bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4136743: Current Oral Anticoagulation Use Among Patients With Atrial Fibrillation and Risk Factors Associated With Inadequate Treatments: A Report From a UK Population Cohort Study
Authors: Kang Amiee , O'Brien Ellen , Jiang Jenny , Abdul Sultan Alyshah , Henderson Merena , Mandala Vishnu , Lip Gregory
Published: November 2024

Background:
The worldwide prevalence of atrial fibrillation (AF) continues to grow with approximately 60 million cases each year.

Aim:
To understand demographic and clinical attributes of patients receiving adequate DOAC (direct oral anticoagulant) treatment, DOAC undertreatments, or no OAC (oral anticoagulant) treatments, thus providing valuable perspectives into the current landscape of stroke prevention in AF within the UK.

Methods:
We used the Clinical Practice Research Datalink (CPRD) Aurum database from January 2020 to March 2021 for this retrospective observational study. Patients’ characteristics from various cohorts (standard dose [SD], low dose [LD] per label, LD inconsistent per label prescribing, and untreated) were evaluated based on OAC treatment. Duration of index OAC treatment, time to discontinuation and incidence rates across OAC treated cohorts were assessed. A machine learning method (Elastic Net) identified factors associated with being undertreated or untreated.

Results:
The final sample included 13,341 patients (mean age 78.5 and female 47%). Within a 180-day timeframe post-diagnosis, 76% of patients received OAC treatment, while 24% did not receive any OAC therapy. Among those treated with DOAC (n=9947), 74% were administered SD (n=7238), 18% received LD per labels (n=1756) and 10% were inappropriately prescribed LD of DOACs (n=953). Both LD cohorts tended to have shorter duration of OAC therapy (figure) and higher discontinuation rates (per 100 person-years; LD per label: 42.97; LD not per label: 39.11) compared to the SD cohort (SD: 31.67). Patients who were untreated were associated with elevated bleeding risk factors such as renal disease and prior bleeding history; patients who received inappropriate LD were associated with age above 75, renal disease, GI conditions with PPI (proton pump inhibitor) concomitant treatments when compared to SD cohort.

Conclusions:
In our study, a considerable proportion of AF patients remained untreated/undertreated and were associated with bleeding risk factors, highlighting the unmet needs within this population. Exploring potential alternative treatment options with enhanced safety profiles could offer substantial benefits to patients in need.
Abstract 4136754: Psychoactive medication use in pediatric heart transplant recipients: An assessment of prevalence, risk factors, and outcomes
Authors: Schauer Jenna , Aljohani Othman , Cantor Ryan , Fraser Anna , Haregu Firezer , Hope Kyle , Kirklin James , Thompson Consuela , Urschel Simon , Zaim Nadia , Zhao Hong , Brosbe Micah
Published: November 2024

Background:
There is increasing recognition of the mental health burden experienced by pediatric heart transplant (HTx) recipients. Mental health concerns can impact physical health and increase risk of poor health outcomes. Using the Pediatric Heart Transplant Society (PHTS) database, we assessed the use of psychoactive medications as a proxy for mental health issues. We assessed the prevalence of psychoactive medication usage, pre- and post HTx factors, and post HTx outcomes associated with psychoactive medication usage.

Methods:
We queried the PHTS database for patients >5 years of age at time of follow-up who underwent HTx between January 2015 and June 2023. Patients with use of any psychoactive medication were identified. Sub-analyses were performed for use of antianxiety/antidepressant and attention-deficit/hyperactivity disorder (ADHD) medications. Multivariate logistic regression models were utilized to assess risk factors and impact on outcomes, including graft survival, coronary artery vasculopathy (CAV), and rejection at 1, 3, and 5 years post-HTx.

Results:
Among 1792 patients older than 5 at 1 year post HTx, 301 (16.8%) were prescribed at least one psychoactive medication; 246 (13.7%) were prescribed medication for antianxiety/antidepressant medications and 59 (3.3%) for ADHD. Utilization of psychoactive medication decreased at 3 years (14.8%, N= 240 of 1629) and 5 years post HTx (11.3%, N=230 of 2029).

Patients on psychoactive medications at 1 year post HTx tended to be older (OR=2.1, p<0.001), had higher priority listing status (OR=2.3, p<0.05), and longer bypass time (OR=1.6, p<0.05). Black patients were less likely to be prescribed psychoactive medication at 3-years post HTx than white patients (OR=0.57, p<0.05) or other races (OR=0.43, P <0.001).

There was no association of psychoactive medication usage on graft survival, CAV, or rejection at 1 year post HTx. At 3 years post HTx psychoactive medication usage was associated with significantly higher prevalence of CAV (p<0.05). At 5 years post HTx graft loss (p<0.005) and CAV (p<0.05) were significantly increased in patients on psychoactive medications.

Conclusions:
A significant proportion of pediatric HTx patients take psychoactive medications. This population may be at risk for worse long-term outcomes. There is a need to assess the mental health burden of pediatric HTx and to identify modifiable factors to improve assessment and treatment of mental health issues and its impact on outcomes.
Abstract 4136767: Racial/Ethnic and Sex Disparities in the Outcomes and Treatment of In-Hospital Cardiac Arrest: A Nationwide Analysis From the United States
Authors: Mohamoud Abdilahi , abdallah nadhem , Ismayl Mahmoud , Linzer Mark , Karim Rehan , Wardhere Abdirahman , Johnson Dawn , Goldsweig Andrew
Published: November 2024

Background:
In-hospital cardiac arrest (IHCA) is associated with significant morbidity and mortality. The relationships of race/ethnicity and sex to outcomes and treatment patterns among patients with IHCA remain poorly understood.

