103,321 patients were included, with an average age of 64.6 years and 52.8% women. Overall, 4.4% had incident AF over the 5-year follow-up period. FIND-AF Taiwan had better discrimination (area under received operating characteristic 0.792, 95% confidence interval [CI] 0.777-0.807) than CHA2DS2-VASc (0.737; 0.721-0.754) and C2HEST (0.750; 0.733-0.766). After adjustment, individuals at higher risk were at increased hazard for heart failure hospitalisation (hazard ratio 15.32; 95% CI 9.19-25.54), transient ischaemic attack or ischaemic stroke (28.4; 21.01-38.47), progression to moderate or severe chronic kidney disease (1.18; 1.09-1.27), cardiovascular mortality (1.32; 0.88-1.98), and all-cause mortality (1.23; 1.11-1.36). We derived a supervised machine learning algorithm for AF in a Western Pacific population and demonstrated that higher risk was associated with hospitalisation for other cardio-renal diseases and death. This tool could be used to target interventions to reduce hospitalisation.
Right ventricular (RV) function is closely associated with prognosis in isolated tricuspid regurgitation. Beyond conventional longitudinal indexes, nonlongitudinal RV deformation may provide additional prognostic information. The authors aimed to evaluate whether 3-dimensional (3D) RV circumferential strain (RV-CS) provides incremental prognostic value in patients undergoing isolated tricuspid valve surgery (ITVS). Patients scheduled for ITVS were prospectively enrolled and underwent 3D echocardiography 1 day before surgery. 3D RV longitudinal strain, CS, and area strain were derived using commercially available software. The primary endpoint was a composite of all-cause mortality or heart failure hospitalization. From April 2018 to December 2024, 251 patients were enrolled; 171/251 (68.1%) were women, and the mean age was 57 ± 14 years. During a median follow-up of 495 days, 48/251 patients (19.1%) reached the primary endpoint. Baseline 3D right ventricular circumferential strain (3D RV-CS) was lower in patients with events than in those without events (P < 0.001) and showed modest but had the highest Harrell's C-index for adverse events discrimination (0.695; 95% CI: 0.618-0.774; P < 0.001) among all tested RV function parameters. Patients with impaired 3D RV-CS, defined as |3D RV-CS| < 14%, had lower 1-year event-free survival than those with preserved 3D RV-CS (54.2% vs 92.5%; log-rank P < 0.001). After multivariable adjustment, impaired 3D RV-CS remained independently associated with adverse events. Adding 3D RV-CS improved risk reclassification beyond European System for Cardiac Operative Risk Evaluation II, TRI-SCORE, and Society of Thoracic Surgeons score models. 3D RV-CS provides complementary prognostic information in patients undergoing ITVS and may improve preoperative risk stratification.
Dilated cardiomyopathy (DCM) is a major cause of heart failure and sudden cardiac death and has traditionally been regarded as a predominantly monogenic disorder. However, advances in next-generation sequencing have revealed a more complex genetic architecture with increasing recognition of oligogenic and polygenic contributions; particularly in patients presenting with extracardiac manifestations. In such cases, careful phenotypic characterization and integrative interpretation of genetic findings are essential for accurate diagnosis and management. We report the case of a 46-year-old man who presented with progressive exertional dyspnoea (the New York Heart Association class II-III). His medical history was notable for childhood-onset epilepsy, visual impairment, musculoskeletal abnormalities, and infertility. Transthoracic echocardiography demonstrated severe left ventricular dilatation with reduced ejection fraction (20%). Cardiac magnetic resonance imaging confirmed severe biventricular systolic dysfunction and revealed mid-to-basal myocardial fibrosis on late gadolinium enhancement imaging. Given the prominent multisystem involvement and exclusion of secondary causes, a syndromic cardiomyopathy was suspected. Comprehensive genetic testing identified likely pathogenic frameshift variants in the CD36 and TNXB genes, while additional variants of uncertain significance were detected in MT-TK and STXBP1. These findings suggested a potential oligogenic contribution involving pathways related to myocardial energy metabolism and extracellular matrix integrity. Guideline-directed medical therapy for heart failure with reduced ejection fraction was initiated, and the patient was enrolled in multidisciplinary follow-up with genetic counselling for first-degree relatives. This case highlights the limitations of a strictly monogenic framework in DCM and underscores the importance of considering oligogenic mechanisms in patients with syndromic features. Integrative evaluation combining detailed phenotyping, advanced cardiac imaging, and genetic analysis may provide valuable insights into complex cardiomyopathy phenotypes and support personalized clinical management.
Cardiac dextroposition involves a rightward shift of a normally configured heart, setting it apart from mirror-image dextrocardia. This anatomical variant can alter typical thoracic relationships, rendering conventional fluoroscopic reference points unreliable and increasing the complexity of electrophysiological procedures. A 57-year-old man was admitted following an out-of-hospital ventricular fibrillation arrest attributed to pre-excited atrial fibrillation. Chest radiography identified rightward displacement of the heart's silhouette. Further diagnostic imaging confirmed cardiac dextroposition without abnormalities in atrioventricular or great-vessel orientation, thus distinguishing it from mirror-image dextrocardia. Electrophysiological study revealed that mapping the anteroseptal accessory pathway was complicated by altered fluoroscopic landmarks. Successful radiofrequency ablation was achieved with the aid of three-dimensional electroanatomical mapping and intracardiac echocardiography, resulting in the elimination of pre-excitation without causing atrioventricular nodal injury. The integration of advanced imaging modalities facilitated accurate localization and ablation, despite the abnormal cardiac position. This case demonstrates that even in the setting of significant anatomical displacement, safe and effective ablation of anteroseptal pathways can be accomplished through the application of multimodal mapping techniques.
