bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4141819: Platelet Transcriptomic Profiling in Acute Myocardial Infarction
Authors: Barrett Tessa , Schlamp Florencia , Muller Matthew , Lee Angela , Cornwell Macintosh , Luttrell-Williams Elliot , Smilowitz Nathaniel , Hochman Judith , Ruggles Kelly , Reynolds Harmony , Berger Jeffrey
Published: November 2024

Introduction:
Platelets play a central role in the pathophysiology of myocardial infarction (MI), including thrombosis and inflammation. Nonetheless, few studies have used unbiased transcriptomics to characterize platelets at the time of an MI. Further, the relationship between platelet phenotype and MI subtype is uncertain.

Aim:
To investigate the platelet transcriptome during acute MI and by MI subtype (MI with obstructive coronary artery disease (MI-CAD) or with no obstructive coronary arteries (MINOCA).

Methods:
Platelet RNA-sequencing was performed in females referred for invasive coronary angiography for MI (n=40), or for evaluation of stable angina (n=38). MI cases were categorized into either MI-CAD or MINOCA according to the presence or absence of a ≥50% diameter stenosis in ≥1 major epicardial coronary artery.

Results:
Among females with MI (47.5% MI-CAD, 52.5% MINOCA), the median age was 63 years, 70% were white, 45% Hispanic, and co-morbidities including hypertension (45%), diabetes (22.5%), and dyslipidemia (60%) were common. There were no differences in age, race, ethnicity, BMI, hypertension, diabetes, or dyslipidemia between participants with MI and those with stable angina. In total, 1421 genes were differentially expressed (p<0.05), with 657 up- and 764 downregulated platelet transcripts in MI relative to stable angina. By ingenuity pathway analysis, canonical pathways associated with actin cytoskeleton, integrin, interferon signaling, and mitochondrial dysfunction were positively enriched in MI platelets, and oxidative phosphorylation and RHOGDI signaling were negatively enriched. When stratified by MI subtype, 531 genes (p<0.05) were differentially expressed (334-up, 197-downregulated) in MI-CAD vs MINOCA. MI-CAD platelets were positively enriched in genes in canonical pathways associated with neutrophil degranulation, neutrophil extracellular traps, and atherosclerosis signaling versus MINOCA. Among all patients with MI, unbiased clustering analysis classified participants into 3 distinct groups that differed in composition by clinical MI subtype (group A – 100% MINOCA, B – 80% MINOCA, and C – 0% MINOCA, P<0.001).

Conclusions:
The platelet transcriptome is enriched in transcripts linked to classical platelet activation responses (actin cytoskeleton, integrin, interferon signaling, and mitochondrial dysfunction) in the setting of MI. Among individuals with MI, platelet RNA sequencing discriminated individuals with MI-CAD versus MINOCA.
Abstract 4141834: Impact of a quality health care program in Mexico: Preliminary results of “Calidad con Corazon”. The AHA GWTG-CAD pilot project in Mexico
Authors: Lugo Gavidia Leslie Marisol , Saucedo Jorge , Leiva-Pons Jose , De Los Rios Manuel , Gutierrez- Fajardo Pedro , Arias-Mendoza Alexandra , Guerra Lopez Arturo , Cossio-Aranda Jorge
Published: November 2024

Introduction:
The healthcare system in Mexico is complex and fragmented which becomes an impediment to implementing national-wide quality improvement initiatives in the cardiovascular area. The American Heart Association Get With The Guidelines® (GWTG) Quality program has become an important tool to improve healthcare standards for patients in US.

Aims:
To develop for the first time, the “Calidad Con Corazon Program” to apply the AHA GWTG framework in Mexico to improve adherence to guideline-directed medical therapies(GDMT) for the treatment of patients with CAD.

Methods/Approach:
Calidad con Corazon program included 10 PCI-capable hospitals from five states in Mexico, representing both public and private health systems. Data included patients with ACS/STEMI/NSTEMI diagnosis. All hospitals were provided quality improvement consultations to identify barriers and develop action plans. This analysis includes data from the first 18 months of the project (Sep 2022 to May 2024).

Results:
We included 2087 patients; Overall, the mean age was 62.1±13.7 and included 73.8% males, with a history of hypertension (57.3%), dyslipidemia (13.6%), diabetes Mellitus (42%), and myocardial infarction (12.3%). Clinical presentation was predominantly STEMI in 66% (n=1378). A progressive improvement overtime was observed on the proportion of patients receiving an ECG in <10 min after arrival to the PCI-hospital, from 53.3% of cases pre-program to 86.2% at 12-18 months after the program (p<0.001). The result was a decrease from a mean of 22.8 minutes to 8.2 minutes respectively (p<0.001). STEMI/NSTEMI patients showed an increase in the proportion of GDMT at discharge for statins(95.2% to 96.9%), betablockers(81.5% to 86%), aspirin(95.4% to 97.1%) and ARB/ACEi(79.5% to 88%). Procedure improvements included a decrease in missing ECG documentation(11.7% to 4.1%), an increase in LVEF measurement (82.7% to 92%), and lipid profile measurement(42.9% to 83.3%).

Conclusion:
Hospitals participating in the first national quality improvement program in Mexico adopting the AHA’s GWTG framework for patients with ACS demonstrated improvement in hospital procedure protocols over a 18 months period, reflected as an improvement in the performance metrics.
Abstract 4141864: Eosinophil Regulated Necrosis in Murine Model of Eosinophilic Heart Disease
Authors: Osuji Immaculeta
Published: November 2024

Background:
Many patients with sustained hypereosinophilia develop cardiac complications, and eosinophilic heart disease (EHD) is the major cause of morbidity and mortality in these patients. The mechanism of EHD is poorly understood. Since eosinophil granule proteins can cause cardiomyocyte damage and one mechanism of their release is regulated necrosis, this study tested the hypothesis that eosinophils undergo regulated necrosis
in vitro
and that this is damaging to cardiomyocytes in a mouse model of EHD.