Methods:
We conducted a retrospective cohort study using the National Inpatient Sample database from 2016 to 2020 to identify adult patients with IHCA and compare in-hospital outcomes stratified by race/ethnicity (White, Black, Hispanic) and sex. The primary outcome was in-hospital mortality. Secondary outcomes included rates of in-hospital procedures. Multivariable logistic regression was used to adjust for potential confounders.

Results:
Among 207,770 patients with IHCA, 26.6% had ventricular tachycardia/fibrillation (VT/VF) and 73.4% had pulseless electrical activity (PEA)/asystole. In the VT/VF subgroup, Black males (aOR 1.42, 95% CI 1.21-1.66), Black females (aOR 1.25, 95% CI 1.05-1.50), and Hispanic females (aOR 1.30, 95% CI 1.01-1.66) had higher odds of mortality compared to White males (Figure 1). In the PEA/asystole subgroup, Black males (aOR 1.25, 95% CI 1.11-1.39) and Hispanic males (aOR 1.22, 95% CI 1.07-1.40) had higher odds of mortality, while White females had lower odds (aOR 0.88, 95% CI 0.82-0.94) compared to White males (Figure 2). Black patients were less likely to receive percutaneous coronary intervention (aOR 0.53, 95% CI 0.43-0.66 for males; aOR 0.54, 95% CI 0.42-0.69 for females) and coronary artery bypass grafting (aOR 0.50, 95% CI 0.30-0.82 for males; aOR 0.47, 95% CI 0.27-0.81 for females) compared to White males in VT/VF arrests. Additionally, Black males had the highest adjusted odds of renal replacement therapy in VT/VF arrests (aOR 1.47, 95% CI 1.21-1.80), while Hispanic males had the highest adjusted odds in PEA/asystole arrests (aOR 1.49, 95% CI 1.27-1.74) compared to White males. The remaining outcomes of interest in both VT/VF and PEA/asystole arrests are shown in Figure 1 and Figure 2 respectively.

Conclusion:
Significant racial/ethnic and sex disparities exist in outcomes and treatment patterns among patients with IHCA, with differences observed in both VT/VF and PEA/asystole subgroups. Targeted efforts and further studies are needed to better understand and address these disparities and improve outcomes in these severely ill patients.
Abstract 4136781: Stethoscopes to Sequencers: How Next Generation Sequencing Aids Pediatric Cardiac Intensive Care Diagnosis
Authors: Onorato Angela , Gosselin Rachel , CHAUDHARI BIMAL , Alvarado Chance , Garg Vidu , Bigelow Amee
Published: November 2024

Background:
Despite a high burden of rare genetic diseases among children admitted to cardiac intensive care units (CICUs), comprehensive guidelines for genetic testing in children with heart disease, particularly those that are critically ill, are lacking. Traditional testing methods, such as karyotype, chromosomal microarray (CMA) and candidate gene panels, are often employed based on suspected diagnoses. Rapid advancements in next-generation sequencing (NGS) technologies allow for more comprehensive genetic evaluation which is already recommended for patients with ventricular dysfunction, primary arrhythmias, and pulmonary hypertension (PH). Broad application of NGS in intensive care settings for pediatric heart disease has not been extensively investigated.

Aims:
Evaluate diagnostic efficacy of NGS in critically ill pediatric patients with cardiac disease.

Methods:
Retrospective cohort of patients who underwent exome or genome sequencing in a pediatric CICU between January 2020 and August 2023.

Results:
Exome or genome sequencing was performed on 49 patients with median testing age of 46 days (IQR 7-609). Primary cardiac phenotypes included congenital heart disease, ventricular dysfunction, arrhythmia, and PH. Forty-two pathogenic or likely pathogenic variants were identified and 23 (46.9%) resulted in a genetic diagnosis, of those, 16 (69.6%) were associated with a cardiac phenotype. Positivity rate did not differ between primary cardiac phenotypes but was significantly higher when the patient had associated multiple congenital anomalies (Fig. 1). Genome sequencing trended towards a higher positivity rate (54.5%) than exome (31.3%), though did not meet statistical significance (Fig. 1). Notably, 84.6% and 38.5% of the identified pathogenic variants would have remained undetectable by CMA and many commercially available gene panels, respectively.

Conclusion:
Exome and genome sequencing demonstrate high diagnostic yield across isolated and non-isolated cardiac disease and various cardiac phenotypes with diagnostic efficacy surpassing CMA and many commercial gene panels. As NGS technologies evolve, they promise to streamline diagnoses and enhance therapeutic decision-making for this patient population.
Abstract 4136788: Lipoprotein(a) Levels and the Risk of Ventricular Arrhythmia: Insights from a Comprehensive Retrospective Cohort Study
Authors: Sani Maryam , Harb Tarek , Leucker Thorsten , Chrispin Jonathan
Published: November 2024

Background:
Sustained ventricular arrhythmias (VAs) are associated with an elevated risk of sudden cardiac death (SCD). Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which in turn associated with increased risk of VAs. However, whether Lp(a) is linked with VAs independent of ASCVD remains unknown.

Objective:
To examine the association of Lp(a) with VAs in a population-based, retrospective cohort study utilizing data from the TriNetX Research Network.

