bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4139829: New Insights in Non-syndromic Mitral Valve Dystrophy: Role of Inflammation and Macrophages
Authors: Le Vely Benjamin , Delwarde Constance , toquet claire , Aumond Pascal , Charon Emilie , Remy Séverine , Anegon Ignacio , Le Scouarnec Solena , Schott Jean-Jacques , Le Tourneau Thierry , Mass Elvira , Merot Jean , Capoulade Romain
Published: November 2024

Background:
Myxomatous mitral valve dystrophy (MVD) is the first cause of mitral valve prolapse (MVP), a common disease affecting 2 to 3 % of the population. The first causal mutation in the FLNA gene (FLNA-P637Q), was associated with MVD in 2007. Recently, the FlnA-P637Q KI rat model was generated and phenotyped. Using multimodality imaging, MVD was diagnosed as early as 3 weeks (D21) and signature of chemotaxis and immune cell migration was described at the transcriptomic level.

Aims:
This study aims to delineate the contribution of macrophages recruitment and activation to the pathophysiology of MVD.

Methods:
New-born (D0), two days (D2) and seven days (D7) KI and WT animals were phenotyped. Anatomopathological score was used to assed MV morphological alterations. MV cell proportions were analyzed by flow cytometry (D7 and D21), and molecular phenotyping was done by bulk RNAseq (D7). WT and KI MVs were dissociated for valvular interstitial cells (VICs) primary culture and subsequent
in vitro
studies.

Results:
At D21, a 2-fold increased proportion of myeloid cells in KI MV compared to WT was detected by flow cytometry (13% vs 7%, p<0.05). Interestingly, although no morphological differences were seen after birth (D0 and D2; p>0.05), MV remodeling, characteristic of MVD, was observed and quantified at D7 (histological score: 7 in KI vs 4 in WT; p<0.001). Consistently, transcriptomic data of D7-MV revealed enrichment of GO-Terms (p<0.05) related to morphogenesis and development, cytoskeleton and extracellular matrix, and cellular activation and differentiation. Chemotaxis and cytokine related pathways were also enriched (p<0.05), but no difference in myeloid cell proportions was seen by flow cytometry at D7 (7% in WT and KI, p>0.05). Furthermore, monocytes adhesion assay showed an increased monocytes adhesion to KI-VICs compared to WT-VICs (p<0.01). This could be partly mediated by ICAM1 over-expression observed in KI-VICs (p<0.05). Of note, TNFa pro-inflammatory stimulation exacerbated ICAM1 expression in KI-VICs and monocytes adhesion.

Conclusion:
At seven days, the FLNA-KI rats model display MVD associated to a pro-inflammatory signature without increase in macrophage proportion, as observed at later stages. In vitro, KI-VICs have a higher expression of adhesion molecule ICAM1 and are more susceptible to inflammatory stimuli. This results in increased adhesion of monocytes to VICs.
Abstract 4139864: Effect of P2Y12 Inhibitors on Plasma Metabolomic Changes in Patients with Acute Myocardial Infarction
Authors: Eyileten Ceren , Wicik Zofia , Koutentakis Michail , Gasecka Aleksandra , Siller-Matula Jolanta , Postula Marek
Published: November 2024

Introduction/Background:
Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown.

Research Question/Hypothesis:
The research question focuses on predictive analysis of drug response to P2Y12 inhibitors in patients with AMI prior to the initiation of treatment.

Aim of the Study:
In the present study, we aimed to investigate the metabolic profiles of plasma samples from AMI patients to identify potential disease biomarkers and to study patients after AMI treated with ticagrelor or clopidogrel.

Methods:
Twenty-two (22) patients with the first AMI were randomized to ticagrelor or clopidogrel. Plasma samples were obtained at three time points (24 hours, 72 hours, and 6 months) from AMI patients. Metabolic profiles of the plasma of 22 AMI patients and 11 controls (longitudinal sample size (N) = 77) were obtained, and over 1000 plasma metabolites were assayed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The Aligned Rank Transform (ARTool) R package was used as a nonparametric equivalent to the multi-factorial repeated measures analysis of variance (ANOVA) and post hoc analysis.

Results:
Trigonelline from the alkaloid group of metabolites was identified as a uniquely affected metabolite in paired comparisons for AMI patients. After 6 months, trigonelline levels were higher in patients on ticagrelor compared to those on ticagrelor at 72 hours after the switch and those on clopidogrel at 24 hours (p.adjusted (p.adj) = 0.017, p.adj = 0.038, respectively). Other affected groups of metabolites included triacylglycerols (TAGs) and triglycerides (TGs). Up and down-regulated metabolites are presented in Figure 1. Glycolithocholic acid sulfate (GLCAS) and Citrulline were upregulated, while TG was downregulated in clopidogrel group compared to ticagrelor group. phospholipids were found to be significantly lower in the AMI patients compared to control group (p<0.001, see Figure 2).

Conclusion:
Our study showed that increasing levels of the trigonelline metabolite are associated with long-term response to ticagrelor treatment. Trigonelline is a product of niacin metabolism and a common plant alkaloid that has been shown to reduce platelet aggregation. It acts by affecting β-cell regeneration, insulin secretion, activities of enzymes related to glucose metabolism, reactive oxygen species (ROS), axonal extension, and neuron excitability.
Abstract 4139893: Observed to Expected GDMT prescription after HFrEF hospitalization for Medicare beneficiaries: A Candidate Hospital Quality Measure
Authors: Cascino Thomas , Hou Hechuan , Kim Dennie , Pagani Francis , Aaronson Keith , Funk Kylee , Cabrera Lourdes , Hider Ahmad , Funk Russell , Barnes Geoffrey , Watkins Daphne , Likosky Donald , McCullough Jeffrey
Published: November 2024

Background:
Despite well-known morbidity and mortality benefits, implementation of guideline-directed medical therapy (GDMT) for HFrEF patients remains suboptimal. Understanding the center-level variation in observed-to-expected GDMT prescribing could support targeted improvement initiatives.

