bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4132769: Carnosine Supplementation Improves Walking Ability of Peripheral Arterial Disease Patients
Authors: baba Shahid , Dwivedi Amit , Chaudhari Mamata , Doelling Benjamin , Kulkarni Manjuri , Hoetker David , O Toole Timothy , Haysley Leslie , Krivokhizhina Tatiana , Lorkiewicz Pawel , Riggs Daniel , Bhatnagar Aruni
Published: November 2024

Introduction:
Peripheral artery disease (PAD) is a significant cause of cardiovascular morbidity and mortality, characterized by atherosclerosis in the skeletal muscle. Currently no mechanism-based therapeutics are available for this diseased population. In the muscle, histidyl dipeptides, such as carnosine (ranging between 5-10 mM) possess the abilities to bind with toxic lipid peroxidation products, such as acrolein. Preclincial studies show carnosine is depleted in the ischemic leg, increasing intramuscular carnosine improves angiogenesis, and blood flow in the ischemic leg. In humans, carnosine levels are increased in the muscle with carnosine supplementation. However, little is known whether carnosine levels are affected in PAD patients and its effect on their walking ability.

Hypothesis:
Carnosine supplementation will improve walking ability of PAD patients.

Methods:
We recruited normal (males: n=48; females: n=52; age: 50 ±10 years) and PAD subjects (males: n=52; females: n=41; age: 67±8 years; ankle brachial index (ABI): 0.65±0.18 measured urinary histidyl dipeptides, histidyl dipeptide-aldehyde conjugates, and oxidative stress markers: N-Acetyl-S-(3-hydroxypropyl)-L-Cysteine (3-HPMA) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA), both are acrolein metabolites. PAD subjects (n=7; n=5 females and n=2 males; ABI: 0.68±0.08, age: 63±8 years) were supplemented with carnosine 2 g/day for 3 months, measured distance covered in a six-minute walk test (6MWT), ABI, blood profile at baseline and after completion.

Results:
In PAD subjects urinary carnosine was decreased (normal: 20±29
vs
PAD:11±14 nmoles/mg creatinine, p<0.024), carnosine aldehdye conjugates were increased (carnosine propanal: 1.46±1.27 vs normal 0.56±1.08 nmoles/mg creatinine, p<0.0001; and carnosine propanol: 4.66±2.80 vs normal 1.52±1.21 nmoles/mg creatinine, p<0.0001). Oxidative stress markers were increased in the PAD subjects (CEMA: 341±210
vs
normal: 119±86 ng/mg creatinine, p<0.0004 and 3HPMA: 6.57±6.32 ng/mg protien
vs
normal: 5.49±5.28 ng/mg creatinine, p<0.001). Following carnosine supplementation, blood profile was unchanged. Distance covered in 6MWT increased by 166±204 feet (before: 577±129 vs 743±152 feet after, p<0.048) and there was an increasing trend in ABI (before: 0.68±0.08 vs 0.80±0.19; after, p<0.18).

Conclusion:
Urinary carnosine could serve as a biomarker to evaluate PAD pathology and carnosine supplementation may improve walking ability of PAD patients.
Abstract 4132838: Coronary Collaterals Provide Cardioprotection in Hemorrhagic ST-elevation MI (STEMI)
Authors: Vora Keyur , Shah Chirag , Sighaka Sighaka Damien , Saleh Akrum , Panyala Nitya , Kumar Andreas , Kalra Ankur , Dharmakumar Rohan
Published: November 2024

Introduction:
Development of intramyocardial hemorrhage (IMH) in acute STEMI following reperfusion is estimated to affect 35-50% of patients. IMH is a lethal event as it contributes to larger MI size, compromised myocardial salvage, adverse left ventricular (LV) remodeling, lower LVEF, and consequential major adverse CV events post-MI. Whether coronary collateral circulation reduces the deleterious effects of IMH has not been investigated.

Hypothesis:
We hypothesized that coronary collaterals could reduce the extent of post-reperfusion IMH volume and offer cardioprotection to hemorrhagic MI patients.

Methods:
MIRON-CL (NCT05898425) recruited and studied STEMI patients (n=294) reperfused via PCI. Pre-PCI coronary angiography allowed for assessment of collateral vessels using the Rentrop grading system, from Grade 0 (no collaterals) to Grade III (complete collateral filling). Post-PCI cardiac MRI, performed 3 days later, was used to determine area affected (extent of myocardial edema) from T2 maps, extent of IMH from T2* maps and MI size from LGE as %LV. Statistical analyses were used to examine relationships between collateral grades, MI size, IMH, and area affected.