Methods:
To develop a model of EHD, hypereosinophilic mice were challenged with cardiac myosin; biomarkers and histologic outcomes were assessed. For
in vitro
studies, we used bone marrow derived eosinophils and cell death assessed by biochemical and morphologic outcomes (annexin V binding, membrane permeabilization, citrullinated histone 3 (citH3), extracellular DNA and granule protein).

Results:
EHD mice showed eosinophil-rich inflammation in the heart associated with cardiomyocyte necrosis and later fibrosis. Heart inflammation was decreased in eosinophil-deficient mice. Release of cell-free DNA and troponin was detectable in plasma. Immunohistochemistry for citH3, a marker of regulated necrosis, highlighted eosinophils in the tissue, suggesting they are undergoing regulated necrosis. To study regulated necrosis of eosinophils
in vitro
, eosinophil were stimulated with known to induce different types of cell death and stimuli that mimic activation by conditions in the inflammatory microenvironment. While all stimuli induced dose and time-dependent cell death, we noted two different patterns: while some stimuli (e.g. CD95 ligation) caused eosinophils to transition through annexinV+/7AAD- stage (early apoptosis), other stimuli (e.g. PMA and ionomycin) had increased ratio of 7AAD+ cells, suggesting they directly enter necrotic pathway. By microscopy, cells stimulated with CD95, PMA and ionomycin were positive for citH3, while only the ones stimulated with PMA had NET-like structures. This was further seen with staining for DNA and an eosinophil granule protein.

Conclusion:
Together, our data show that mouse eosinophils undergo specific and distinct cell death pathways, and this may have varying effects on disease outcomes.
Abstract 4141874: Social Determinants Of Aging Speed Among Hispanic/Latino Adults From The Hispanic Community Health Study/Study Of Latinos (HCHS/SOL, 2008-2017)
Authors: Mesa Robert , Llabre Maria , Lee David , Rundek Tatjana , Zeki Al Hazzouri Adina , Kezios Katrina , Gallo Linda , Filigrana Paola , Daviglus Martha , Pirzada Amber , Elfassy Tali
Published: November 2024

Background:
From 2018 to 2060 the proportion of US seniors (age 65+) will increase from 16% to 23%, with much of this growth driven by Hispanic/Latino seniors. Adverse social determinants of health (SDoHs) are drivers of poor health outcomes and accelerated aging.

Objective:
To examine the association between SDoHs (education, income, and nativity) and aging speed among Hispanic/Latino adults.

Methods:
The Hispanic Community Health Study/Study of Latinos is a longitudinal cohort of Hispanic/Latino adults from four US urban communities. Participants completed questionnaires, underwent clinic examinations, and provided biospecimens at visit 1 (V1: 2008-2011) and visit 2 (V2: 2014-2017). Education, income, and nativity were self-reported at V1. The Klemera-Doubal Method, an algorithm consisting of equations using biomarkers from different organ systems (waist-to-hip ratio, pulse pressure, lipids, glycosylated hemoglobin, alanine aminotransferase, cystatin C, and albumin-to-creatinine ratio), was used to calculate biological age (BA) among 5,316 females and 3,087 males ages 30 to 75 at either V1 or V2. Aging speed was defined as the difference between change in BA from V1 to V2 and follow-up time from V1 to V2. We used multivariable linear regression models to determine the sex-specific association between each SDoH with aging speed.

Results:
At V1, mean chronological age was 47 years for females and 46 years for males. Over an average of six years, females aged biologically by 5 years and males aged biologically by 4 years. Compared with having more than a high school education, aging speed was greater by 0.69 years (95% CI: 0.45, 0.94) among females with less than a high school education but not among males (ß=0.57, 95% CI: -0.04, 1.17). Compared with an income ≥$50K, aging speed was greater by 0.67 years (95% CI: 0.30, 1.04) among females with an income <$30K but not among males (ß=0.62, 95% CI: -0.08, 1.31). Compared to those born in the 50 US states/DC, being foreign born was associated with slower aging speed by 0.39 years (95% CI: -0.72, -0.06) among females but not among males (ß=0.52, 95% CI: -0.35, 1.39).

Conclusion:
Over six years, Hispanic/Latino males and females demonstrated slower biological aging compared with chronological aging. Lower income, lower educational attainment, and being born in the 50 US states/DC were associated with greater biological aging (faster aging speed) among Hispanic/Latino females.
Abstract 4141883: The out-of-hospital cardiac arrest in patients with acute myocardial infarction and pre-existing aortic stenosis.
Authors: Muzafarova Tamilla , Motovska Zuzana , Hlinomaz Ota , Kala Petr , Hromadka Milan , Mrozek Jan , Sramko Marek , Hutyra Martin , Petr Robert , Vichova Teodora , Ionita Oana , Jarkovsky Jiri
Published: November 2024

Background:
Pre-existing significant aortic stenosis (sAS) in patients with out-of-hospital cardiac arrest (OHCA) may lead to ineffective chest compressions due to the pathophysiology and hemodynamics of stenosis, reducing the probability of return of spontaneous circulation, and the resuscitation may be complicated.

Aim:
To analyze the influence of sAS on the risk of OHCA in patients with acute myocardial infarction (AMI-OHCA), on the complicity of resuscitation and survival.

Methods:
The analysis was based on the national all-comers’ registry of coronary interventions enriched by information from the National Registry of Reimbursed Health Services and the Registry of Deaths. Complicity of resuscitation was defined as the necessity of mechanical ventilation up to hospital admission. The association between AS, patient characteristics and mortality was analyzed using logistic regression, multivariate model was used for adjusting for co-founders.