Methods:
We conducted a retrospective analysis of the data from 89 healthcare organizations within the TriNetX Research Network. Patients over 18 years old with available serum Lp(a) measurement were included. Participants were divided into two cohorts based on their Lp(a) levels: cohort 1 (Lp(a) ≤75 nmol/L), and cohort 2 (Lp(a) ≥76 nmol/L). Follow-up time to VA occurrence was calculated from the time of Lp(a) level measurement within each cohort. The composite endpoint was the incidence of VAs to include ventricular tachycardia, ventricular fibrillation, ventricular flutter, or cardiac arrest due to underlying cardiac conditions. We compared the two cohorts using Kaplan-Meier survival analysis along with cox proportional hazard regression analysis after propensity score matching.

Results:
50,752 patients were included in cohort 1 and 24,474 in cohort 2. After propensity score matching, both cohorts had 23,668 patients. In cohort 1, 307 patients experienced VAs, compared to 303 in cohort 2 (Table 1). The mean age was 53.3 ± 15.7 years, with 53.35% of participants being female, 10.75% being Black, and 69.89% being White. The Kaplan-Meier survival analysis showed a higher survival probability at the end of the study period for the Lp(a) ≤75 compared to the Lp(a) ≥76 cohort (95.11% vs 85.35%, p=0.002). The hazard ratio (HR) for VA was 0.768 (95% CI: 0.652-0.904, p = 0.002), indicating that lower Lp(a) levels are associated with reduced VA risk.

Conclusion:
This study shows that increased Lp(a) levels are independently associated with a higher incidence of VA. Future research should focus on the mechanisms underlying the relationship between Lp(a) levels and VA, and whether Lp(a) reduction can reduce the risk of VA and other cardiovascular outcomes.
Abstract 4136799: Disparities in Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia
Authors: Shustak Rachel , Perlstein Abigail , Artis Amanda , Zavez Alexis , Tam Vicky , Martino Giordana , Brothers Julie
Published: November 2024

Introduction:
The prevalence of heterozygous familial hypercholesterolemia (HeFH) is 1:250. Untreated individuals have up to a 20-fold increased risk for premature coronary artery disease (CAD). In adults, low socioeconomic status (SES) individuals, bear a disproportionate share of the CAD burden. In this context, we sought to examine the association of social determinants of health and age at HeFH diagnosis and treatment.

Methods:
We performed a retrospective single-center study of children with HeFH who presented to the Lipid Heart Clinic at the Children’s Hospital of Philadelphia (2012-2022). The primary outcome was age at HeFH diagnosis. The secondary outcome was age at statin initiation. Multivariable linear regression models were used to examine the association between the primary exposure of interest, Child Opportunity Index (COI) and the outcomes. Secondary exposures included race, ethnicity, health insurance, and primary language. To explore potential referral bias, we compared the COI of the study cohort to that of the institution’s catchment area, defined as within a two-hour drive of the primary clinic.

Results:
We evaluated 577 patients. The median age at presentation was 12 (9, 14) years and the median LDL-C was 199 (169, 235) mg/dL; 58% were prescribed a statin with a median age of statin initiation of 13 (10, 15) years. The median COI for the cohort was 84 (62, 95). There was no association between COI, ethnicity, health insurance, or primary language and the age at HeFH diagnosis or statin initiation. On multivariable analysis, black race was associated with older age at HeFH diagnosis compared to white race (adjusted estimate 1.2 +/- 0.49 yrs, p = 0.014). There was no difference in age at statin initiation by race. Higher LDL-C, male sex, and lower BMI percentile were associated with younger age at statin initiation. The COI distribution of the study cohort was significantly different than that of the catchment area (p < 0.001). 70% of the study cohort were of high and very high COI compared to 57% of the catchment area.

Conclusion:
Black race was associated with older age at HeFH diagnosis, however, there were no disparities in age at statin initiation. The COI of the cohort was significantly higher than that of the catchment area suggesting that low COI populations are under-referred for HeFH evaluation. Future efforts should focus on improving barriers to universal screening and identifying obstacles to HeFH diagnosis and referrals.
Abstract 4136846: Sex Differences in Hypertension Diagnosis among Young Adults
Authors: An Jaejin , Novelli Anna , Huang Xuan , Fischer Heidi , Reynolds Kristi , Ni Liang , Choi Soon Kyu , Morrissette Kerresa , Zhang Yiyi
Published: November 2024

Background:
Young adults, especially men, may experience delays in diagnosis of hypertension, which subsequently affect timely treatment and control of high blood pressure (BP).

Question:
Compared with young adult women, how soon are young adult men diagnosed with hypertension after having high BPs during clinical encounters?

Aim:
To estimate the time to first diagnosis of hypertension in young adult men and women, and to identify factors associated with a delayed diagnosis of hypertension.

Methods:
Using electronic health records, we identified adults aged 18-39 years with systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, based on average of three consecutive separate outpatient BPs within two years of each other, between 2009-2016 from Kaiser Permanente Southern California. We followed them from the third qualifying BP until hypertension diagnosis, membership disenrollment, end of study (12/31/2019), or death, whichever occurred first. We used the cumulative incidence function and Cox proportional hazards models to estimate the time to first diagnosis of hypertension and identify factors associated with diagnosis.

Results:
Among 2,443 young adults (mean age 31 years, 57% men) with high BP, 37% were diagnosed with hypertension during a median of 5.9 years. Compared with women, a lower percentage of men were diagnosed with hypertension (30% vs 47%) and men received their diagnoses later (median time to diagnosis: 2.3 vs 1.4 years) (
Figure
). Among the total population, 19% of men and 12% of women did not have follow-up BP measures within one year following their third qualifying high BP. Among those diagnosed, 80% initiated with antihypertensive medications within one year following their diagnosis. Factors associated with a delayed diagnosis of hypertension included being male, younger, having lower systolic or diastolic BP, a lower body mass index, and the absence of dyslipidemia or (pre)diabetes.