Cardiac computed tomography (CT)-derived extracellular volume (ECVCT) estimates myocardial interstitial expansion by quantifying the distribution of iodinated contrast within the extracellular space, providing a CT marker of focal and diffuse fibrosis as well as amyloid infiltration. In single-energy CT, ECVCT is calculated from the change in myocardial and blood-pool attenuation between non-contrast and delayed scans, adjusted for haematocrit. Spectral CT, including photon-counting CT (PCCT), can quantify ECVCT from energy-resolved data and may reduce reliance on a separate true non-contrast scan. Across several disease cohorts, ECVCT correlates well with cardiac magnetic resonance (CMR)-derived ECV and, in selected studies, with histological collagen volume fraction, supporting potential for global and regional assessment. ECVCT can add myocardial tissue characterization to examinations already performed for coronary and structural heart disease, including opportunistic screening for concomitant transthyretin amyloidosis during transcatheter aortic valve implantation planning, risk stratification in aortic stenosis, and adjunct phenotyping after CT coronary angiography in troponin-positive acute chest pain or heart failure work-up. Furthermore, CT is more accessible, better tolerated, and potentially cheaper than CMR. However, clinical adoption is potentially limited by added workflow steps due to the delayed acquisition, additional radiation exposure, and heterogeneous approaches to acquisition, reconstruction, and analysis, which reduce reproducibility and complicate the definition of normalcy rates and diagnostic thresholds. Developments in PCCT, automation, and synthetic haematocrit may streamline protocols, but require further calibration and agreement-focused validation. Consensus guidance and prospective multicentre outcome studies are needed to standardize protocols, harmonize reporting, define reference ranges, and support clinically actionable thresholds.
Kawasaki disease (KD) occurring in childhood has been epidemiologically associated with increased adult cardiovascular risk, particularly in children who develop coronary aneurysms during the acute phase. However, the causal nature of this association remains uncertain. This study employed genetic causal association analysis to investigate potential causal effects of KD on adult-onset cardiovascular complications. This study provides new data from our cohort, representing the largest sample size for a KD genome-wide association study (GWAS) analysis and has not been reported before. We first enrolled a prospective KD cohort of 316 patients who received whole-exome sequencing (WES) analysis. We then performed a GWAS analysis and conducted further analyses using summary-level statistics from the IEU Open GWAS database, the GWAS Catalog, and our East Asian KD cohorts. The inverse variance weighted (IVW) method served as the primary analytical approach. All analyses were performed using R software. We established the largest WES-based KD cohort to date, with 316 children receiving WES and GWAS analyses. Then, in the following assessment, no significant causal associations were observed between KD and major adult cardiovascular outcomes. Replication analyses in European populations revealed modest evidence of potential causal associations with specific conditions. The IVW method indicated weak causal associations with ventricular arrhythmia (OR = 1.0296, 95% CI = 1.0037-1.0562, P = 0.025) and chronic heart failure (OR = 1.0110, 95% CI = 1.0007-1.0213, P = 0.0354) in particular traits. However, neither association was reproduced across independent GWAS datasets or corroborated by sensitivity analyses; therefore, these observations should be regarded as exploratory. This analysis provides genetic evidence that does not support a strong causal relationship between childhood KD and an increased risk of most adult cardiovascular diseases. Given the limited KD GWAS sample sizes and relaxed instrument-selection thresholds, these findings should be interpreted cautiously. However, they do not exclude clinically important long-term cardiovascular sequelae in patients with coronary artery involvement after KD.
Risk factor associations for subsequent events among coronary heart disease (CHD) survivors often appear weakened or paradoxical compared with first CHD event associations, confounding clinical interpretation and risk prediction. This study sought to test whether these observations are a systemic feature of studying disease survivors or unique to specific risk factors requiring biological explanation. A retrospective longitudinal cohort study of 3 275 736 cardiovascular disease (CVD)-free adults and 57 165 CHD survivors was conducted using linked electronic health records from England (Clinical Practice Research Datalink, CPRD). The association of 15 CHD risk factors, documented at cohort entry and again at the time of the first CHD, was compared with both first and subsequent CHD, respectively. The performance of a 10-year primary prevention risk score was also assessed in both settings. Absolute risk over 5 years was 32.4% in those with CHD compared with 1.33% in the CVD-free cohort. There was attenuation of all subsequent CHD event risk factor associations, proportional to first CHD event effect size. Nine risk factors retained a concordant association, while others showed neutral or paradoxical association with subsequent CHD events compared with first CHD events. A 10-year risk model for primary prevention performed well for first events [area under the curve (AUC) .84-.85] but poorly for subsequent events (AUC ∼.55). Risk factor 'weakness' after CHD appears to be a systemic phenomenon and consistent with the operation of index event bias. Association findings in this context should not be used to infer or dismiss causality nor to deprioritize proven therapies such as low-density lipoprotein cholesterol lowering. Broader progress in understanding subsequent event risk associations will require new methods that address index event bias.
We utilized an Alzheimer's disease (AD) polygenic risk score (PRS) to discover associations with novel rare variants (RVs). PRSs for European ancestry (EA) participants of the Alzheimer's Disease Sequencing Project were calculated using summary statistics from a large genome-wide association study. Participants were classified into high (n = 5738) and low (n = 5324) PRS groups based on the median PRS and on the lower and upper 35% of the PRS distribution. Risk variants were disproportionately enriched in the low-PRS group, while protective ones were disproportionately enriched in the high-PRS group. Genome-wide significant (GWS) associations for increased AD risk were identified with RVs spanning a 3.5-Mb region on chromosome 14. GWS protective variants in ALDH9A1, BICC1, and PAN3 were identified in the upper 35% PRS group. Our findings provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.