Results:
Our dataset included all patients with AMI-OHCA in the country in the period from 2017 to 2021 (N=4,414), of whom 1.8% (N=80) patients had pre-existing sAS and were followed up at the medical institutions (Table 1). The incidence of sAS was 1.7% in those who suffered OHCA and 1.8% in AMI patients without this complication,
p=0.66
. The AMI-OHCA patients were divided into three groups – those who died during OHCA (N=238, sAS in 4.2%), those who were admitted after OHCA on mechanical ventilation (N=3,255, sAS in 1.8%), and spontaneously ventilating patients (N=921, sAS in 1.2%). Multivariate analysis showed that sAS was not recognized as a risk factor for the use of mechanical ventilation in AMI-OHCA patients, odds ratio (OR) 1.61 (95%CI 0.83;3.09), p=0.16, however sAS presents a significant risk of pre-hospital mortality of AMI-OHCA patients, multivariate OR 3.4 (95%CI 1.20;9.58), p= 0.02. Additionally, the in-hospital, 30-day, and long-term prognosis of AMI patients after OHCA is adversely affected by AS with odds ratio of 2.47 (95%CI 1.38;4.41), 2.83 (95%CI 1.61;4.95), and 1.81 (95%CI 1.38;2.38) vs. non-VHD respectively.

Conclusion:
Pre-existing sAS has a significant adverse influence on the survival of AMI-OHCA patients and is a significant risk factor of pre-hospital mortality. Therefore, patients with AS should be carefully screened for coronary artery disease, antithrombotic therapy should be considered, and the earlier planning of valvular intervention after AMI should be evaluated.
Abstract 4141896: Genetic Mimics of GLP-1Ra and SGLT2i Therapy, Heart Failure and Chronic Kidney Disease Outcomes
Authors: Remala Subbaramireddy , Liang Liming , Shah Amil , Buckley Leo
Published: November 2024

Background:
GLP-1 receptor agonists (GLP-1Ra) prevent atherosclerotic and chronic kidney disease (CKD) progression events in type 2 diabetes. In obesity without diabetes, GLP-1Ra lower the risk of atherosclerotic cardiovascular events. Less is known about the effects of GLP-1Ra on heart failure (HF) events and CKD progression events in people without type 2 diabetes and the benefits of adding GLP-1Ra to standard-of-care SGLT2 inhibitor therapy.

Objective:
Assess the association between genetic mimics of GLP1-Ra and SGLT2 inhibitor therapy on the risk of coronary artery disease (CAD), HF, and CKD.

Methods:
We used whole exome sequencing data from the All of Us Research Program to construct genetic instruments mimicking GLP1-Ra and SGLT2i therapy. The genetic instruments included variants in the GLP1R and SLC5A2 genes that associated with lower hemoglobin A1c levels in elastic net regression models with linkage disequilibrium pruning (r
2
< 0.3). Thus, higher genetic scores mimicked lifelong treatment with a GLP-1Ra or SGLT2 inhibitor. Having both higher GLP-1Ra and higher SGLT2i genetic scores mimicked lifelong exposure to combined therapy (
Figure
).

Results:
We included 245,388 All of Us participants (mean age 55 years, 59% females, 38% males, and 2% other genders). Higher GLP-1Ra genetic scores associated with a lower risk of CAD (OR [95% CI] per 1-standard deviation [SD]: 0.97 [0.95-0.99]; P=0.004), HF (OR [95% CI] per 1-SD: 0.95 [0.93-0.98]; P<0.001) and CKD (OR [95% CI] per 1-SD: 0.95 [0.93-0.97]; P<0.001). The associations between the GLP-1Ra genetic score and HF and CKD were not modified by the SGLT2 inhibitor genetic score (
Figure
).

Conclusion:
Lifelong exposure to genetic variants mimicking the pharmacologic effects of GLP1-Ra is associated with a lower risk of CAD, HF, and CKD. GLP-1Ra may provide cardio-kidney protection beyond SGLT2i alone. These results also suggest that GLP-1Ra may prevent new-onset CAD, HF and CKD in the general population.
Abstract 4141908: Variant Burden and Severity of Cardiac Phenotype in Duchenne Muscular Dystrophy Cardiomyopathy
Authors: Geddes Gabrielle , Ware Stephanie , Schwantes-An Tae-Hwi , Abreu Marco , Parent John , Howell Jennifer , Earl Conner , Soslow Jonathan , Markham Larry
Published: November 2024

Introduction:
Duchenne muscular dystrophy (DMD) has cardiac phenotype variability ranging from mild ventricular dysfunction to death from heart failure in the second decade. This variability has not been explained by specific
DMD
variants.

Question:
This study was designed to identify target genes, other than
DMD
, as cardiomyopathy (CMP) severity modifiers.

Methods:
Genome sequencing results were analyzed from 54 well phenotyped DMD males and either severe CMP (cardiac mortality or left ventricular ejection fraction (EF) < 40% at < 20 years of age, n = 18) or mild CMP (EF > 40% at > 20 years of age, n = 36). We compared variants within CMP groups as follows: 1) all study subjects, 2) siblings discordant for CMP severity, and 3) subjects without relatives. Combined Annotation-Dependent Depletion (CADD) was used to assess individual rare variant burden by filtering to retain coding variants with a raw CADD-generated C-Score >2.5. Using the C-Score, we calculated the difference between group mean (DBGM) between the CMP groups for each gene. For each of the three analyses groups, we normalized DBGM summative C-Score and determined which genes had a DBGM summative C-Score >3 standard deviations from the mean (SDM). We evaluated genes that were present on the gene list for all three analyses.

Results:
The cohort by CMP severity is depicted in Figure 1a. Comparisons yielded 8,155 genes with a C-Score > 2.5 in at least one patient. Number of genes with DBGM >3SDM in respective CMP group analysis above: 1) 159 genes 2) 134 genes 3) 136 genes. Nine genes had DBGM summative C-Scores >3 SDM in all three analyses. Of these, 5 genes,
ANKLE1
,
ESRRA
,
GXYLT1
,
MTCH2
, and
QRFPR,
had scores suggestive that these genetic variants could be protective against severe CMP. Whereas 4 genes,
FRAS1
,
GEMIN4
,
PKD1L2
, and
PRSS2
had scores suggestive that these genetic variants could be a risk factor for severe CMP.