Conclusion:
This study highlights that young adult men are at a higher risk of delayed hypertension diagnosis, emphasizing the need for healthcare system level interventions to improve the recognition, diagnosis, and treatment of hypertension in this population.
Abstract 4136861: Title: Protein interaction profiling of the Kv11.1 potassium channel reveals new therapeutic targets for Long QT Syndrome
Authors: Egly Christian , Barny Lea , DO TRI , Plate Lars , Knollmann Bjorn
Published: November 2024

Background:
The voltage-gated potassium ion channel K
V
11.1 plays a crucial role in cardiac repolarization. Genetic variants in K
V
11.1 lead to Long QT Syndrome (LQTS), a condition associated with fatal arrhythmias. Approximately 90% of missense variants linked to LQTS cause intracellular protein transport (trafficking) dysfunction. Some K
V
11.1 channel blockers act as chemical chaperones (e.g., E-4031) and increase K
V
11.1 channel trafficking. However, these drugs cannot be used in LQTS patients. The underlying mechanisms, such as the protein networks involved in folding and quality control for K
V
11.1 channel trafficking remain largely unexplored.

Methods:
We used affinity-purification (e.g., coimmunoprecipitation) coupled with mass spectrometry to quantify protein interaction changes in human embryonic kidney cells expressing wild-type K
V
11.1 or two trafficking-deficient channel variants in the presence or absence of chemical chaperone E-4031. After co-immunoprecipitations and protein digestions, peptides were identified using multiplexed mass spectrometry.

Results:
We identified 572 protein interactions enriched in K
V
11.1-expressing cells. We used bioinformatic analysis to make a cellular model showcasing likely K
V
11.1 protein interactions localization from early biogenesis and transcription to plasma membrane expression (Figure 1). We revealed proteins responsible for protein folding, translation, proteasomal degradation, and others with most protein interactions significantly elevated in the genetic variants compared to wild-type (Figure 2). Upon 24-hour treatment with E-4031, some of these interactions were reduced towards wild-type and indicated potential molecular targets for therapeutic intervention (Figure 3).

Conclusions:
We report the discovery of novel K
V
11.1 protein-protein interactions that could be therapeutically targeted to improve K
V
11.1 trafficking and treat Long QT Syndrome.
Abstract 4137198: Cardiac Index At The Time Of Pulmonary Artery Pressure Monitor Implantation And Inotrope Requirement Within 1 Year
Authors: Siddique Talha , Mitchell Ashley , Panza Gregory , Jaiswal Abhishek , Scatola Andrew
Published: November 2024

Introduction:
Pulmonary artery pressure monitoring with an implantable device (PAPM) improves heart failure hospitalizations (HFH) in patients with symptomatic heart failure. We sought to explore whether cardiac index (CI) predicted need for initiation of inotrope within 1 year of PAPM.

Purpose:
To examine the association between CI at PAPM implantation and need for inotropes within 1 yr.

Methods:
We retrospectively analyzed 277 consecutive HF patients who underwent PAPM from 1/1/19 through 10/31/22 with at least 1 yr post-implant follow-up. Demographic and clinical characteristics were compared between those who required inotropes within 1 yr (n=60) vs those who did not (n=217) (Figure 1). Independent samples t-test was used for continuous data and chi-square analysis for categorical data. Logistic regression was used to examine CI as a predictor of inotrope requirement within 1 yr, controlling for age, ejection fraction and glomerular filtration rate.

Results:
The average age was 69 (12) yr, 54% were male and 60 required inotropes. Patients requiring inotropes had significantly lower CI (2.2±0.6 L/min/m
2
vs 2.6±0.7 L/min/m
2
, p < 0.001). CI was a significant independent predictor of inotrope requirement within 1 yr [odds ratio (OR)=0.3, 0.2-0.6; P<.001). Every increase in CI by 1 L/min/m
2
resulted in 70% lower odds of requiring inotropes (Figure 2). After adjustment, CI remained a significant predictor of inotrope need (OR=0.4, 0.2-0.7; p<0.001); every increase in CI by 1 L/min/m
2
reduced odds of inotrope requirement by 60%.

Conclusion:
Lower cardiac index at the time of PAPM implantation in symptomatic heart failure patients was associated with an increased need for inotrope within one year. This may identify a cohort of patients at risk of progressing to advanced heart failure. Prospective studies should examine the role of PAPM in management of HF patients with a low presenting cardiac index as well as patients with a PAPM and on inotrope.
Abstract 4137249: Left atrial functional reserve predicts recurrence of atrial arrhythmia following catheter ablation in patients with persistent atrial fibrillation
Authors: Yoshida Yuriko , Nakanishi Koki , Daimon Masao , Iwama Kentaro , Hirose Kazutoshi , Mukai Yasuhiro , Seki Hikari , Yamamoto Yuko , Hirokawa Megumi , Nakao Tomoko , Oshima Tsukasa , Matsubara Takumi , Shimizu Yu , Oguri Gaku , Kojima Toshiya , Hasumi Eriko , Fujiu Katsuhito , Morita Hiroyuki , Kurano Makoto , Takeda Norihiko
Published: November 2024

Background:
Left atrial (LA) functional remodeling plays an essential role in the pathophysiological mechanisms of atrial fibrillation (AF). LA reservoir strain (LARS) measured by speckle-tracking echocardiography (STE) exhibits acceptable predictive value for recurrent atrial arrhythmia in patients with paroxysmal AF, while its performance in persistent AF remains inconclusive. Recently, LA functional reserve, a novel concept of LA mechanics in response to acute-volume overload, is drawing attention.