Hypothesis:
The risk-adjusted observed to expected (O/E) ratio for GDMT prescribing would vary between hospitals and be associated with mortality and readmissions.

Methods:
This cohort study included 100% of Medicare fee-for-service beneficiaries admitted for HFrEF and discharged between Jan 2009 and Dec 2017. Patients were excluded if they were readmitted or died within 60 days of discharge. The primary outcomes were: (1) prescription filling of ≥2 of 3 classes of GDMT (proposed quality measure of GDMT; SGLT2i not yet approved for HFrEF) within 60 days and (2) composite endpoint of death and readmission within 61-120 days post-discharge. The exposures of interest were: (1) center O/E GDMT prescription ratios to evaluate interhospital hospital variability and (2) GDMT quality measure prescription. Risk adjustment was performed via logistic regression, conditioning on demographics, comorbidities, neighborhood distress score, and pre-admission medication utilization.

Results:
In total, 296,900 patients were treated at 1,917 hospitals. Patients had a mean (SD) age of 77 (12) years and were 47.0% female (n=139,398). BB, ACE/ARB, and MRA were filled by 56.5%, 48.5%, and 21.2% of patients, respectively. In total, 42% were prescribed and filled ≥2 GDMT classes. Interhospital variability existed in O/E GDMT prescription (Figure). The adjusted difference in GDMT quality metric prescribing was 23.2% between top and bottom quartile hospitals (52.6% and 29.5%). GDMT prescription was associated with a 5.98% (95% CI -5.5 - -6.46%) lower probability of risk-adjusted death or readmission per patient in the subsequent two months.

Conclusions:
Large-scale interhospital variability exists in GDMT prescribing for HFrEF patients. While optimal GDMT is indicated for all HFrEF patients, assessing center-level O/E GDMT prescribing enables comparisons against achievable performance benchmarks and should be considered a potential quality indicator.
Abstract 4139896: Prognosis of Pulmonary Arterial Hypertension after Treatment for Congenital Portosystemic Shunt in Children
Authors: Matsuoka Ryohei , Nagata Hazumu , Kobayashi Masaru , Uike Kiyoshi , Nagatomo Yusaku , Terashi Eiko , Hirata Yuichiro , Yamamura Kenichiro , Ohga Shouichi
Published: November 2024

Introduction:
Congenital portosystemic shunt (CPSS) is a rare vascular malformation which forms shunts between the portal and systemic veins. Pulmonary arterial hypertension (PAH) in CPSS patients heightens mortality risk.

Research Questions:
It remains unclear which patients’ characteristics are associated with the developing PAH in CPSS individuals. Additionally, it is not yet determined whether CPSS closure improves the prognosis of PAH in these patients.

Methods:
This single-center case-control study explored the data from 31 CPSS patients at Kyushu University Hospital, Japan between 2005 and 2023. Hemodynamics and portal pressure, crucial for treatment decisions, were assessed by cardiac catheterization in all treated patients. Based on these findings, patients were divided into two groups: PAH (n = 6) and non-PAH (n = 25). The primary outcome was the clinical characteristics of PAH, including patients` background, laboratory data, and cardiac catheterization findings. The secondary outcome was the effects of CPSS closure.

Results:
CPSS closure was performed in 28 of the 31 patients. There was no significant difference in age at diagnosis (median: PAH group 117 months vs. non-PAH group 18 months, p = 0.11) or prevalence of congenital heart disease (67% vs. 52%, p = 0.66) between the two groups. The prevalence of portal vein hypoplasia was 83% in the PAH group and 36% in the non-PH group. The PAH group exhibited significantly higher levels of total bilirubin (1.2 vs. 0.8 mg/dl, p = 0.02) and ALT (42 vs. 21 IU/l, p = 0.02). Before treatment, the PAH group had significantly higher median pulmonary artery pressure (39 vs. 12 mmHg, p < 0.01) and pulmonary vascular resistance (7.3 vs. 0.95 unit/m
2
, p < 0.01) compared to the non-PAH group. However, this study showed no significant difference in cardiac index between the two groups (5.3 vs. 4.9 l/min/m
2
, p = 0.31). In the PAH group, all cases initiated pulmonary vasodilator therapies before CPSS closure. Among them, 2 patients were able to reduce pulmonary vasodilator therapies and the other 2 patients were able to discontinue them after CPSS closure. Any patients were not deceased during this observational period.

Conclusions:
The clinical features of the PAH group include portal vein hypoplasia and hepatic dysfunction. Approximately one-third of PAH was reversible in the present study. Early diagnosis followed by CPSS closure and pulmonary vasodilators may improve the prognosis of CPSS-associated PAH.
Abstract 4139898: A Non-invasive
In Vivo
Experimental Model of Heart Failure Using Optogenetic Tachypacing in Larval Zebrafish
Authors: Savoie Emma , Ramadan Ahmed , Purvis Katherine , Stoyek Matthew , Quinn Alex
Published: November 2024

Background:
Tachycardia can drive heart failure (HF). Traditionally, this is experimentally modeled using an implantable pacemaker, an invasive, technically demanding, and low-throughput methodology. Genetically-expressed light-activated ion channels (‘optogenetics’) provide an alternative approach for
in vivo
cardiac stimulation, which if applied in transparent zebrafish embryos, may be used for non-invasive, cost-effective, high-throughput HF and drug screening studies.

Objective:
Establish a non-invasive
in vivo
experimental model of HF using optogenetic tachypacing in larval zebrafish.

Methods:
Larval zebrafish expressing cation-nonspecific channelrhodopsin-2 (ChR2), chloride-specific anion channelrhodopsin-1 (ACR1), or green fluorescent protein (GFP, as a light-exposed, non-paced control) in cardiomyocytes were exposed to intermittent tachypacing (15s on, 15s off) by programmed light pulses from 2-7 days post fertilization (dpf). At 7 dpf: (i)
in vivo
atrial and ventricular mechanical function was assessed by end-diastolic area (EDA), end-systolic area (ESA), and ejection fraction (EF) with video microscopy; (ii) cardiac structure was measured by atrial and ventricular area in fixed larvae with fluorescent imaging; and (iii) gene expression of cardiac-specific HF biomarkers (atrial and brain natriuretic peptide [
anp
,
bnp
], atrial- and ventricular-specific myosin heavy chain-a and -b [
myh6
,
myh7
], and a-smooth muscle actin [
acta2
]) was quantified by qPCR. Values across groups were compared by one-way ANOVA, with Šídák
post hoc
tests.