Conclusion:
DBGM summative C-Scores from DMD genome sequencing generated 9 candidate genes from 8,155 genes for stratifying CMP phenotypic variability. Further translational evaluation of these genes as modifiers of DMD CMP severity is warranted. If confirmed, these modifiers could provide therapeutic insight specific to DMD CMP.
Abstract 4141915: Catheter Ablation for Atrial Fibrillation May Improve Mortality in Patients with Heart Failure with Preserved Ejection Fraction, Similar to Reduced Ejection Fraction
Authors: Benjamin Patrick , Oyenubi Olamide , FOHLE EMMANUEL , Shahmoradi Vahe , khan Dawlat , Maryniak Andrii
Published: November 2024

Introduction:
Atrial remodeling in HFpEF typically results in impaired ventricular diastolic function, and the maintenance of sinus rhythm would be key to improve clinical outcomes in these patients. The CABANA trial provides limited evidence for the benefits of AF ablation in HFpEF patients. While observational studies suggest otherwise, the results of upcoming RCTs like AMPERE and CABA-HFPEF may offer deeper insights.

Objective:
This study examines the inpatient outcomes of hospitalized HFpEF patients with AF who underwent catheter ablation

Methods:
A retrospective analysis of a nationwide inpatient database from 2017 to 2019 was conducted. The study included patients diagnosed with both HFpEF and AF. A propensity score-matched cohort compared HFpEF and AF patients who underwent catheter ablation with those who did not.

Results:
Among 8.2 million HFpEF patients, 2.6 million had AF, and 24,015 underwent catheter ablation. Mortality was significantly lower in the ablation group compared to the control group (4.6% vs. 1.7% in unmatched cohort, 3.8% vs. 1.7% in matched cohort). The adjusted hazard ratio for mortality was 0.43 (95% CI: 0.34-0.55, p<0.00), indicating a 57% lower risk of death in the ablation group.

Conclusion:
Catheter ablation may offer mortality benefits for HFpEF patients with AF, as suggested by this study. This could foreshadow the findings of ongoing trials like AMPERE and CABA-HFPEF, indicating that ablation could be a valuable treatment option for this high-risk patient group not responding well to standard therapies.
Abstract 4141918: Kidney and cardiac biomarkers and risk of adverse kidney outcomes in patients with type 2 diabetes and kidney disease, cardiovascular disease, or both
Authors: Mc Causland Finnian , Claggett Brian , Solomon Scott , Chaturvedi Nishi , de Zeeuw Dick , Malachias Marcus , McGrath Martina , McMurray John , Neuen Brendon , Vaduganathan Muthiah , Pfeffer Marc
Published: November 2024

Introduction:
Kidney (estimated glomerular filtration rate [eGFR] and urine albumin/creatinine ratio [UACR]) and cardiac biomarkers (high-sensitivity troponin T [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP] predict cardiovascular (CV) and kidney outcomes in a wide spectrum of patients. However, the discriminatory ability of these biomarkers in isolation and in combination is less clear.

Methods:
We examined data from participants in the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) with available baseline measurements (n=5,597). Cox models were fitted to explore the individual and collective discriminative ability of eGFR, log-UACR, log-NT-proBNP, and log-hsTnT with a kidney composite outcome (kidney failure [dialysis or transplant], kidney-related death, sustained doubling of serum creatinine). Subsequently, the combined biomarker model was additionally adjusted for clinical covariates (age, sex, race, BMI, insulin use, baseline BUN, history of stroke, amputation, or heart failure). Discriminatory capacity was assessed by differences in C-statistics.

Results:
Over a median follow-up of 2.7 years, 344/5,597 (6.1%) participants experienced the kidney composite outcome. At baseline, mean eGFR was 52 ±23 mL/min/1.73m
2
; median baseline UACR, hsTnT, and NT-proBNP were 300 [62, 914]mg/g, 15 [7, 24]pg/mL and 176 [77, 430]pg/mL, respectively. For the kidney composite outcome, the C-statistic was 0.583 for eGFR alone, 0.622 for NT-proBNP, 0.686 for hsTnT, and 0.842 for UACR. The combined 4-biomarker model C-statistic was 0.847, which increased to 0.865 with the addition of clinical covariates (Table 1).

Conclusion:
Among participants of ALTITUDE, higher UACR was the most important prognostic biomarker of future adverse kidney events, beyond that of a multivariable clinical model. The addition of eGFR, hsTnT, and NT-proBNP to UACR marginally improved model discrimination, with further improvement by adding clinical variables.
Abstract 4141927: Risk of myocardial infarction in paroxysmal vs. non-paroxysmal atrial fibrillation: an individual patient-level data analysis of 71,466 patients from COMBINE AF
Authors: Ntaios Georgios , Goette Andreas , Palazzolo Michael , Antman Elliott , Ruff Christian , Braunwald Eugene , Link Mark , Mahaffey Kenneth , Eikelboom John , Granger Christopher , Patel Manesh , Wallentin Lars , Giugliano Robert
Published: November 2024

Background:
Prior data suggest the MI risk may be higher with paroxysmal AF (PAF) vs. non-paroxysmal AF (non-PAF). Proposed mechanisms include tachycardia-induced oxidative stress (via LOX-1) with microvascular flow abnormalities, ischemia downstream of a fixed coronary obstruction, and plaque rupture.

Methods:
We compared MI rates in pts with PAF vs. non-PAF in COMBINE AF, a patient-level metanalysis of 4 RCTS of DOACs vs warfarin (ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY,ROCKET AF). Secondary endpoints were ischemic stroke and CV death. Cox proportional-hazards models stratified by trial and adjusted for elements of the CHADS-VASc score were constructed. Sensitivity analyses were performed across subgroups, omitting pts on lower-dose DOAC regimens, and accounting for competing risk of death.