Research Questions:
Are LARS and LA functional reserve associated with recurrent atrial arrhythmia after catheter ablation in patients with persistent AF?

Methods:
Ninety-two patients who underwent first catheter ablation for persistent AF were included in the study. LARS at rest and LA functional reserve were assessed by STE 1-4 days before catheter ablation. LA functional reserve was calculated as change in LARS after passive leg lifting. Recurrence of arrhythmia was defined as atrial arrhythmia of ≥ 30 seconds duration after a 2-month blanking period.

Results:
The median values of LARS and LA functional reserve were 14.4 % (interquartile range [IQR] 10.9 to 18.2) and 1.0% (IQR -1.2 to 3.6), respectively. During a mean follow-up of 13.2 ± 9.9 months, 29 (31.5%) patients experienced recurrent AF. When we stratified patients into 2 groups according to LARS and LA functional reserve (below vs. above median values), patients with impaired LA functional reserve (< 1.0%) were at higher risk of AF recurrence (log-rank test p value=0.026), but this was not observed for LARS (Figure). In multivariable Cox proportional hazard analysis, impaired LA functional reserve was associated with recurrent atrial arrhythmia independent of AF risk factors, left ventricular ejection fraction and LARS at rest (adjusted hazard ratio 3.99, p=0.004).

Conclusions:
Evaluation of LA functional reserve may provide valuable information for optimal patient selection as well as follow-up strategy after catheter ablation in patients with persistent AF.
Abstract 4137272: The Impact of Genotype in Dilated and Arrhythmogenic Cardiomyopathy: Insights from the SHaRE Registry
Authors: Padalia Kishan , Slaven Sarah , Medo Kristen , Graw Sharon , Claggett Brian , Bundgaard Henning , Helms Adam , Heymans Stephane , Ho Carolyn , Khan Sadiya , Lakdawala Neal , Olivotto Iacopo , Owens Anjali , Prasad Sanjay , Axelsson Anna , Reza Nosheen , Shore Supriya , sinagra Gianfranco , Tayal Upasana , Verdonschot Job , Wheeler Matthew , Taylor Matthew , Merlo Marco , Fornaro Alessandra , Parikh Victoria , Wilsbacher Lisa , Mestroni Luisa
Published: November 2024

Background:
The impact of genotype on the risk of arrhythmia and heart failure in dilated and arrhythmogenic cardiomyopathy (DCM/ACM) is not well defined. Better understanding of genetic risk factors is needed to improve patient risk stratification, management, and outcomes.

Methods:
In this observational study, we leveraged the international Sarcomeric Human Cardiomyopathy Registry (SHaRe) to analyze the effect of arrhythmic gene variants on clinical events in patients with DCM/ACM (excluding arrhythmogenic right ventricular cardiomyopathy). Patients were stratified by the presence of pathogenic variants in 8 genes most commonly associated with ACM (AR(+):
LMNA
,
DSP
,
FLNC
,
RBM20
,
PLN
,
SCN5A
,
DES
, and
TMEM43
). We assessed for risk of clinical events including ventricular arrhythmia (VA), atrial fibrillation (AF), heart failure (HF), death, and the overall composite of any of these events. Analyses were adjusted for age at diagnosis, sex, and baseline left ventricular ejection fraction (EF). Patients were also stratified by EF ≥50% in subgroup analyses.

Results:
A total of 1373 genotyped adults with DCM/ACM from 6 centers were included with median follow-up of 5.5 (IQR 2.4-10.4) years. Mean diagnosis age was 48 (± 15) years, and 39.5% were female. The cohort included 185 (13.5%) AR(+) patients. AR(+) compared to genotype-negative patients (N=486, 35.4%) had increased risk of VA (HR 5.02, 95% CI 3.46-7.29) and AF (HR 3.02, 95% CI 2.20-4.10). Risk of HF (HR 2.32, 95% CI 1.55-3.49) and the overall composite (HR 2.12, 95% CI 1.68-2.67) were also increased (
Figure
). Risk of each event remained significant after adjusting for age, sex, and baseline EF (
Table
). AR(+) patients with EF ≥50% also had increased risk of VA (HR 4.56, 95% CI 2.16-9.63), AF (HR 2.94, 95% CI 1.72-5.03), and the overall composite (HR 2.15, 95% CI 1.41-3.28).

Conclusions:
Genetic testing enables powerful risk stratification for both arrhythmias and heart failure in DCM/ACM independent of age, sex, or EF.
Abstract 4137337: Targeting Macrophage NCOR1 to Alleviate Inflammation in Heart Failure with Preserved Ejection Fraction
Authors: Gorica Era , Mohammed Shafeeq , Mengozzi Alessandro , Ruschitzka Frank , Hamdani Nazha , costantino sarah , Paneni Francesco
Published: November 2024

Background:
Inflammatory response is a key player in heart failure with preserved ejection fraction, however the underlying mechanisms remain unclear. Recent evidence indicates that macrophage inflammation driven by the transcriptional coregulatory protein NCOR1 could play a pivotal role in disease states.

Hypothesis:
NCOR1 orchestrates macrophage inflammation and cardiac dysfunction in HFpEF.