Results:
124 patients were hemorrhagic and 170 were non-hemorrhagic. Patients with no collaterals (Grade 0; CL-) exhibited significantly higher IMH volumes (7.41 ± 5.33% LV) compared to those with collaterals (Grade I: 5.23 ± 3.21% LV, Grade II: 3.11 ± 2.78% LV, Grade III: 2.05 ± 1.89% LV; p<0.001). Total area affected post-PCI was larger in CL- (37.62 ± 15.32% LV) compared to CL+ (21.48 ± 13.21% LV, p<0.001). Presence of collateral circulation (Grade>0 combined; CL+) was correlated with smaller MI sizes (CL-: 38.66 ± 14.63% LV vs. CL+: 19.84 ± 13.72% LV, p<0.001) and reduced MVO volumes (CL-: 8.07 ± 6.60% LV vs. CL+: 2.17 ± 2.35% LV, p<0.001). Patients with no collaterals had a significantly higher adj. risk of IMH (OR: 5.71, 95% CI: 3.16-10.33, p<0.0001).

Conclusion:
Coronary collaterals reduce post-reperfusion IMH volume in STEMI patients and provide significant cardioprotection: reductions in area affected, MVO and MI size. Insight into collateral grade offers opportunities to improve risk stratification and management of revascularized STEMI patients.
Abstract 4132909: Hemodynamic Indices of Right Ventricular Function Differentially Predict Adverse Clinical Outcomes in Heart Failure with Preserved vs Reduced Ejection Fraction
Authors: Kosyakovsky Leah , Parekh Juhi , Zern Emily , McNeill Jenna , Pomerantsev Eugene , Picard Michael , Dudzinski David , Lau Emily , Ho Jennifer
Published: November 2024

Background:
While the critical role of right ventricular dysfunction (RVD) in heart failure (HF) is increasingly recognized, the prevalence and prognostic impact of RVD across HF subtypes is poorly understood.

Research Questions/Aims:
We aimed to characterize differences in hemodynamic indices of RV function among patients with HF with preserved vs reduced ejection fraction (HFpEF, EF≥50% vs HFrEF, EF<50%) and to examine associations of RVD with longitudinal clinical outcomes by HF subtype.

Methods:
We identified patients with prevalent HF undergoing clinically indicated right heart catheterization at Massachusetts General Hospital (2005-2016). We examined three RV hemodynamic indices: right atrial to wedge pressure ratio (RA/PCWP), RV stroke work index (RVSWI), and pulmonary artery pulsatility index (PAPi). We used multivariable linear regression to assess differences in RV indices in HFpEF vs HFrEF. We then used Cox models to examine the association of each index with HF hospitalizations (HFH), major adverse cardiac events (MACE), and death, stratified by HF subtype. Models were adjusted for age, sex, BMI, hypertension, diabetes, lung disease, sleep apnea, and prior MI.

Results:
Of 2,062 patients (age 66 years, 33% women), 1,242 (60%) had HFrEF and 820 (40%) had HFpEF. RVD (RVSWI <450 mm Hg*ml/m
2
) was present in 27% of HFrEF vs 21% of HFpEF patients. Those with HFpEF had higher RA/PCWP (β 0.12, SE 0.05, p=0.012) and RVSWI (β 0.22, SE 0.05, p<0.001) relative to HFrEF. Over 4.1 median years follow-up, 915 HFH, 1,066 MACE, and 1,116 death events occurred. Among those with HFrEF, lower PAPi was associated with greater risk of HFH (HR 0.84 (0.77, 0.92); p<0.001) and MACE (HR 0.88 (0.81, 0.96); p=0.003), and higher RVSWI was associated with greater risk of death (HR 1.17, (1.07, 1.27); p<0.001,
Figure
). In contrast, in those with HFpEF, only higher RA/PCWP was associated with greater risk of death (HR 1.11 (1.00, 1.23); p=0.042).

Conclusion:
RVD occurs frequently in both HFrEF and HFpEF, and hemodynamic measures of RV function are associated with greater risk of MACE, death, and HFH. Importantly, the prognostic value of RV indices varied by HF subtype, highlighting key differences in the role of RVD in HFrEF vs HFpEF.
Abstract 4133040: Cardiac Favored Transcription of the Exogenous Gene in Mice after A Single Systemic Delivery of AAV9-cBIN1
Authors: Ha Thuy , Li Jing , Balmaceda Pia , Shaw Robin , Hong Tingting
Published: November 2024

Introduction:
Heart failure (HF) is associated with high mortality and morbidity, and there are limited therapeutic options available to improve cardiac muscle function. Recent studies suggest that the impairment of cardiomyocyte T-tubule microdomains is a key factor in HF pathophysiology. AAV9-cBIN1 gene therapy effectively addresses this impairment. However, the kinetics and biodistribution of AAV9-cBIN1 have not been explored, limiting the knowledge of the transcription efficiency and organ specificity of cBIN1 gene therapy when delivered systemically.