Results:
Of 71,466 pts, 16,609 (23%) had PAF at enrollment. Pts with PAF vs non-PAF were similar age (median 72 vs 72. P=0.15), but more likely women (43 vs 36%), with prior CAD (35 vs 31%), and on aspirin (41 vs 32%); but less likely Asian race (12 vs 15%) or with CHADS-VASc score
>
4 (59 vs 60%), p
<
0.002 for each. During >160,000 pt-yrs of follow-up, 1033 MIs occurred: 277 (1.67%) in pts with PAF vs 766 (1.40%) in pts with non-PAF, corresponding to rates of 0.81% and 0.70% per pt-year. The HR
adj
for MI with PAF vs non--paroxysmal AF was 1.17 [1.02-1.35], p=0.028 (Fig). Ischemic stroke occurred in 364 (2.19%) vs 1425 (2.60%) pts with PAF vs non--paroxysmal AF (HR
adj
0.81 [0.72-0.91], p<0.001). CV death occurred in 625 (3.77%) pts with PAF vs 3027 (5.52%) with non-paroxysmal AF (HR
adj
0.75 [0.68-0.81], p<0.001). No significant effect modification of pt characteristics on MI risk by AF pattern were present, although a trend was seen for higher MI risk with PAF vs non-PAF in pts with prior CAD (HR 1.34 [1.12-1.59]) vs no prior CAD (HR 0.96 [0.76-1.22]), P
INT
0.06. Results were consistent across trials, by anticoagulant, excluding lower dose DOACs, and accounting for competing mortality risk.

Conclusions:
This individual patient-level metanalysis of 71,466 pts from COMBINE AF shows that the adjusted risk of MI is higher in pts with PAF than non--paroxysmal AF, while the adjusted risks of ischemic stroke and CV death were lower in pts with PAF.
Abstract 4141929: Genetic Evidence for GIP as a Therapeutic Target for Peripheral Artery Disease
Authors: Sorondo Sabina , Adkar Shaunak , Depaolo John , Levin Michael , Leeper Nick , Damrauer Scott , Klarin Derek
Published: November 2024

Background:
Peripheral arterial disease (PAD), when comorbid with type 2 diabetes (T2D), is associated with increased risk of adverse limb events, and therapeutic options for these patients are limited. The STARDUST trial recently demonstrated that Liraglutide significantly improves lower limb perfusion in PAD patients with concomitant T2D in an open label randomized setting, potentially expanding the use of Glucagon-like Peptide-1 Receptor (GLP1R) agonists to this population. Using data from the Million Veteran Program (MVP), we aimed to estimate the effects of GLP1R and gastric inhibitory peptide (GIP) agonists on PAD using genetic proxies.

Methods:
We obtained previously published GWAS summary statistics for T2D from the DIAMANTE consortium, and performed an association analysis for PAD in MVP at the GLP1R and GIP loci. For our primary analysis in MVP, association testing was performed with clinical PAD using logistic mixed models controlling for age, sex and population structure. We performed a colocalization analysis of PAD and T2D association signals at these loci using hyprcoloc, and then tested the association with PAD stratified by T2D status. Genome-wide significance (5x10e-8) was used to determine statistical significance for our primary analysis.

Results:
We identified 51330 participants with and 256807 participants without PAD in MVP. Among the European population, we observed evidence of association for PAD at the GIP locus (lead variant rs35895680, OR = 1.048, P = 1.723e-10 for the C risk allele), but not at the GLP1R locus (lead variant rs113678890, OR = 1.6434, P = 1.150e-3). The lead PAD variant at the GIP locus was observed to be the lead T2D variant in the recent DIAMANTE consortium GWAS analysis, and we observed evidence of colocalization between T2D and PAD at the GIP locus, (Posterior Probability of the same causal variant = 0.99). Logistic regression for rs35895680 in the MVP PAD data revealed significant associations in both diabetics (OR=1.04, P = 9.02e-5) and non-diabetics (OR 1.04, P = 1.35e-3), without evidence of heterogeneity (P = 0.60281).

Conclusions:
These findings highlight GIP as a promising target for PAD intervention, potentially benefiting a broader patient population beyond those with concomittent diabetes. Consequently, future trials incorporating therapies inhibiting both GLP1R and GIP, such as tirzepatide, could offer superior therapeutic benefits for PAD compared to GLP1R agonists alone.
Abstract 4141933: Supraventricular Tachycardia (SVT) Related Mortality Rates Among Adults (25 Years and Above) in The United States from 1999 to 2020; A CDC WONDER Database Study.
Authors: Sohail Rohab , Mansoor Hafsa
Published: November 2024

Introduction:
Supraventricular tachycardia (SVT) is known to affect children and teenagers predominantly but can also occur in adults. However, due to a presumed good disease outcome, fatality rates of SVT in adults (above 25 years) are yet to be explored.

Aim:
This study aims to shed light on the mortality trends of SVT in the adult population across the United States from 1999 to 2020.

Methodology:
The CDC WONDER database was used to identify SVT-related deaths using ICD-10 code I47.2 in adults (above 25 years) from 1999 to 2020. The reported data was in the form of crude rate and age-adjusted mortality rate (AAMR) per 100,000 individuals and was stratified by year, ten-year age groups, gender, races, census region, census division, states, and rural-urban division. The Joinpoint regression was then used to determine the changes in trends and annual percentage change (APC).