Results:
In vivo
, atrial and ventricular EDA were greater in ChR2 (+191%,
p
<0.0001; +66%,
p
<0.0001) and ACR1 (+58%,
p
=0.005; +40%,
p
=0.0004) hearts compared to control, as was ESA (ChR2: +245%,
p
<0.0001; +67%,
p
<0.0001 and ACR1: +89%,
p
<0.0001; +53%,
p
<0.0001). Atrial EF was lower in ChR2 (-26%,
p
=0.0006) and ACR1 (-26%,
p
=0.0032) hearts, while ventricular EF was unchanged. Atrial and ventricular area were also greater in fixed ChR2 hearts (+191%,
p
<0.0001; +35%,
p
=0.0005), while only atrial area was greater in ACR1 hearts (+55%,
p
=0.0236). Expression of
anp
,
bnp
, and
myh6
were greater in both ChR2 (11x, 22x
,
58x;
p
<0.05 for each) and ACR1 (6x, 4x, 15x;
p
<0.05 for each) hearts.

Conclusion:
Intermittent optogenetic-tachypacing with either ChR2 or ACR1 induces HF in larval zebrafish, which may represent novel experimental models for insight into HF mechanisms and as pre-clinical tools for the development of new HF therapies.
Abstract 4139913: Obstructive sleep apnoea predicts a worse survival in patients with obstructive hypertrophic cardiomyopathy following septal myoectomy
Authors: meng yanhai , Nie Changrong , Lu Zhengyang , Zhu Changsheng , Wang Shuiyun
Published: November 2024

Background:
Obstructive sleep apnoea (OSA) is highly prevalent in patients with obstructive hypertrophic cardiomyopathy (oHCM), and the severity of OSA appears to worsen following septal myoectomy. The effect of OSA on the survival of oHCM following myoectomy remains uncertain. In this study, we aimed to investigate the clinical outcomes in oHCM patients with different severities of OSA.

Method:
We prospectively enrolled 330 oHCM who underwent septal myoectomy at our institution from January 2015 to December 2019. All patient underwent a standard polysomnography was performed on . The total apnea-hypopnea index (AHI), representing the number of respiratory events per hour of sleep, was calculated using the total recording time as the denominator. Mild, moderate, and severe OSA were respectively defined as an AHI >5 events/h, ≥15 events/h, and ≥30 events/h.

Result:
Of 330 patients, 152 patients had OSA including 87 patients with mild OSA and 65 patients with moderate or severe OSA. Compared to patients without OSA, patients with OSA were much older ( 44.00 ± 12.18 vs. 52.22 ± 10.33 vs. 51.38 ± 10.31, p <0.001), less likely to be female [75 (42.1%) vs. 27 (31.0%) vs. 10 (15.4%), p<0.001], had a higher body mass index (24.81 ± 3.35 vs. 26.32 ± 3.00 vs. 27.77 ± 3.26, p<0.001), a higher proportion of atrial fibrillation, hypertension, and history of smoking. The proportion of coronary artery bypass graft and valvular intervention were comparable between patients with and without OSA. The Cox maze procedure seems higher in patients with OSA than that in patients without OSA [ 10(5.6%) vs. 12 (13.8%) vs. 4 (6.2%) , p= 0.057]. During a median follow-up of 23.1 (16.8-44.6) months, 2 death, 35composite endpoint (2 death, 10 patients readmitted for atrial fibrillation ablation, 21 patients for heart failure, and 2 patients for other arrhythmias, 1 patient experienced a stroke) were observed. The Kaplan-Meier survival curve showed no difference in all cause mortality but higher composite endpoints in patients with moderate or severe OSA(Image 1). Cox hazard regression model revealed that compared to patients without OSA, patients with moderate or severe OSA was independently associated with a worse survival [HR: 2.54, 95%CI (1.08 - 6.00), p=0.033)(Image 2).

Conclusion:
OSA is common in patients with oHCM, and patients with moderate or severe OSA may indicate a worse survival.
Abstract 4139964: Evolving Baseline Risk in Patients With Transthyretin Amyloid Cardiomyopathy: A Systematic Literature Review of Clinical Trials
Authors: Masri Ahmad , Wright Richard , Betts Marissa , Lavoie Louis , Shree Aiswarya , Hennum Liana , Tamby Jean-Francois , Falvey Heather , Dev Sandesh , Nativi-Nicolau Jose
Published: November 2024

Background:
Transthyretin amyloid cardiomyopathy (ATTR-CM) is estimated to occur in 120,000 US adults and remains underdiagnosed. However, awareness of ATTR-CM has improved following the introduction of new diagnostic tools and disease-modifying treatments. Hence, patients (pts) enrolled in contemporary clinical trials could be at an earlier stage of the disease than pts in past clinical studies.

Aim:
To assess temporal trends in the baseline risk of pts with ATTR-CM enrolled in clinical trials.

Methods:
Embase, MEDLINE, CENTRAL, and conference websites were searched on November 23, 2023, for peer-reviewed articles and abstracts. Randomized and single-arm clinical trials examining treatments for ATTR-CM were included, and baseline characteristics and outcomes in pts treated with placebo (PBO) were compared across studies.