Aim:
This study aims to elucidate the kinetics and biodistribution of AAV9-cBIN1 in a murine model.

Method:
Adult male C57BL/6J mice (n=20) were administered a single retro-orbital injection of AAV9-CMV-cBIN1-V5 at a dose (2x10^12 vg/kg) known to effectively transduce the majority of cardiomyocytes. Mice were sacrificed at pre-determined time points: prior to injection (Day 0, n=2) and post-injection at Days 3, 7, 14, 28, 56, and 84 (n=3/group). Tissues were harvested from the heart, lung, liver, kidney, skeletal muscle, and spleen. Genomic DNA was extracted and analyzed using qPCR to determine vector genome (vg) copies. For transcriptional analysis of the AAV9-transduced exogenous gene, mRNA was extracted and converted to cDNA for qRT-PCR quantification of
cBin1-V5
, normalized to the housekeeping gene
Hprt1
.

Results:
All mice survived to their designated sacrifice times. Kinetic analysis demonstrated a time-dependent expression of the exogenous
cBin1-V5
gene, with peak expression observed at 4 weeks in both the heart and liver, with expression declining in the liver after this peak (Figure 1A). Genomic DNA analysis showed a gradual increase and plateau of viral genome distribution in the heart between 2-4 weeks, while in the liver, distribution peaked sharply between Days 3-7 and then decreased. When correcting the gene transcription of
cBin1-V5
(ΔCq of
V5/Hprt1
) for vector DNA vg copies in the tissue, the transcription efficiency in the heart was higher than in the liver (Figure 1B). Outside of the liver and heart,
cBin1-V5
mRNA expression was undetectable in all other tissues by Day 56.

Conclusion:
In adult male mice, a single systemic administration of AAV9-cBIN1 results in robust transduction and higher transcription efficiency in the heart compared to the liver. AAV9-cBIN1 holds promise for targeted gene therapy in cardiac tissues, with minimal off-target expression in other organs.
Abstract 4133170: Insulin resistance triggers histamine release from endothelial cells, which disrupts endothelial barrier function and causes vasoconstriction.
Authors: Brishti Masuma Akter , Leo M
Published: November 2024

Diabetic vascular dysfunction is a serious health concern, affecting ~38 million people in the USA, according to the 2020 CDC-National Diabetes Statistics Reports. Type 2 diabetes (T2D) causes several vascular changes leading to major clinical consequences such as stroke and ~3-fold elevated risk of cardiovascular diseases (CVD) and the underlying causes of vascular dysfunction in T2D are complex. The anatomical position of endothelial cells (ECs) between the circulating blood and vessel walls makes them the first to encounter and respond to cellular stressors in the bloodstream. Here, we investigated the role of long-term increases in plasma histamine levels as observed in T2D and its effects on ECs and vascular contractility. The high-fat diet-low-dose streptozotocin protocol induced T2D in C57BL/6J mice. Endothelial cell function was analyzed using Western blotting,
in vitro
blood-brain barrier assays, histamine measurements, immunofluorescence, and pressurized artery myography. In our T2D model, EC-mediated histamine synthesis occurred after the onset of IR. A spike in plasma histamine levels was observed immediately following the onset of insulin resistance, followed by a brief plateau. A second spike in plasma histamine levels was noted four weeks later. In isolated control ECs, the addition of external histamine showed a concentration-dependent increase in histidine decarboxylase expression, and cellular histamine levels were observed, which was inhibited by the H2R blocker, famotidine. The tight junction marker, JAM-A (CD321), expression in diabetic cerebral arteries was ~42% less compared to the non-diabetic controls. Transendothelial Electrical Resistance testing showed a ~2-fold higher permeability with diabetic ECs than controls. Pressure myography on isolated cerebral arteries indicated that external histamine passed through the lumen of arteries from T2D mice 4 weeks after onset of IR constricted whereas control arteries dilated. Additionally, T2D mice cerebral artery myogenic tone at 60 mmHg was 70% greater compared to control arteries. These data indicate that the onset of IR triggers an increase in circulating histamine levels, which in turn stimulates histamine synthesis and release from endothelial cells leading to the loss of endothelial barrier function, blood-brain barrier leakage, and vasoconstriction. We are currently investigating the molecular pathways that precede the increase in circulating histamine levels during T2D.
Abstract 4133257: Circulating Ketone Bodies, Lipoprotein(a) and Incident Cardiovascular Outcomes and Mortality: Insights from The UK Biobank
Authors: Chevli Parag , Mirzai Saeid , Kazibwe Richard , Rikhi Rishi , Bhatia Harpreet , Slipczuk Leandro , Gianos Eugenia , Pagidipati Neha , Shapiro Michael
Published: November 2024