Results:
From1999 to 2020, 31,036 (AAMR=0.6) SVT-related deaths were reported. AAMR showed an initial steep decline from 0.9 in 1999 to 0.5 in 2011 (APC -5.11 [95% CI -6.08 to -4.14]), followed by a gradual increase till 2020 (0.8) (APC 5.14 [95% CI 3.41 to 6.90]). The crude death rates increased with age and were reported to be highest in ages greater than or equal to 85 (9.1); the trend showed a steep decrease from 1999 (12.4) to 2008 (7.9) (APC -4.35 [95% CI -5.36 to -3.33]), followed by a gradual decline till 2017 (7.8) (APC -0.66 [95% CI -2.04 to 0.73]), and ultimately rising sharply till 2020 (10.6) (APC 9.23 {95% CI 3.32 to 15.47]). Among races, Blacks and Whites displayed the highest mortality (0.7). Blacks showed an initial decrement from 1999 (1.0) to 2017 (0.6) (APC -2.71), followed by a rise back to 1.0(2020) (APC 19.58), while whites showed an initial fall (0.9 (1999) to 0.6 (2008), APC -4.91), followed by no change till 2017 (APC 0.18), and ultimately rise to 0.9 in 2020 (APC 13.66). Although no significant gender or geographical variations were observed, more deaths were seen in rural areas (1.0) than in Urban (0.6).

Conclusion:
Following an initial decline, the incidence of SVT-related mortality has been increasing over the years, pre-dominantly among the 85+ age group, Blacks, and rural populations. However, due to a limited understanding of the epidemiology of SVT in adult populations, more extensive research is needed to formulate better preventive and management strategies.
Abstract 4141934: Psychosocial Stress Subgroups and Cardiovascular Disease (CVD) Events in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Ajibewa Tiwaloluwa , Colangelo Laura , Chirinos Diana , Kershaw Kiarri , Carnethon Mercedes , Allen Norrina
Published: November 2024

Introduction:
Heightened psychosocial stress is a CVD risk factor. While stressors are common and often co-occur, identifying sources and patterns of psychosocial stress exposure may provide insight into individual susceptibility to CVD. Therefore, we sought to identify and examine the longitudinal associations of baseline psychosocial stress subgroups with CVD events in MESA.

Methods:
Data from 6,349 adults (aged: 62.2±10.2 years; 52.9% women) from the MESA cohort with no prior CVD event at baseline (years 2000-2002) were used in this analysis. Latent class analysis (LCA) was used to specify distinct stress subgroups based on 6 variables: chronic burden, neighborhood safety, adequate food shopping, neighborhood noise, lifetime- and past-year discrimination. Five classes were determined after examining traditional fit indices. Adjudicated fatal and nonfatal CVD events were ascertained in annual follow-up visits through the year 2019. Cox proportional hazards models with sequential adjustment of baseline variables were used to examine the associations between subgroup membership and CVD events.

Results:
Five distinct stress subgroups were identified via LCA and were labeled “moderate neighborhood noise” (12.1%), “excessive noise/crime” (6.4%), “elevated on all” (6.3%), “high discrimination/safe neighborhood” (21.4%), “optimal” (53.8%) (see figure). By the year 2019, 1,121 participants had experienced a CVD event. Membership in the “elevated on all” and “high discrimination/safe neighborhood” subgroups (see table) were associated with higher risk of a CVD event when adjusted for sociodemographic characteristics and cardiovascular health metrics. However, when adjusted for measures of anxiety and depression, possible mediators, only membership in the “high discrimination/safe neighborhood” subgroup was associated with increased risk of a CVD event.

Conclusions:
Among 5 distinct stress subgroups those experiencing high discrimination had higher risk for CVD events.
Abstract 4141935: Targeting Tyrosine Kinase Inhibitor-Associated Cardiotoxicity with NPA7: A Novel Dual Activating Peptide
Authors: Ma Xiaoyu , Malsawmzuali JC , Moroni Dante , Zheng Ye , Sangaralingham Jeson , Burnett John
Published: November 2024

Background:
Tyrosine kinase inhibitors (TKIs), such as sunitinib, are highly effective in treating cancers. However, they have severe cardiovascular (CV) side effects that include cardiotoxicity via cardiomyocyte injury and death resulting in myocardial dysfunction. There are no FDA-approved drugs to prevent or treat cardiotoxicity, which have been linked mechanistically to mitochondrial dysfunction and oxidative stress, highlighting the need for new therapeutics. Two recognized CV protective pathways are the particulate guanylyl cyclase A receptor (GC-A)/cGMP and the Mas receptor (MasR)/cAMP pathways. We recently engineered NPA7 a novel peptide that activates both pathways.

Aim:
Here we investigated NPA7’s ability to protect against sunitinib-induced cardiotoxicity in human cardiomyocytes (HCMs) and defined its role on mitochondrial function.

Methods:
HCMs were treated with DMSO or sunitinib (10 µM) together with PBS or NPA7 (10 µM). Intracellular reactive oxygen species (ROS) was assessed by DHE staining. CCK8 assay was performed to measure cell viability. TOM20 staining were performed by immunofluorescence and the mitochondrial length was analyzed. The protein levels of mitochondrial dynamics markers (fission: MFF, Fis1; fusion: OPA1 and MFN1) proteins were measured by western blot. Cell surface area was assessed by phalloidin staining with mRNA levels of hypertrophic gene markers (NPPA and MYH7) in HCMs using real-time PCR.

Results:
Sunitinib increased DHE staining and intracellular ROS in HCMs, which was decreased with NPA7 treatment. NPA7 enhanced HCM cell viability in the presence of sunitinib. TOM20 staining showed a marked reduction in mitochondrial length in sunitinib group, compared to DMSO group, whereas NPA7 treatment rescued mitochondria length (DMSO= 6.15 ± 0.94 μm, Sunitinib= 2.42 ± 0.63 μm, NPA7= 5.4 ± 1.19 μm; P < 0.05). Moreover, NPA7 inhibited mitochondrial fission protein levels (MFF and Fis1) and increased mitochondrial fusion protein levels (OPA1, MFN1) in HCMs treated with sunitinib. Sunitinib treatment notably increased HCM cell surface area and hypertrophic gene markers (NPPA and MYH7), whereas NPA7 abolished these markers of hypertrophy.