Results:
We reviewed 39 publications derived from 4 randomized and 4 single-arm trials. Studies enrolled pts between 2008 and 2021, although 1 study (INOCARD, 2022) did not report years of enrollment. Several baseline characteristics were comparable across studies, including sex, age, race/ethnicity, genotype, and troponin I level. NYHA class at baseline varied with year of enrollment, with fewer NYHA class III pts in recent trials (Figure). Recent trials also showed a trend toward lower NT-proBNP levels (medians ranging from 1911-3178 pg/mL) and higher eGFR levels (means ranging from 54.7-69.0 mL/min/1.73 m
2
). In PBO groups, all-cause mortality (ACM) rates at 12 months dropped from 9% in ATTR-ACT (enrolled 2013-2015) to 6.9% in ATTRibute-CM (enrolled 2019-2020) and 5.6% in APOLLO-B (enrolled 2019-2021); ACM rates at 30 months dropped from 42.9% in ATTR-ACT to 25.7% in ATTRibute-CM.

Conclusions:
This systematic review found that disease-modifying treatments and diagnostic advances have led to earlier diagnosis of pts with ATTR-CM. Recent clinical trials appear to have enrolled pts with a better prognosis. Comparisons of results across these trials are limited and should acknowledge the potential impact of variability in baseline risks among trial populations.
Abstract 4139981: Protective Effects of Cell Cycle Inhibition on Tubular Metabolism in Chronic Kidney Disease
Authors: Hammoud Safaa , Kern Justin , Osaki Yosuke , Funk Steven , Brooks Craig , Gewin Leslie
Published: November 2024

Introduction:
Chronic kidney disease (CKD) is a significant healthcare challenge globally and renal proximal tubules (PT) are key targets of injury. Others have shown that patients with CKD have a dysregulated cell cycle in PT, but it remains unclear whether cell cycle progression in CKD is adaptive or maladaptive. Our recent findings indicate that inhibiting cyclin-dependent kinases 4/6 (CDK4/6) is protective in CKD. However, the underlying mechanisms remain incompletely understood.

Research questions and aims:
Cell cycle progression is linked to metabolism, and we aim to investigate how CDK4/6 inhibition can alter metabolism. Mitochondrial function is closely intertwined with metabolism, and chronic kidney injury is associated with both impaired mitochondrial function and decreased oxidative metabolism. However, mitophagy, the clearance of dysfunctional mitochondria, protects against CKD progression. This raises the question of how CDK4/6 inhibition affects metabolism, mitochondrial function and mitophagy.

Methods:
To define how cell cycle alters metabolism, we measured respirometry using a Seahorse bioflux analyzer on primary PT treated with palbociclib, a CDK4/6 inhibitor. Additionally, we injured mice with uninephrectomy/angiotensin II (UniNx/AngII) +/- palbociclib. To measure glucose oxidation, we incubated injured kidney tissues with
14
[C]-pyruvate and measured the production of
14
CO
2
. We analyzed mitochondrial structure in injured kidneys +/- palbociclib using structure illuminated microscopy (SIM). To assess the effect of CDK4/6 inhibition on mitophagy, we used a reporter mouse model “Mito-QC” injured by UniNx/AngII. Mito-QC mice have tandem mCherry-GFP tag fused to the mitochondrial outer membrane protein, but GFP is pH sensitive and is quenched during mitophagy.

Results:
Our data indicate that blocking CDK4/6 with palbociclib enhances mitochondrial oxygen consumption in primary PT. Additionally, palbociclib increases glucose/pyruvate oxidation in injured kidneys. Palbociclib preserves mitochondrial connectivity in response to UniNx/AngII-induced kidney injury, as detected by SIM. Moreover, palbociclib-treated mice had increased mitophagy following kidney injury.

Conclusion:
Our study shows that CKD4/6 inhibition increases oxidative metabolism and improves mitochondrial function. These effects may be mediating some of the protective effects of palbociclib in chronic renal injury.
Abstract 4139996: Impact of Anticoagulation on Incidence of Cerebrovascular Accident After Epicardial Left Atrial Appendage Occlusion: A Retrospective Descriptive Analysis
Authors: Feldman Daniel , Emaish Tariq , Zhi Lianteng , Murad Dina , Ammari Zaid
Published: November 2024

Introduction:
Atrial fibrillation is one of the most prevalent cardiac arrhythmias globally. In patients with atrial arrhythmias, the left atrial appendage (LAA) has been implicated in up to 90% of thrombus formation. Surgical LAA exclusion in addition to continued anticoagulation (AC) is recommended as a Class 1A recommendation, however true incidence of cerebrovascular accident (CVA) after LAA occlusion in the absence of continued AC is uncertain.

Aims:
This retrospective analysis aims to further explore the impact of AC on cerebrovascular accidents after epicardial LAA occlusion.

Methods:
A retrospective cohort analysis of individuals who underwent open cardiac surgery where LAA occlusion was performed. All patients who were 18 years or older at the time of admission were included and only those who died during the index admission were excluded. The study spanned from October 2015 to December 2022 at a tertiary healthcare system in the northeastern United States. The exposure is whether the patient was discharged on AC. The primary outcome was the incidence of CVA, and the secondary outcome was bleeding events, both at one-year post-index visit.

Results:
A total of 934 patients were included in the analysis with 471 (50.4%) being discharged without AC. Of those, 462 subjects had a history of atrial arrhythmia. A total of 5 subjects had a CVA, 3 of which were not discharged on anticoagulation. A total of 37 (4.0%) subjects had a major bleeding event, of which 21 (2.3%) were discharged on AC. (Table 1)

A subgroup analysis of only those with a history of arrythmia revealed 327 (70.8%) patients in the subgroup were discharged on AC. Of this subgroup, the mean CHA2DS2-VASc score was 4.0
+
2.1 for those discharged on AC and 3.5
+
2.3 for those not discharged on AC. A total of 2 CVA occurred, both in the group not discharged on AC. Bleeding events occurred in 19 (4.1%) subjects, 14 (3.0%) of which were discharged on AC. (Table 2)