Background:
Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent epidemiological studies have revealed an association between ketone bodies (KB) and adverse cardiovascular outcomes, offering a unique insight into metabolic health and its impact on mortality risk. Elevated levels of both Lp(a) and KB may synergistically amplify pathological processes, including endothelial dysfunction, inflammation, and oxidative stress, through their involvement in shared pathophysiological pathways, thereby exacerbating disease progression beyond the impact of each biomarker individually.

Methods:
Utilizing data from the UK Biobank, KB were measured by nuclear magnetic resonance spectroscopy and serum Lp(a) concentrations were measured using an immunoturbidimetric assay. Four groups were created as follows: Group 1: Lp(a)<125 nmol/L and Total KB<75
th
percentile (<94 μmol/L); Group 2: Lp(a)≥125 nmol/L and Total KB<75
th
percentile; Group 3: Lp(a)<125 nmol/L and Total KB≥75
th
percentile; and Group 4: Lp(a)≥125 nmol/L and Total KB≥75th percentile. Multivariable-adjusted Cox proportional hazard models were used to examine the association of Lp(a) and total KB with incident cardiovascular outcomes and mortality.

Results:
A total of 72,704 UK Biobank participants (mean age 56 y, SD=8, 55% women) without prevalent CVD or HF with a median follow up of 13.4 years were included. In the fully adjusted model, compared with those in the reference group (Group 1), participants in Group 2, Group 3, and Group 4 demonstrated a 14%, 17%, and 38%, increased risk of incident ASCVD events, respectively (p<0.01 for all). However, those with Lp(a) ≥ 125 nmol/L and total KB < 75th percentile demonstrated no increased risk of HF, all-cause mortality, stroke, or CVD mortality. Participants with elevated levels of both Lp(a) and KB had significantly increased risk of all outcomes (Table). There was no evidence for a statistically significant interaction between Lp(a) and KB on any outcome.

Conclusion:
Consistent with prior literature, Lp(a) was associated with atherosclerotic outcomes. However, elevated KB was associated with all outcomes, irrespective of Lp(a) levels.
Abstract 4133460: VCAM1 contributes to pathogenesis during influenza-induced exacerbation of atherosclerosis.
Authors: CHINNAPPAN BASKARAN , DeVito Louis , Constantinesco Nicholas , Moras Crystal , Srikanth Sashwath , Alcorn John , Gopal Radha
Published: November 2024

Background and hypothesis:
Influenza is a significant public health and economic threat around the world. Although pneumonia is the most common complication associated with influenza, there are several clinical reports demonstrating increased risk for cardiovascular disease. Influenza infection induces interferons, proinflammatory cytokines and chemokines, and recruits’ macrophages and neutrophils to control the virus. However, an excessive influx of innate immune cells and dysregulated production of inflammatory mediators results in pathological responses during influenza infection. Studies have shown that influenza infection correlates with increased incidence of myocardial infarction. Atherosclerosis is the most known cause of ischemic heart diseases and stroke. Vascular cell adhesion molecule-1 (VCAM1) has been shown to promote adhesion of monocytes and promotes atherosclerosis. In this study, we hypothesize that VCAM1 plays a role in exacerbation of atherosclerosis during influenza infection.

Methods:
High-Fat diet (HFD)-fed Apoe
-/-
mice were infected with influenza A/PR/8/34 (H1N1) and weight loss, survival rate, and gene expression of vascular endothelial adhesion molecules, inflammatory cytokines and chemokines were measured. HFD-fed Apoe
-/-
mice were infected with influenza, and treated with anti-VCAM1 antibody, and weight loss and cellular responses were measured.