Methods:
HFpEF was induced in mice using a validated model combining high-fat diet and L-NAME for 15 weeks. Cardiac function was assessed using high-resolution ultrasound imaging and LV samples were used to study macrophage polarization and inflammation by FACS. We generated myeloid-specific NCOR1-KO mice to investigate the
in vivo
effects of macrophage NCOR1 depletion on HFpEF. In vitro experiments included RAW 264.7 cells polarization and the assessment of macrophage phenotype switching in the presence or the absence of NCOR1. To study the crosstalk of macrophages with the surrounding cardiac cells, cardiomyocytes (H9c2) and endothelial cells (HAECS) were exposed to conditioned media from cultured RAW.

Results:
The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages as proved by qPCR, WB, and flow cytometry analysis. Of interest, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) – and lung congestion were significantly reduced in mice with macrophage NCOR1 deletion as compared to WT littermates, while exercise tolerance was significantly improved. These findings were associated with a reduction of myocardial inflammation (TNF-a, IL6, IL-1b) in Ncor1-KO mice.
In vitro
assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage conditional medium (Fig.1).

Conclusion:
Targeting macrophage NCOR1 could represent a promising approach to blunt myocardial inflammation in HFpEF.
Abstract 4137359: Electrocardiographic ST–T area assessed by a computerized quantitative method were associated with increased risk of cardiovascular disease, especially ischemic stroke, in patients with cardiovascular risk factor
Authors: Hirata Yuki , Kabutoya Tomoyuki , Hoshide Satoshi , Kario Kazuomi
Published: November 2024

Background:
ST changes in the lateral leads, which reflect ischemic changes, are associated with cardiovascular events. However, quantitative assessment of the ST–T area and its association with cardiovascular events remains unclear.

Hypothesis:
Electrocardiographic ST–T areas in lateral leads (V5 and V6) quantitatively assessed by machine analysis were associated with cardiovascular events.

Methods:
We enrolled 4,654 subjects from the Cardiovascular Prognostic Coupling Study in Japan (Coupling Registry), who had one or more cardiovascular risk factors. The primary endpoint was composite (cardiovascular death, myocardial infarction, stroke), and the secondary endpoints were myocardial infarction and stroke. ST–T area was assessed as the area enclosed by the baseline from the end of the QRS complex to the end of the ST–T segment using a computerized quantitative method. We used the lower magnitude of ST–T area in the V5 or V6 lead for the analysis. The endpoints were compared between the lowest quartile of ST–T area (Q4) and the others (Q1–3).

Results:
The mean follow-up period was 53 ± 17 months. The composite endpoint was 159 cases, myocardial infarction in 27 cases and cerebral infarction in 72 cases. The lowest quartile of ST–T area (N= 1,162) had significantly more cardiovascular events than the other Q1–3 groups (N= 3,492, hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.64–3.10) after adjusting for age, gender, and other covariates. The onset of myocardial infarction did not reach statistical difference (HR 2.05, 95% CI 0.94–4.46, p=0.072), but the lowest quartile of ST–T area significantly more ischemic stroke than the other Q1–3 groups (HR 2.37, 95% CI 1.48–3.75 p<0.001)

Conclusions:
The lower summations of ST–T area assessed by a computerized quantitative method were associated with increased risk of cardiovascular disease, especially ischemic stroke, in patients with one or more cardiovascular risk factors.
Abstract 4137396: Evolution of Tricuspid Regurgitation and Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction: Insights from the PURSUIT-HFpEF Registry
Authors: Okada Masato , Tanaka Nobuaki , Iwakura Katsuomi , Seo Masahiro , Hayashi Takaharu , Yano Masamichi , Yamada Takahisa , Yoshio Yasumura , Hikoso Shungo , Nakatani Daisaku , Sotomi Yohei , Sakata Yasushi
Published: November 2024

Background:
Tricuspid regurgitation (TR) is prevalent in patients with heart failure with preserved ejection fraction (HFpEF). However, due to its high vulnerability to hemodynamic loads, the long-term observation may heighten its prognostic values.

Purpose:
To investigate the evolution of TR and its impact on clinical outcomes in patients with HFpEF.

Methods:
An analysis was performed from a prospective multicenter observational registry for HFpEF (PURSUIT-HFpEF Registry) conducted in the Osaka region of Japan. A total of 1238 patients hospitalized for acute heart failure (HF) (diagnosed by using Framingham criteria) met the inclusion criteria: an LVEF ≥50% and brain natriuretic peptide level ≥100 pg/ml. After excluding patients who died within 1 year, we included 761 patients (age 82 ± 9 years; men, 45%; atrial fibrillation, 37%) whose echocardiographic data at discharge and 1 year were available.

Results:
At discharge, 165 patients (21.7%) had moderate to severe TR, which increased to 185 patients (24.3%) at 1 year. Patients were categorized into 4 groups based on the TR evolution: no or mild TR that remained unchanged (n = 522 [69%]), no or mild TR that worsened to moderate to severe (n = 74 [9.7%]), moderate to severe TR that improved to no or mild (n = 54 [7.1%]), and moderate to severe TR that remained unchanged (n = 111 [15%]). During a subsequent follow-up of 33 months, patients with persistent moderate to severe TR had significantly higher mortality rates than the other groups (25.7% vs. 27.0% vs. 27.8% vs. 44.1%, log-rank p < 0.001). Even after adjusting for age, sex, body mass index, left atrial diameter, and left ventricular filling pressure, persistent moderate to severe TR was independently associated with subsequent mortality (hazard ratio, 2.06, 95% confidence interval 1.42-2.99, p < 0.001)