Conclusion:
The findings of this retrospective analysis suggest that AC after surgical LAA intervention may be beneficial in reducing the risk of CVA, particularly in patients with a history of atrial arrhythmias. This is, however, accompanied by a higher incidence of bleeding events. Ultimately, given the low number of outcomes recorded, larger multicenter prospective studies will need to be conducted to understand the true impact of AC on CVA and bleeding risks following surgical LAA intervention.
Abstract 4140057: Defining Severe Heart Failure across the Ejection Fraction Spectrum in DAPA-HF and DELIVER
Authors: Inciardi Riccardo , Lu Henri , Claggett Brian , Desai Akshay , Jhund Pardeep , Lam Carolyn , Kosiborod Mikhail , Inzucchi Silvio , Martinez Felipe , De Boer Rudolf , Hernandez Adrian , Shah Sanjiv , Kober Lars , Ponikowski Piotr , Sabatine Marc , Petersson Magnus , Langkilde Anna Maria , McMurray John , Vaduganathan Muthiah , Solomon Scott
Published: November 2024

Background:
Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk. Until recently, severe HF has largely been considered only in those with reduced ejection fraction. The ESC HFA has put forth a consensus definition for severe or advanced HF that may be applicable across the ejection fraction (EF) spectrum.

Hypothesis:
Patients with severe HF experience a higher rate of CV outcomes. The safety and efficacy of SGLT2i dapagliflozin is consistent regardless of the severe HF status.

Aims:
To assess the prevalence, CV outcome risk, and treatment response to the SGLT2i dapagliflozin among patients with severe HF.

Methods:
DAPA-HF and DELIVER were randomized, double-blind trials, testing dapagliflozin vs placebo in 11,007 patients with symptomatic HF across the full spectrum of EF. Severe HF was adapted from the ESC HFA definition: NYHA class III/IV, evidence of HF with reduced, mildly reduced or preserved EF, elevated natriuretic peptides, HF hospitalization within previous 12 months, and adverse patient-reported symptom burden (KCCQ-TSS<75). Outcomes were assessed and the treatment effect of dapagliflozin was measured for the primary endpoint of CV death or first worsening HF event (including HF hospitalization and urgent HF visit) by severe HF status.

Results:
Overall, 730 (6.6%) fulfilled the severe HF definition (296 [40.6%] with EF ≤40%, 192 [26.3%] with EF 41-49%, and 232 [33.2%] with EF ≥50%). Patients with severe HF had a higher comorbidity burden and higher NT-proBNP values. Over a median follow-up of 22.4 months, the primary endpoint occurred in 231 patients, at a rate of 20 (17-23) per 100py. Patients with severe HF experienced a higher rate of events compared to patients without severe HF (adjusted hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.20-1.75), across the spectrum of LVEF (P
interaction
=0.85). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of the severe HF status (P
interaction
=0.10,
Figure 1
). The safety profile of dapagliflozin was also consistent irrespective of the severe HF status (
Figure 2
).

Conclusions:
In a large, global contemporary HF trial population, “severe HF” was associated with excess risk of CV events across the spectrum of EF. Treatment with the SGLT2i dapagliflozin appears safe and effective in reducing the risk of CV death or worsening HF in this population.
Abstract 4140074: Risk of the Post-Partum Period Among Women with Diagnosed and Treated Type 2 Long QT Syndrome (LQT2)
Authors: Neves Raquel , Bains Sahej , Bos Johan , Giudicessi John , Ackerman Michael
Published: November 2024

Background:
Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy. Among women with LQT2, the post-partum period has been considered high risk for cardiac events. However, whether this risk persists after establishing their diagnosis and implementing their LQT2-directed treatment program remains to be determined.

Objective:
To describe the management and outcomes of LQT2 women during the 9 months post-partum period.

Methods:
A retrospective analysis of 1869 patients with LQTS treated and evaluated at a tertiary center specializing in Genetic Heart Disease from January 2000 to November 2023 was performed to identify women with diagnosed and treated LQT2 who had a pregnancy during follow-up. Data were abstracted for patient demographics, clinical characteristics, symptomatic status, and treatment plans before and after pregnancy.

Results:
Overall, 30 pregnancies occurred in 22 women with LQT2. Their average QTc was 489 ± 34 ms with 7 patients (32%) having a resting QTc > 500 ms. Prior to their first post-partum period, 5/22 (23%) were symptomatic with 2 (9%) experiencing a LQT2-triggered sudden cardiac arrest (SCA). Before their post-partum period, their LQT2-directed therapy comprised preventative measures only in 7 (23%), drug therapy in 16 (53%), combination therapy in 7 (23%), and 10 women (43%) had an implantable cardioverter defibrillator (ICD). Pre-emptive treatment intensification was done for 24/30 post-partum periods. Only a single VF-terminating ICD therapy occurred in 1 (3%) of the 30 post-partum periods involving a 21-year-old with p.Lys610Asn-KCNH2 variant, QTc = 490 ms, and a pre-diagnosis presentation of seizures.

Conclusion:
Although the post-partum period is regarded as a ‘high risk’ window of time for women with LQT2, the risk of a LQT2-triggered cardiac event after diagnosis and implementation of contemporary therapies is very low. This designation of “high risk” among correctly diagnosed and treated women is misleading and generates inappropriate and unnecessary anxiety.
Abstract 4140083: Clinical Characteristics and the Response to IV Antihypertensive Therapy in Severe Hypertensive Disorders in Pregnancy: A Retrospective Cohort Study
Authors: Tanski Christopher , Huybrechts Krista , Singh Katherine , Lappen Justin
Published: November 2024

Objective:
Evidence-based recommendations guiding first-line antihypertensive agent selection for treatment of sustained severe hypertension in pregnancy (SSHP) are lacking. Our aim was to identify patient characteristics associated with response to initial IV antihypertensive therapy for SSHP.

Study Design:
We performed a single center retrospective cohort study using EHR data from Jan-Dec 2021. Patients with SSHP, defined as a blood pressure (BP) ≥ 160/110 mmHg for ≥ 15 minutes, were identified from institutional data generated for a state quality improvement project. Patients receiving initial treatment with IV labetalol or hydralazine were included. Patients were excluded if they received nifedipine, did not have a repeat BP measurement within 30 minutes of treatment, had resolution of SSHP without treatment, or did not receive at least two doses of the initial agent prior to changing therapy. Response was defined as a resolution of SSHP with ≤ 2 doses of IV therapy. Variables of interest were identified a priori. Baseline characteristics between groups were compared with standardized mean differences. Multivariable analysis was performed using LASSO regression with 10-fold cross-validation.