Results and conclusions:
Increased weight loss and decreased survival of mice were observed in response to influenza infection in HFD-induced atherosclerosis in Apoe
-/-
mice. Further, the expression of VCAM1, and the levels of IL-6, CCL2, CCL3, CCL5 were significantly increased in aorta in Apoe
-/-
mice when compared to PBS-treated controls. Increased survival, decreased weight loss, decreased lesion area, decreased frequency of CD11b
+
F4/80
+
Ly6C
+
, CD4
+
RORgt
+
cells and increased frequency of CD4
+
FoxP3
+
Treg cells were observed in aorta in response to antibody mediated VCAM1 neutralization. These results suggest that VCAM1 plays a pathological role in influenza-induced exacerbation of atherosclerosis.
Abstract 4133488: Persistent Disparities in Chronic Ischemic Heart Disease-Related Mortality across Age, Sex, Race/Ethnicity in the United States, 1999 - 2020
Authors: Kwaah Patrick , Mensah Samuel , Appah Grace , Carboo Abraham , Boampong Amoafo , Djanie Stephen Nii-Ashie , Kwakye Ama Owusuaa , Agyemang Emmanuel Ababio , Kekrebesi Joseph , Donaldy Webster , Nti Patrick
Published: November 2024

Background:
Chronic Ischemic Heart Disease (CIHD) is a heterogeneous group of cardiac diseases that cause significant morbidity and mortality. Previous studies demonstrated a decline in CIHD mortality rate (MR) but there is paucity of data on contemporary trends across different demographics in the United States (US). We examined the national trends in age-adjusted CIHD-MR (overall and stratified by demographics) in the US from 1999 to 2020.

Methods:
We retrospectively analyzed national death certificate data from the CDC WONDER database from 1999 to 2020. The underlying cause of death from CIHD was identified with ICD-10 code I25 in adults aged ≥35 years and the age-adjusted mortality rate was calculated per 100,000 population. We categorized race/ethnicity as Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Latino or Hispanic, and other non-Hispanic groups. Trends in age-adjusted CIHD-MR (AAMR) were analyzed by age, gender, race/ethnicity, and geographic region were evaluated with Joinpoint regression, and expressed as an average annual percentage change (AAPC) with a 95% confidence interval. For sensitivity analysis, we repeated the study with data from death certificates that had CIHD as a contributing cause of death.

Results:
Out of 3.55 billion people aged ≥ 35 years, 5,985,088 died of CIHD (AAMR: 158.2 per 100, 000) [53.9% male, 81.6% NHW, 38.8% ≥85 years]. The AAMR was highest in males, the Northeast region, and NHB (Table 1). The AAMR was highest in those aged ≥85 years and was directly related to age (35-44 years: 8.3 per 100,000; ≥85 years: 1,943 per 100,000). The CIHD AAMR declined significantly overall in males, all races/ethnicities, and geographical areas (Table 1). Reanalysis (Sensitivity analysis) with any mention of CIHD as a contributing cause of death showed similar trends.

Conclusion:
Over the 22 years, CIHD-related mortality in the US has declined overall and for almost all demographic groups. However, there are age, gender, and racial disparities in the CIHD AAMR. These findings highlight the need for further longitudinal studies to understand the drivers of these disparities and for focused public health interventions to improve CIHD mortality outcomes in these populations.
Abstract 4134148: Reduced BMPR2 in Monocytes De-represses HERV-K and Sustains Inflammation in Pulmonary Arterial Hypertension
Authors: Adil Mir , Cao Aiqin , Lago-Docampo Mauro , Zhang Chongyang , Rabinovitch Marlene
Published: November 2024

Background&Rationale:
Human endogenous retroviral (HERV) elements are embedded in 8% of our genome. They remain quiescent but can be transiently activated by viral infection to induce an interferon (IFN) response. In pulmonary arterial hypertension (PAH), HERV-K expression is elevated in myeloid cells, and thus can promote inflammation observed in pulmonary arteries (PAs) with progressive obstructive remodeling. PAH is linked to a mutation or a decrease in BMPR2 expression which our laboratory has recently shown in monocytes (MONO). HERVs are silenced by SUMOylated (S) TRIM28 (KAP1, a methylase) and SPEN (a histone deacetylase) factors that are also sequestered by the lnc RNA
XIST
which is increased in females to inactivate the extra X-chromosome. When TRIM28 is phosphorylated (P) by DNA-PK, it loses methylase activity and can act as a transcription factor.

Hypothesis:
Reduced
BMPR2
in MONO results in DNA-PK mediated P-TRIM28 causing demethylation of
XIST
targets (X-related genes) and
HERV-K
thus increasing their expression. Competitive SPEN binding to the increased
XIST
also de-represses
HERV-K
.