Conclusions:
We report, for the first time, that NPA7 protects against sunitinib induced oxidative stress, mitochondrial fragmentation, hypertrophy and cell death in HCMs. These data support a novel therapeutic approach against TKI-induced cardiotoxicity with NPA7 to which no therapies exist.
Abstract 4141937: Long Noncoding RNA SNRKAS as a SNRK Inhibitor Triggers Endothelium Senescence
Authors: Lu Qiulun , Shrestha Sanjiv , Song Ping
Published: November 2024

Background:
Although sucrose non-fermenting 1-related kinase (SNRK) in endothelial cells (EC) has a critical role in anti-inflammation and anti-fibrosis in the kidney, whether SNRK controls EC senescence and vascular aging, and how SNRK is regulated have never been studied. Long noncoding RNAs (lncRNAs) are involved in endothelial function and are altered during aging and in response to various senescence stimuli. However, whether lncRNA controls SNRK protein levels, which regulate EC senescence and cardiovascular diseases (CVD), is still poorly understood.

Methods:
Immunohistochemistry was performed on mouse aortic samples. RNA fluorescence in situ hybridization (RNA-FISH) staining was taken with young and aged arteries. Young and senescent primary human ECs were used for molecular signaling analysis, and SNRK expression was manipulated using plasmid overexpression and depletion. Senescence-associated β-galactosidase (SA-β-gal) staining was performed
in vitr
o and
in vivo
.

Results:
Analyzing the expression of senescence-associated lncRNAs by qRT-PCR in human endothelial cells, we identified a long noncoding antisense (AS) transcript of SNRK, SNRKAS, which was upregulated by forkhead box A2 (FOXA2) activation in senescent human EC
in vitro
and EC from aged human vessels
in vivo
. SNRKAS, acting in a cis-regulatory manner, downregulated SNRK expression via RNA-mRNA interaction in EC. The passaging of primary EC and X-ray irradiation (XRI) substantially decreased SNRK protein levels, while elevating SNRKAS levels; SNRK overexpression reversed XRI-induced protein and mRNA upregulation of p16, a cellular senescence marker. Furthermore, SNRK was required for the expression of lamin B1, while negatively regulating the stimulator of interferon genes (STING) signaling in EC. Finally, endothelial SNRK deficiency in mice promoted endothelial senescence, aortic stiffness, and atherogenesis
in vivo
.

Conclusions:
We conclude that lncRNA SNRKAS acts as a negative regulator of endothelial senescence via downregulation of SNRK.
Abstract 4141948: Direct and Indirect Relationships between Historic Redlining and Prevalence of Diabetes
Authors: Campbell Jennifer , Walker Rebekah , Linde Sebastian , Egede Leonard
Published: November 2024

Background:
Structural racism has emerged as an important contributor to poor health outcomes. Historic redlining, the previously legal practice of systematically denying credit access and insurance, resulted from Home Owners’ Loan Corporation (HOLC) residential security maps graded on a color coded scale (A (Green)=Best; B (Blue); C (Yellow); D (Red)=Hazardous), hence the term redlining. The goal of this study was to investigate the direct and indirect relationships between historic redlining and prevalence of diabetes in a national sample.

Methods:
We combined census tract level data across multiple sources: a) diabetes prevalence from CDC PLACES 2019 database, b) HOLC grade from Mapping Inequality project, and c) incarceration risk, poverty, housing, education, employment, job environment, economic mobility, and demographics, from Opportunity Insights database. The assignment of redlining to present-day census tract was done based on overlap with historically HOLC graded areas. The final analytic sample consisted of 9,590 US census tracts. Structural equation modeling was then used to investigate direct and indirect relationships between redlining and diabetes prevalence through possible mediators of health care access, community resources, social capital, and social risk. Stata v16 was used for the analysis and analyses were adjusted for population.

Results:
Higher prevalence of diabetes was directly associated with more redlining within a census tract (0.28, p<0.001). All indirect paths were significant with the three strongest indicating diabetes prevalence is indirectly associated with redlining via health care access (0.48, p<0.001); community resources measured via education level (-0.44, p<0.001); and social risk measured via income (-0.23, p<0.001). Figure 1 shows standardized coefficients to allow comparison with higher numbers indicating stronger relationships.

Conclusions:
Consistent with our conceptual framework, redlining has significant direct and indirect relationships with diabetes prevalence. Indirect relationships include health care access, community resources including employment and education, social capital, and social risk factors of low income and high incarceration.
Abstract 4141955: A Case of Dilated Cardiomyopathy and Systemic Thromboembolism in a Young Patient on Testosterone Replacement Therapy
Authors: Sabri Muhammad , Ijaz Naila , Nadeem Ramsha , Checchio Lucy , Riaz Faiza
Published: November 2024

Introduction:
Whereas low testosterone levels have been associated with poor cardiovascular outcomes and testosterone replacement therapy (TRT) in middle-to-older age adults with cardiovascular risk factors is considered safe, there is little data on the adverse cardiovascular effects of TRT in young adults.

Case Report:
A 38-year-old male with a past medical history of hypogonadism, recently started on intramuscular testosterone cypionate injections, presented to the hospital with altered mentation. Laboratory workup was remarkable for hemoglobin of 19 g/dL. Computed tomography (CT) angiogram of the head demonstrated a left middle cerebral artery infarct with a filling defect, requiring mechanical thrombectomy. A transthoracic echocardiogram (TTE) was done which revealed a dilated left ventricle (LV) with severely reduced LV systolic function, EF 20%, and global hypokinesis. There was no LV thrombus or evidence of a patent foramen ovale with contrast saline injection. He did not have any episodes of atrial fibrillation on telemetry monitoring. His hospital course was further complicated by an inferolateral ST elevation myocardial infarction (STEMI) due to distal left anterior descending (LAD) artery occlusion. He underwent drug-eluting stent placement and was started on dual antiplatelet therapy. Repeat TTE demonstrated new apical akinesis along with an LV apical thrombus of 1.1 x 0.8 cm. CT abdomen/pelvis with contrast demonstrated left renal and right iliofemoral thrombosis and the patient was also started on systemic anticoagulation.