Results:
We identified 200 patients with SSHP, of which 114 (57%) received labetalol and 86 (43%) hydralazine. 173 (86.5%) patients were responders: 97 (85.1%) for labetalol vs 76 (88.4%) for hydralazine (p=0.50). Differences between responders and non-responders are listed in the Table. In regression analysis factors significantly associated with non-response included: pre-pregnancy BMI (OR 1.07; 1.02-1.12 per unit increase, kg/m
2
) pre-treatment MAP > 125 mmHg (2.90; 1.10-7.62), and preterm gestational age (< 34 weeks OR 4.71; 1.10-20.20; 34-37 weeks, OR 3.18; 1.10-9.16) (Table).

Conclusions:
In patients with SSHP, multiple clinical factors are associated with response to initial therapy. Each unit increase in pre-pregnancy BMI) is associated with 7% higher odds of non-response. Clinical characteristics may guide risk stratification and antihypertensive dosing strategies for patients requiring acute treatment for SSHP.
Abstract 4140084: A Case of Transient Cortical Blindness occurring during Percutaneous Transluminal Coronary Angiography for Acute Coronary Syndrome.
Authors: Adelakun Adeniyi , Farouji Iyad , haddad ahmad , Szwed Stanley
Published: November 2024

Description of case:
A 55 yo man with no PMHx presented with a few hours of intermittent left-sided chest tightness.

Serial EKG revealed dynamic ST-T wave changes in lateral leads—Figure 1.

His lipid panel was abnormal, and the High-Sensitive Troponin T trended up—table 1.

Based on the hemoglobin A1C result of 10.6, he was newly diagnosed with DM.

Coronary angiography shows two vessel diseases. The left circumflex artery's first obtuse marginal artery branch (LCX-OM1) received a stent in the first instance.

During the planned PTCA for treatment of LAD 48 hours after, he developed sudden bilateral loss of vision while on the table just before stent deployment.

In this case, with the emergence of the symptom of vision loss, PTCA was halted to allow the operator to rule out an acute cerebrovascular accident (CVA) through urgent CT head and MRI brain scans.

He consented to complete the LAD PTCA the day after, which achieved the intended restenosis without complications.

Discussion:
Bilateral transient cortical blindness (TCB) is a reversible syndrome of vision loss affecting both eyes in the presence of normal visual pathways due to a brief disturbance in the occipital cortices. TCB is more commonly associated with cerebral angiography but has been rarely reported after coronary angiography.

Angiographic contrast toxicity is one of the proposed pathophysiologic mechanisms. During our case, approximately 30 mL of iohexol was used before TCB, while about 120 mL of iodixanol was used for the repeat and conclusive procedure.

We are not aware of a previous report in which PTCA was recommenced hours after being halted due to TCB in a patient suffering acute coronary syndrome.

The absence of symptom recurrence when the PTCA was recommenced, which underscored the benign nature of TCB, enabled the patient to receive conclusive, definitive treatment for his acute coronary condition.
Abstract 4140097: Effect of Disclosing a Polygenic Risk Score for Coronary Heart Disease on Adverse Cardiovascular Events: 10-year Follow-up of the MI-GENES Randomized Clinical Trial
Authors: Naderian Mohammadreza , Hamed Marwan , Vaseem Ali , Norland Kristjan , Dikilitas Ozan , Teymourzadeh Azin , Bailey Kent , Kullo Iftikhar
Published: November 2024

Introduction:
The MI-GENES randomized clinical trial (NCT01936675) assessed the effect of disclosing a polygenic risk score (PRS) for coronary heart disease (CHD), in addition to a clinical risk based on Framingham risk score (FRS), on LDL-C levels. The trial enrolled participants from Olmsted County, Minnesota, without cardiovascular disease, at intermediate CHD risk (10-y risk: 5-20%), and not on statins. There was a significant LDL-C reduction in the integrated risk score group (IRS
g
; received PRS information in addition to the FRS) compared to the FRS group (FRS
g
; received their risk based on FRS), due to more frequent statin initiation.

Research Question:
Does disclosure of an IRS for CHD lead to a lower rate of major adverse cardiovascular events (MACE)?

Methods:
Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain cardiovascular events, testing for CHD, and risk factor changes, by blinded review of electronic health records. The primary outcome was time from randomization to the first MACE— defined as cardiovascular death, nonfatal MI, coronary revascularization, and nonfatal stroke. Analyses were done using Cox and linear mixed-effects models.

Results:
We followed all 203 participants, who completed the MI-GENES trial, 100 in FRS
g
and 103 in IRS
g
(mean age at the end of follow-up 68.2±5.2 years, 48% male). During a median follow-up of 9.5 years, 9 MACE occurred in FRS
g
and 2 in IRS
g
(HR, 0.20; 95% CI, 0.04 to 0.94;
P
=0.042, Figure 1A). In FRS
g
, 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRS
g
(HR, 0.51; 95% CI, 0.32 to 0.81;
P
=0.004, Figure 1B). IRS
g
participants had a longer duration of statin therapy during the first four years post-randomization (Figure 1C) and a greater reduction in LDL-C for up to 3 years post-randomization (Figure 1D). No significant differences between the two groups were observed for hemoglobin A1C, blood pressure, weight, and smoking cessation rate during follow-up.