Approach:
We used THP-1 MONOs with
BMPR2
shRNA and induced pluripotent stem cell (i) MONOs derived from
BMPR2
mutant PAH patients and assessed
HERV-K
,
XIST
, IFNs and related our findings to DNA-PK–P-TRIM28 and sequestration of SPEN.

Results:
XIST
and
HERV-K
mRNA were significantly elevated in THP-1 MONOs with shBMPR2 vs. shControl and in PAH-iMONO vs. control iMONO based on gender. Reduced
BMPR2
also increased IFN genes. These findings were consistent with nuclear DNA-PK and P-TRIM28 shown to bind in affinity purification mass spectrometry analysis. Bisulfite conversion assay demonstrated decreased methylation of HERV-K in
BMPR2
-deficient MONOs attributed to a reduction in the methylase S-TRIM28. RNA-IP in THP-1 MONOs with shBMPR2 vs. shControl indicated increased binding of
XIST
with TRIM28 and SPEN, suggesting a competitive reduction in binding to HERV-K.

Conclusions:
Loss of BMPR2 increases
XIST
and
HERV-K
in MONO related to DNA-PK induced P-TRIM28 and reduced methylase S-TRIM28. Increased
HERV-K
may also be a function of the increase in
XIST
sequestering its deacetylase SPEN. These molecular features underlie a chronic
HERV-K
-IFN inflammatory response in PAH. They may explain the female predisposition to PAH, because the increase in
XIST
in females heightens the propensity to activate
HERV-K
-IFN signaling and chronic inflammation in PAs infiltrated by MONO.
Abstract 4134249: Cardiovascular Risk Factors and Associations of Chronic Inflammatory-Related Disease in the Multi-Ethnic Study of Atherosclerosis
Authors: Manning Evan , Shroff Gautam , Jacobs David , Duprez Daniel
Published: November 2024

Background:
Inflammation plays a role in the development of cardiovascular disease (CVD). We have defined various non-cardiovascular and non-cancer conditions, both infectious and non-infectious, with a common basis of inflammation; collectively termed Chronic Inflammatory-Related Disease (ChrIRD). We have previously described that ChrIRD is common, associated with baseline inflammatory marker levels, associated with high mortality, and has a bidirectional association with CVD. The clinical implications of these data require further study.

Aims:
We hypothesize that many traditional risk factors for CVD are also associated with ChrIRD and that ChrIRD has additional unique risk factors. We also hypothesize that the treatment of traditional CVD risk factors is associated with a decreased likelihood of ChrIRD.

Methods:
We studied MESA participants free of overt CVD or significant illness at baseline. ChrIRD was determined based on review of ICD codes for hospitalizations and deaths. Incident CVD was adjudicated by review of medical records. We performed proportional hazards regression (time-dependent for CVD) to identify factors associated with a first diagnosis of ChrIRD. All variables were simultaneously entered into the model.

Results:
Participants (n=6155) had mean age 62±10 years and 47% male gender. ChrIRD was observed in 24% and CVD in 18%; including 8% with both conditions. Participants with a diagnosis of CVD, older age, higher heart rate, higher BMI, current or ever smoking status, higher HDL, higher baseline IL6 and GlycA levels, and NSAID use had increased likelihood of ChrIRD. Whereas those with female sex, higher total cholesterol, and statin use had a decreased likelihood of ChrIRD. Participant race/ethnicity, blood pressure, diabetes status, antihypertensive use, aspirin use, baseline CRP level, and baseline D-dimer level were not associated with ChrIRD. Regression results are summarized in Table 1.

Conclusions:
ChrIRD shares some risk factors with CVD, while other risk factors are opposite.

Better understanding of ChrIRD could eventually lead to improved patient care.
Abstract 4134273: Low 5-hydroxytryptamine levels are associated with adverse outcomes in patients with heart failure with preserved ejection fraction
Authors: Ogawara Ryo , Misaka Tomofumi , Okochi Satoshi , Ichimura Shohei , Sato Yu , Yokokawa Tetsuro , Sato Akihiko , Shimizu Takeshi , Oikawa Masayoshi , Kobayashi Atsushi , Yoshihisa Akiomi , Takeishi Yasuchika
Published: November 2024

Background:
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome and its pathophysiology is not fully understood. A monoamine, 5-hydroxytryptamine (5-HT), is involved in diverse biological functions and suggested to play a role in cardiovascular diseases. However, the clinical relevance of 5-HT in HFpEF remains unclear.