Discussion:
Data suggests that physiologic levels of testosterone exhibit cardioprotective effects and low testosterone levels are associated with increased cardiovascular mortality. However, studies have also shown that testosterone use is associated with an increased risk of thrombosis and coronary artery disease. Additionally, testosterone use has been associated with myocardial apoptosis and adverse cardiac remodeling from dysregulation of androgenic receptors, which results in dilated cardiomyopathy. There is an ongoing debate on the safety of TRT, however, studies on TRT have largely included the middle and older male population and there is little data on younger patients. Herein, we demonstrate a case of TRT in a patient with several cardiovascular risk factors, who developed evidence of possible TRT-associated cardiomyopathy in addition to hypercoagulability.
Abstract 4141959: Neighborhood Disadvantage is Associated with Uncontrolled Blood Pressure and Therapeutic Inertia among Older Adults with Hypertension
Authors: Saban Michael , Tootooni M. Samie , Markossian Talar , Wozniak Amy , Hiura Grant , Probst Beatrice , Habicht Katherine , Kramer Holly
Published: November 2024

Blood pressure (BP) control among older adults may differ by neighborhood due to differences in access to healthy foods, safe places to exercise, and stress. Neighborhood disadvantage may also influence clinician behaviors for hypertension management.

This retrospective observational study utilized electronic health data from 52,750 primary care visits among 8,434 adults age ≥ 65 years with hypertension between January 1, 2017, and March 10, 2020 to examine the association of Area Deprivation Index (ADI) with odds of uncontrolled BP during a clinic visit and with therapeutic inertia (TI). Higher ADI values indicate higher deprivation. TI was defined as the absence of a prescription for or escalation of a new BP lowering medication during clinic visits with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. Binary generalized linear mixed models were used to determine the association of ADI quartiles with uncontrolled BP and with TI during a clinic visit while adjusting for demographics, comorbidities, insurance status, and the intra-patient correlation. Among the 8,434 patients, the mean age at the first visit was 74.3 years (standard deviation 7.8), 57.7% were female, and race/ethnicity was self-reported as non-Hispanic (NH) White in 69.1%, NH Black in 15.9%, NH Other in 5.0%, and Hispanic in 8.2%. The median ADI was 41 (interquartile range: 26-53). The percentage of clinic visits with uncontrolled BP ranged from 39.1% in the first to 44.1% in the fourth ADI quartile.

Figure 1 shows the unadjusted and adjusted odds of uncontrolled BP and TI by ADI quartiles. Adjusted odds of uncontrolled BP during a clinic visit was 1.17 (95% confidence interval (CI) 1.06, 1.28) in the fourth vs. first ADI quartile. Among the 21,928 clinic visits with uncontrolled BP, TI occurred in 79.5%, 82.2%, 83.0%, and 81.6% of visits in ADI quartiles one, two, three, and four, respectively. Adjusted odds of TI during a clinic visit was 1.16 (95% CI 1.01, 1.33) in the fourth vs. first ADI quartile.

Our findings of higher odds of uncontrolled BP and TI during clinic visits with patients residing in neighborhoods with higher vs. lower ADI suggest that neighborhood disadvantage is associated with both uncontrolled BP and TI in older adults.
Abstract 4141966: Myotonic Dystrophy type I (DM1) Impairs Cardiac Bioenergetics and Disrupts Cardiac Mitochondrial Fusion-Fission Dynamics
Authors: Adesanya Oluwafolajimi , Nabie Pouya , Natua Subhashis , Kalsotra Auinash
Published: November 2024

Background:
DM1 is the commonest cause of adult-onset muscular dystrophy, affecting 1-in-2100 people in the U.S. DM1 is a (CTG)n trinucleotide repeat expansion disease in the 3’UTR of the DMPK gene. Once expressed, the repeat RNA form toxic hairpins, which sequester the muscle blind-like (MBNL) family of splicing factors. This induces tissue-wide disruption of alternative splicing events, resulting in DM1 symptoms, including muscle weakness, neurological defects, and cardiomyopathy. Recent reports have demonstrated impaired mitochondrial function in the brain, skeletal muscle, and fibroblast of DM1 patients, these have however, not been reported in the heart, nor have their potential contribution to the pathogenesis of DM1 cardiomyopathy been explored.

Methods:
Using an inducible, cardiomyocyte-specific DM1 mouse model (aka MHCrtTA:TRE960i), we performed extracellular flux analysis on cardiac mitochondrial fractions obtained from heart tissue of control and DM1 mice. This was accompanied by quantification of ATP production, to determine oxidative phosphorylation (OXPHOS) efficiency. Further, we performed transmission electron microscopy (TEM) and TOM20 immunofluorescence (IF) microscopy to assess the integrity of mitochondrial network in DM1 mice. Finally, we performed gene expression studies to identify mis-splicing events involving mitochondria-related genes and validated these in heart tissues obtained from both DM1 mice and deceased human DM1 subjects.

Results:
DM1 induced a multi-state increase in cardiac oxygen consumption rate (OCR) which was however accompanied by decreased ATP levels (2.83µM/10µg vs. 2.45µM/10µg,
p
=0.0079) indicating reduced cardiac OXPHOS efficiency. DM1 also induced a disruption of mitochondria network, with increased mitochondria fragmentation seen on IF microscopy, and expansion of the intermyofibrillar mitochondria compartment seen on TEM. These findings correlated with the mis-splicing of mitochondrial fission factor (MFF), with an increased skipping of
Mff
exon 6 in DM1 mice (ΔΨ: -16.8%,
p
=0.0069) and human DM1 heart tissue (ΔΨ: -19%,
p
<0.01) compared with controls. Interestingly, this resulted in the increased expression of a shortened 29kDa MFF protein isoform in DM1 mice (Δ%29kDa: 47%,
p
=0.0003) and human (Δ%29kDa: 21.1%,
p
<0.0001) heart samples relative to controls.

Conclusion:
DM1 impairs cardiac bioenergetic function potentially through the mis-splicing of critical genes regulating mitochondrial fusion-fission dynamics.