Conclusions:
During a one-year follow-up, changes in the TR severity were not rare in patients with HFpEF. Persistent moderate to severe TR alone was associated with subsequent mortality, highlighting the need to address persistent TR to improve the prognosis.
Abstract 4137414: Uncovering MLKL as a Novel Regulator of Endothelial Cells in the Splenic Niche to Repress Hematopoiesis During Atherosclerosis
Authors: Rasheed Adil , Robichaud Sabrina , Dennison Taylor , Nguyen My-Anh , Geoffrion Michele , Reed Jordan , Wyatt Hailey , Marouf Yacine , Baxi Adir , Lee Richard , Kazan Hilal , Civelek Mete , uiop qwerty , Ouimet Mireille , Rayner Katey
Published: November 2024

Background:
Atherosclerosis occurs as lipid and immune cell rich plaques deposit within the arterial wall of the heart. These immune cells are produced from hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) and spleen, a process known as hematopoiesis that is dictated by their microenvironment, including endothelial cells (ECs).

Objective:
While others have shown adverse remodeling of BM ECs during atherogenesis, whether splenic ECs show a similar dysfunction leading to exacerbated hematopoiesis has not been described.

Methods:
We analyzed RNA sequencing data from chow fed C57Bl/6 mice and high cholesterol diet (HCD) fed
Apoe
-/- mouse BM and splenic ECs obtained from published studies, as well as our own.
In vivo
studies were performed in mice on an atherogenic background (
Apoe
-/-&
Ldlr
-/-) fed a HCD for 4 to 16 weeks. Knockdown of the mixed lineage kinase domain-like protein (
Mlkl
KD) was achieved by weekly administration of antisense oligonucleotides (ASOs) or scrambled control (50mg/kg sc.).
In vitro
studies were performed in primary mouse splenic ECs transfected with siRNA.

Results:
Pathway analysis revealed remarkable tissue-specific responses to an atherogenic milieu, including dysregulation of Lipid Metabolism, Endocytosis and Cell Death pathways in splenic ECs. Interestingly, we previously showed that the mixed lineage kinase domain-like protein (MLKL) regulates the endocytic trafficking of lipids and cell death in macrophages. Indeed using
Mlkl
KD
Apoe
-/- mice, transplantation of
Mlkl
-/- BM into
Ldlr
-/- mice or EC-specific
Mlkl
-/-
Apoe
-/- mice, we show that loss of MLKL drives myelopoiesis and plaque development through regulation of splenic ECs. Both
in vivo
and
in vitro
, silencing
Mlkl
in splenic but not BM ECs potently increased lipid content and disrupted endocytosis by an accumulation of the multivesicular body marker CHMP4B, which mirror the dysregulated pathways we identified above. Furthermore, co-culture with
Mlkl
KD splenic ECs increased HSPC activation (pStat5) and myeloid colony formation, an effect that was lost when ECs were pre-treated with the upstream endocytosis inhibitor Dynasore.

Conclusions:
In conclusion, we establish a novel role for MLKL in regulating the balance of HSPCs, specifically through preservation of splenic, but not BM, ECs that repress hematopoiesis, highlighting the importance of splenic lipid metabolism and endocytosis and its impact on atherogenesis.
Abstract 4137423: Can Machine Learning Help Prioritise Who to Screen for Elevated Lipoprotein(a) (Lp[a]) in the General Population vs a Screen all Approach? An Analysis from UK Biobank
Authors: Stevens Christophe , Barkas Fotis , Brandts Julia , Kwilasi Sunganani , Mahani Alireza , Vallejo-Vaz Antonio J. , Taghavi Azar Sharabiani Mansour , Ray Kausik
Published: November 2024

Background:
Elevated lipoprotein(a) [Lp(a)] is an inherited, currently non-modifiable risk marker that increases lifetime ASCVD risk. Guidance vary on Lp(a) levels at which risk increases; hence prevalence of “elevated” Lp(a) depends on putative thresholds e.g. >1.3 billion people globally have Lp(a)≥125 nmol/L. Lp(a) levels are >90% genetically determined and stable throughout life; hence measurement once in adulthood is recommended. Awareness of Lp(a) levels may change patient management with more intensive control of traditional risk factors. However, testing all adults is costly and the test is not universally available.

Research Question:
Can Machine Learning (ML) models reduce the number needed to screen (NNS) compared to population universal screening for identifying individuals with elevated Lp(a)?

Aims&Objectives:
To derive a model from ML to help prioritise individuals likely to have high levels for Lp(a) testing and compare its yield to universal screening at different Lp(a) cut-points. This approach could enable automatic screening of large databases like EHRs for Lp(a) testing.

Method:
We conducted a cross-sectional predictive analysis using UK Biobank, including individuals ≥40 years old with Lp(a) measurements, split into feature importance, derivation, and validation datasets. Eight ML classification algorithms were used for feature importance analysis and model derivation. Models' performance was evaluated in the validation set using sensitivity and NNS in comparison with the discrimination ability of the following guidelines across different populations: The 2019’s Heart UK and European Atherosclerosis Society (EAS) and Society of Cardiology guidelines, the 2022 EAS Consensus Statement, and threshold used in clinical trial —respective cut-offs: 90,430,125,200nmol/L.

Results:
438,579 patients were included. The best ML models were neural networks with different weights. Regardless of the Lp(a) threshold used, ML models resulted in higher rates of high Lp(a) cases identified per million tests with lower NNS compared to universal screening (Table 1). Using higher Lp(a) thresholds (200-430nmol/L) increased models sensitivity with far fewer tests required to identify those with high Lp(a).