Aims:
This study aimed to elucidate the clinical significance and prognostic value of 5- HT in patients with HFpEF.

Methods:
We conducted a prospective study involving 240 consecutive hospitalized patients with HFpEF (mean age 72 years, 52% male). We measured circulating blood 5-HT levels using the enzyme-linked immunosorbent assay method. Clinical and outcome data were collected.

Results:
Correlation analysis revealed that 5-HT levels were negatively correlated with blood B-type natriuretic peptide concentration and tricuspid regurgitation pressure gradient. When patients were stratified into two groups based on the median 5-HT levels (90.5 ng/mL), Kaplan-Meier analysis showed that HFpEF patients with low blood 5-HT levels had lower event-free survival rates from the composite event of cardiac death and worsening heart failure over a median follow-up period of 725 days (Figure). In a multivariable Cox proportional hazard model adjusting for confounding variables, low levels of 5-HT were independently associated with increased risks of the composite of cardiac events (hazard ratio, 3.25; P < 0.01).

Conclusion:
Low 5-HT levels are associated with adverse outcomes in patients with HFpEF and 5-HT may serve as a useful biomarker for predicting prognosis in such patients.
Abstract 4134298: Dipeptidyl Peptidase 4 Promotes Pressure Overload-Induced Heart Failure through enhancing Antigen Presentation
Authors: Yu Kun , Liao Minyu , Tang Du , Ling Wang , Zhu Wenqiang , Liu Xiaohui , Zhong Jixin , Rao Xiaoquan
Published: November 2024

Background:
Antigen presentation to CD4+ T cells plays a critical role in heart failure (HF). Dipeptidyl peptidase 4 (DPP4) has been shown to promote the activation of T lymphocytes. This study aims to investigate the role of DPP4 in antigen presentation in pressure overload-induced HF.

Methods:
To examine the role of DPP4 in antigen presentation during HF, we tested the recruitment and function of dendritic cells (DCs) in transverse aortic constriction (TAC)-induced HF mice. To further investigate, we generated DPP4 knockout mice and induced bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs were then adoptively transferred into OT-II mice, whose DCs require specific exogenous ovalbumin loading to activate CD4+ T cells. RNA-Seq analysis was performed to elucidate the mechanisms by which DPP4 affects the function of DCs.

Results:
We observed an increased quantity of DCs in the hearts and mediastinal lymph nodes of TAC mice, accompanied by elevated expression of DPP4. These DCs exhibited enhanced antigen-presenting abilities, resulting in increased activation of CD4+ T cells. DPP4 knockout suppressed DC maturation and attenuated their antigen-presenting capabilities. We found that OT-II mice subjected to TAC showed preserved cardiac function compared to wild-type (WT) mice. However, OT-II mice that received adoptive transfer of DPP4+/+ BMDCs exhibited worse cardiac function compared to those receiving DPP4-/- BMDCs, indicating that DPP4 in DCs contributes to HF progression. RNA-Seq analysis indicated that DPP4 in DCs influenced the T cell receptor signaling pathway and T cell differentiation. Mechanistically, DPP4 was found to inhibit the E3 ubiquitin ligase MARCH1 from binding to MHCII, thereby stabilizing MHCII through preventing its ubiquitin-dependent degradation in DCs.

Conclusion:
This study elucidates the significance of DPP4 in enhancing antigen presentation during heart failure. We propose that DPP4 represents a potential therapeutic target for heart failure.
Abstract 4134340: Title: Comorbidities Associated with One Year Mortality and Hospital Readmission After Leadless Pacemaker Implantation
Authors: Brodeur Peter , Ferro Enrico , Maher Timothy , Yang Shu , Waks Jonathan , Tung Patricia , Saad Eduardo , d'Avila Andre , zimetbaum peter , Kramer Daniel , Yeh Robert , Locke Andrew
Published: November 2024

Introduction:
Previous studies have noted racial and ethnic disparities in access to leadless pacemaker implantation (LPI), but none have evaluated the socioeconomic disadvantaged (SED). Additionally, few studies have evaluated outcomes of LPI beyond thirty days on a large scale. This study aimed to determine which comorbidities are associated with one-year readmissions and mortality after LPI, including SED via the Social Deprivation Index (SDI).