Conclusion:
The disclosure of 10-year CHD risk that included a PRS to those at intermediate risk was associated with lower incidence of MACE after a decade, likely due to more frequent and prolonged statin use, leading to lower LDL-C levels.
Abstract 4140178: Plasma Proteomic Biomarkers Are Associated With Physical Frailty In Heart Failure: A Propensity Score Matched Exploratory Study
Authors: Denfeld Quin , Pavlovic Noelle , Lee Christopher , Jacobs Jon , Roberts Davis Mary , Powell Samantha , Gritsenko Marina , Joseph Susan , Habecker Beth
Published: November 2024

Background:
Physical frailty is highly prevalent in heart failure (HF), but we lack an understanding of the underlying pathophysiology. Proteomics evaluation of plasma samples may elucidate potential mechanisms and biomarkers of physical frailty in HF.

Purpose:
To identify plasma proteomic biomarkers that are differentially expressed between physically frail and non-physically frail adults with HF.

Methods:
This was a secondary analysis of a subset of data and plasma samples from a study of frailty among patients with New York Heart Association (NYHA) Functional Classification I-IV HF. Physical frailty was measured using the Frailty Phenotype Criteria. Propensity score matching was used to match pairs of physically frail (n = 20) vs. non-physically frail (n = 20) patients on clinical characteristics. Plasma samples were processed using a sensitive liquid chromatography mass spectrometry platform, utilizing a multiplexed tandem mass tag-labeled quantitative proteomics approach. Differentially expressed proteins were quantified individually using paired t tests with associated log2 fold change of 0.3 and using Fisher’s combined p values.

Results:
The sample (n = 40) was 62.8±16.9 years old, 58% female, and 55% NYHA class III/IV. The log2 fold changes for each of the 2684 proteins were compared with the corresponding -log10 p-values in a volcano plot (
Figure
), which identified 27 proteins significantly different (10 downregulated and 17 upregulated with physical frailty). Of these, 7 proteins were differentially expressed across all three plexes: matrix metalloproteinase-14 was downregulated in frailty, and copine-1, low affinity immunoglobulin gamma Fc region receptor III-A and III-B, probable non-functional immunoglobulin kappa variable 2D-24, glutathione S-transferase Mu 1, and argininosuccinate lyase were upregulated in frailty.

Conclusions:
Proteomic biomarkers related to the immune system, stress response, and detoxification were differentially expressed between physically frail and non-physically frail adults with HF. Patients with HF who are physically frail appear to be in a state of chronic immune and stress response upregulation coupled with downregulation of cellular activation.
Abstract 4140224: Conservative management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis of randomized controlled trials
Authors: Asif Maryam , Kumar Rajanikant , Epia Efeoghene Praise , Abdelnour Mark , Kim Kim Joo Young Belen , Anokye-Kumatia Anne Boakyewaa , Kulkarni Vrunda , Loyi Lego Rimmo , Ali Farhan Abbas Rizvi Syed , Cheema Huzaifa Ahmad , Ahmad Adeel , Rehman Wajeeh , Ahmed Raheel , Dani Sourbha
Published: November 2024

Background:
In recent years, there has been a rise in the adoption of conservative approaches to managing patent ductus arteriosus (PDA) in preterm infants. Systematic appraisal of the clinical evidence supporting this approach is essential for guiding recommendations in clinical guidelines.

Methods:
A comprehensive search of MEDLINE (PubMed), Embase, the Cochrane Library, and ClinicalTrials.gov, spanning from inception to April 2024, was conducted to identify all relevant randomized controlled trials (RCTs) that evaluated conservative management of patent ductus arteriosus (PDA) in preterm infants. Conservative management was defined as approximately ≤25% open-label pharmacological treatment with ibuprofen, indomethacin, or paracetamol and/or ligation/endovascular closure. Our primary outcomes were the risk of all-cause mortality and bronchopulmonary dysplasia. We used RevMan 5.4 to pool risk ratios (RRs) under a random-effects model, ensuring a rigorous and reliable analysis.

Results:
Our review included 6 RCTs. There was no difference in the risk of mortality (RR 0.83; 95% CI: 0.64-1.08, I
2
= 0%) and BPD (RR 0.89; 95% CI: 0.76-1.03, I
2
= 22%) between the conservative management and active treatment groups. The rates of necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, sepsis, pulmonary hemorrhage, and the need for surgical ligation or transcatheter occlusion were similar between the two groups.

Conclusions:
The meta-analysis showed no difference in the risk of all-cause mortality, BPD, or other clinical outcomes between a strategy of conservative management compared to active treatment. These findings support a conservative approach for the management of PDA in preterm infants. Future studies should focus on cost-effectiveness analyses between the two approaches and investigate important subgroups, such as extremely preterm births.
Abstract 4140260: Efficacy and Safety of Radiofrequency-Based Renal Denervation on Resistant Hypertensive Patients: A Systematic Review and Meta-Analysis
Authors: Sobreira Luis , Rocha Dantas Clara , BEZERRA FERNANDO , Tsuchiya Sano Vitor , de Oliveira Macena Lobo Artur , Cardoso Jorge , Kelly Francinny , A de Moraes Francisco Cezar , Colombo Fernanda
Published: November 2024

Introduction:
New therapies for resistant hypertension (RH), including renal denervation (RDN), have been studied.

Aim:
Access the safety and effectiveness of radiofrequency-based RDN vs pharmacological treatment for RH.

Methods:
A thorough literature search was conducted across PubMed, EMBASE, and the Cochrane databases, focusing on studies that compared the effects of radiofrequency-based RDN versus pharmacological treatment for RH. Treatment effects for binary and continuous endpoints were pooled and used, respectively, odds-ratio (OR) and mean differences (MD) with 95% confidence intervals (CI) to analyze continuous outcomes.

Results:
All the 10 included studies were randomized controlled trials, they involved 1.182 patients, and 682 received radiofrequency-based RDN. The follow-up period ranged from 6 to 84 months. Analysis revealed that the RDN group had a significant reduction in office systolic blood pressure (BP) (MD: -9.5 mmHg; 95% CI: -16.81 to -2.29; P=0.01), office diastolic BP (MD: -5.1 mmHg; 95% CI: -8.42 to -2.80; P<0.001), 24 h systolic BP (MD: -4.8 mmHg; 95% CI: -7.26 to -2.42; P<0.001). For 24 h diastolic BP RDN did not have a significant reduction (MD: -2.3 mmHg; 95% CI: -4.19 to -0.52; P=0.012). The heterogeneity between the studies was high, visible in the funnel and Baujat plots. The OR was non-significant for non-serious adverse events, but also clinically significant for hypertensive crises and strokes for the RDN group.