Conclusion:
ML models could reduce the number of tests needed to identify individuals with high Lp(a), increasing efficiency and potentially helping to prioritize Lp(a) testing, with a potentially scalable cost-effective option for health systems.

Work supported by Novartis
Abstract 4137424: Circulating Levels of the Pro-Fibrotic Collagen Hormone Endotrophin are Associated with the Risk of Experiencing Major Adverse Cardiovascular Events in Individuals with Type 2 Diabetes – The Thousand&2 Study
Authors: Laursen Clara , Bahrami Hashmat , Martin Emily , Frederiksen Peder , Genovese Federica , Karsdal Morten , Jorgensen Peter , Rossing Peter , Jensen Magnus
Published: November 2024

Introduction:
Cardiovascular disease (CVD) complications are the leading cause of mortality in individuals with type 2 diabetes (T2D). Abnormal extracellular matrix (ECM) remodelling leads to the release of ECM protein fragments into circulation, reflecting these complications. Endotrophin, a pro-fibrotic and -inflammatory hormone, released during collagen type 6 formation, has been linked to adverse outcomes in T2D, but not previously in a long-term perspective.

Aim:
To assess the 12-year prognostic value of circulating endotrophin levels, measured by PRO-C6, to predict the risk of major adverse cardiovascular events (MACE) in a large cohort of individuals with T2D.

Methods:
Endotrophin levels were measured with the NordicPRO-C6™ ELISA in 909 serum samples from the Thousand&2 study, which was initiated in 2011 and examined individuals with T2D, with and without known CVD. Clinical data were collected at baseline. Follow-up was 100% complete and performed on the 1
st
of May 2024 with the registration of data on MACE from the Danish national registers. The primary outcome was MACE, defined as incident events of hospital admission for ischemic heart disease, heart failure, stroke, or all-cause mortality. PRO-C6 was split into tertiles and examined for survival probability by Kaplan-Meier analysis. Univariate Cox proportional hazard regression analysis was conducted to examine the association between PRO-C6 and the risk of MACE. A multivariable Cox model was additionally conducted, adjusted for age at baseline, sex, systolic blood pressure, duration of diabetes, HbA1c, estimated glomerular filtration rate, use of statins, albuminuria status, and current or prior smoking.

Results:
The baseline mean (±SD) age of the cohort was 64 (±10) years, 66% were males, mean (±SD) PRO-C6 was 11.9 (±7.01) ng/ml, the median follow-up time was 10.6 years, and number of MACE recorded was 472. The risk of experiencing MACE was significantly higher in the third tertile compared to the first and second tertile (Log-Rank p < 0.001). In the univariate Cox model, the estimated hazard ratio (HR), corresponding to a 2-fold increase of PRO-C6, was HR [95% Confidence Interval(CI)] = 2.1 [1.8-2.4], P <0.001. In the fully adjusted Cox model, PRO-C6 remained significantly associated with the risk of MACE (HR [95% CI] = 1.5 [1.2-1.8], P <0.001).

Conclusion:
Elevated circulating endotrophin is associated with MACE in T2D, independent of common risk factors.
Abstract 4137465: Estimating Arterial Stiffness Using a Smart Ring and the Impact of HIIT Exercise: A Pilot Study
Authors: Ohukainen Pauli , Rantanen Aleksi , Pentikainen Heikki , Kosonen Julia , Komulainen Pirjo , Savonen Kai , Koskimaki Heli
Published: November 2024

Introduction:
Arterial stiffness is an important marker of cardiovascular health, but measuring it requires specialized equipment and trained personnel. This study aimed to evaluate a novel method for estimating arterial stiffness using photoplethysmography (PPG) signals recorded by a commercially available device (Oura Ring) and to study the impact of a high-intensity interval training (HIIT) intervention on arterial stiffness.

Research Questions:
1. Can a smart ring provide accurate estimates of arterial stiffness comparable to the reference device (Sphygmocor)?

2. Does a three-month supervised HIIT cycling protocol reduce arterial stiffness?

Aims:
1. Evaluate a PPG-based arterial stiffness estimation method using a smart ring.

2. Assess the efficacy of HIIT in reducing arterial stiffness and improving VO2max.

Methods:
The study comprised two parts:

1. A cross-sectional study (N=300, age 18-78) for collecting arterial stiffness data using the Sphygmocor and the Smart Ring to evaluate the PPG-based algorithm.

2. A randomized exercise intervention pilot study (N=80, a subset of the cross-sectional study), assigned to either a three-month HIIT protocol or a control group. Arterial stiffness was measured pre- and post-intervention using both devices. Pearson’s correlation coefficients assessed the agreement between the novel method and reference device, and effects of the intervention were analyzed using ANCOVA.

Results:
The novel PPG-based method demonstrated good correlation with the Sphygmocor device (R = 0.77 and 0.80 in pre- and post-timepoints, respectively). However, despite improving the participants’ aerobic fitness (average increase in VO2max of 1.41 ml/min/kg; 95% CI: [0.15, 2.67], P = 0.029) the HIIT intervention did not significantly improve arterial stiffness, as measured by both methods.

Conclusions:
The developed smart ring method provides a reliable, non-invasive, and continuous estimation of arterial stiffness. This innovative approach could significantly impact how arterial stiffness is monitored in an everyday setting. The null results of the HIIT intervention suggest that HIIT may not be effective in reducing arterial stiffness, highlighting the need for further research into different exercise modalities for cardiovascular health improvement. This study underscores the potential of wearable technology in cardiovascular health monitoring and the importance of evaluating diverse exercise protocols for arterial health.