Conclusions:
While the pharmacological regimen of 3 or more anti-hypertensive, including a diuretic, still be the first-line option for RH treatment, our results support that radiofrequency-based RDN is superior in reducing global BP and is safe.
Abstract 4140268: Outcomes of Percutaneous Coronary Intervention in Patients With Major Depressive Disorder
Authors: Alkehef Yazan , Atluri Ramtej , alsheikh omer , Khan Arshan , hassan sohail , Mesih Nancy
Published: November 2024

Introduction:
Cardiac catheterization with percutaneous coronary intervention (PCI) has been the cornerstone of treatment in patients who present with myocardial infarction. Different outcomes have been studied in different patient populations. However, it is unclear if patients with major depressive disorder (MDD) have been receiving the appropriate treatment, or if patients with MDD who undergo PCI have different outcomes compared to the general population.

Methods:
Sample size was obtained from the National Inpatient Sample (NIS) from 2016 to 2019. We found 1,221,030 hospitalized patients who underwent PCI. These patients were further stratified based on the presence of MDD. A multivariate regression model was used to adjust for confounders and analyze the variables.

Results:
Only 5,380 (18%) patients with MI and MDD underwent PCI. There was no statistically significant difference regarding in-hospital mortality between patients with MDD who underwent PCI and those who underwent PCI but did not have MDD (2.7% vs. 3%; p=0.49). Patients with MDD who underwent PCI had a higher incidence of cerebrovascular accidents (CVA) compared to those who did not have MDD (1.8% vs 1.4%, p=0.0082). There was a higher incidence of in-stent restenosis (ISR) in patients who had MDD and underwent PCI compared to those who did not have MDD (7.1% vs. 4.9%; p=0.0013). When adjusted for age, comorbidities, gender, and hospital characteristics, patients with MDD had lower mortality than those without MDD with an odds ratio of 0.66.

Conclusion:
Although patients with MDD presenting with MI are a vulnerable population, it is likely that these patients are not always receiving the appropriate treatment. There is a higher incidence of cardiovascular events such as CVA, ISR, amongst other events. When adjusted for age, comorbidities, gender, and hospital characteristics, patients with MDD had lower mortality than those without MDD.
Abstract 4140304: Protein Arginin Deiminase 4 Deficiency Prevents Streptozotocin-induced Diabetic Cardiomyopathy and Heart Failure with Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation
Authors: Schommer Nicolas , Sheehy Casey , Van Bruggen Stijn , Jarrot Pierre-André , Chan William , Westermann Dirk , Wagner Denisa , Heger Lukas
Published: November 2024

Background:
Heart failure (HF) is a complication of Type 1 diabetes mellitus (T1D) causing high mortality. In T1D activated neutrophils overproduce peptidyl arginine deiminase 4 (PAD4).

Aim:
Evaluate the role of PAD4 in the pathobiology of HF development in T1D.

Methods:
T1D was induced in PAD4
-/-
and wild type (WT) mice by i.p. injection of 55 mg/kg of Streptozotocin for 5 days. Echocardiography, lung wet-to-dry ratio and exercise intolerance were performed after 8 weeks to evaluate cardiac structural and functional changes. Cardiac collagen content was assessed by picrosirius green staining, levels of neutrophil extracellular traps (NETs) by co-location of Ly6G
+
, and H3Cit
+
signal in tissue and inflammasome activation by protein aggregates of the inflammasome adaptor ASC in neutrophils determined by immunofluorescence.

Results:
PAD4 deficiency did not affect onset or severity of T1D. T1D WT but not T1D PAD4
-/-
mice showed a significantly increased proportion of ASC speck
+
neutrophils (13.8± 4% vs. 3.3±3.1%; n=5; p=0.007). This resulted in elevated IL-1β levels both in plasma (21.7±7pg/ml vs. 11.4±1pg/ml; n=8; p=0.001) and cardiac tissue (0.08±0.002pg/ml vs. 0.06±0.001pg/ml; n=8/6, p=0.001) of T1D-WT mice. T1D-PAD4
-/-
mice showed reduced cardiac damage (Troponin I: 58±11pg/mL vs. 91.3±37pg/mL; n=12; p=0.005), collagen deposition (1.2±0.5% vs. 3.3±1.3%; n=6; p=0.008) and tissue levels of transforming growth factor-β (0.23±0.03 vs. 0.33±0.04 ng/L). Echocardiography demonstrated preservation of both systolic (Ejection fraction: 63.8±5.4 vs. 43.7±11.4 %; n=8; p=0.001) and diastolic (E/E’: -19.6±4 vs. -29.9±9; n=10; p=0.004) function with PAD4 deletion and reduced clinical HF parameters (Lung wet/dry ratio: 4.1±0.5 vs. 5.9±0.9; n=8; p=0.001; time to fatigue: 28.1±10min. vs. 7.6±4 min.;n=10,p=<0.0001). Flow cytometry analysis showed significantly reduced levels of infiltrating neutrophils (42±2% vs. 52± 3% Ly6G
+
of CD11b
+
CD45
+
events; n=8, p=0.02) in the myocardium and histological analysis showed significantly reduced cardiac NET deposition in T1D- PAD4
-/-
mice (1.1±0.4% vs. 10.2±2.2% H3Cit
+
of LV section; n=5, p=0.008).

Conclusion:
We show, that T1D primes neutrophils for NLRP3 Inflammasome assembly and IL-1β release in a PAD4 dependent manner. Increased cardiac neutrophil infiltration, inflammasome assembly and NET deposition drive profibrotic cardiac remodeling and HF in T1D. Our data suggest PAD4 as a promising target for primary cardiac prevention in T1D.