Methods:
Patients ages ≥18 were identified in the Healthcare Cost and Utilization Project State Inpatient Databases in New York and Florida from 2016-2019 with follow-up into 2020. These states were chosen due to availability for linkage of the 2018 SDI (1-100, higher scores representing more disadvantage). International Classification of Diseases 10 codes for LPI were used. The risk of readmission and mortality was assessed using Cox proportional hazards first in an unadjusted fashion for each comorbidity in the Charlson Comorbidity Index. In addition to demographic variables, only significant variables from the unadjusted analysis were included in the final adjusted multivariable models.

Results:
3,094 patients met inclusion criteria. The readmission and mortality rates at one, three, and twelve months were 17.2%, 31.3%, 50.2% and 5.7%, 7.1%, 10.7%, respectively. The most common diagnoses for readmission were dyspnea/chest pain (9.4%), heart failure (4%), and sepsis (3.8%). Federal insurance, heart failure (CHF), pulmonary disease, diabetes without complications, and renal disease (CKD) were associated with increased risk for twelve-month readmissions. African American race, myocardial infarction, CHF, CKD, and higher SDI were associated with increased risk for twelve-month mortality.

Conclusion:
CHF and CKD put patients at high risk of readmission and mortality. Sepsis was among the most common causes of readmission at twelve months. Patients of higher SED are at increased risk of mortality within one year after LPI.
Abstract 4134364: Predicted Low-Density Lipoprotein Cholesterol and Cardiovascular Outcomes Lowering With Inclisiran in Patients With or Without stroke: Insights from SIRIUS in silico trial.
Authors: Amarenco Pierre , Angoulvant Denis , Bastien Alexandre , Bechet Emmanuelle , Boccara Franck , Boissel Jean-Pierre , Cariou Bertrand , Courcelles Eulalie , diatchenko Alizee , Filipovics Anne , Kahoul Riad , Granjeon-Noriot Solene , Mahe Guillaume , Peyronnet Emmanuel , Portal Lolita , Porte Solene , Wang Yishu , Steg Philippe
Published: November 2024

Introduction:
Inclisiran, an siRNA, targeting PCSK9 mRNA, reduces LDL-c levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower cardiovascular (CV) events in virtual patients with atherosclerotic cardiovascular disease (ASCVD).

Research question:
This analysis predicted the potential efficacy of inclisiran on CV outcomes in virtual patients with or without prior ischemic stroke (IS).

Methods:
The SIRIUS trial was conducted using a calibrated and validated knowledge-based mechanistic computational model of ASCVD applied to a virtual population with LDL-C ≥ 70 mg/dL. Each virtual patient was its own control. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statin with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal IS over 5 years in patients with or without prior IS. Occurrence of fatal and non-fatal (IS) was also individually assessed in time-to-first-event analyses.

Results:
Among 204,691 virtual SIRIUS ASCVD patients, 39 371 (19%) had prior IS. At 5 years, the predicted mean percentage reduction in LDL-C with inclisiran as compared to placebo was –49.17% and –49.88% in patients with or without prior IS respectively. Patients with prior IS were at higher risk of 3P-MACE than patients without IS both with placebo and inclisiran (17.01% vs 14.41% with placebo and 13.44% vs 10.83% with inclisiran). However, the predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm for both prior IS and no prior IS (HR 0.78 medium uncertainty and 0.74 low uncertainty respectively). Compared to placebo, inclisiran was also predicted to consistently reduce fatal and non-fatal IS in patients with or without prior IS (5.45% vs 7.22%; HR: 0.75 medium uncertainty and 1.87% vs 2.54%; HR: 0.73 medium uncertainty respectively).

Conclusion:
SIRIUS provides insights into the potential efficacy of inclisiran on CV events suggesting a substantial 3P-MACE and fatal and non-fatal IS reduction in ASCVD patients including those with prior IS, several years before the availability of results from ongoing outcomes trials (ORION-4, VICTORION-2P).
Abstract 4134384: Sotagliflozin, a Dual Inhibitor of Sodium-Glucose Transporters 1 and 2, Elicits Cardioprotective Effects Through Attenuation of Platelet Activation and Thrombosis
Authors: Stanger Livia , Rickenberg Andrew , Yalavarthi Pooja , Flores Mariane , Yamaguchi Adriana , Pitt Bertram , Holinstat Michael
Published: November 2024

Sodium-glucose cotransporter (SGLT) inhibitors are used in the treatment of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). In the SCORED trial, sotagliflozin (SOTA), a dual SGLT1/2 inhibitor, demonstrated significant reductions in both myocardial infarction (MI) and stroke in patients with T2DM and CKD. These results suggest a cardiovascular (CV) benefit of SOTA in patients with T2DM and CKD who are at increased risk of thromboembolic disease. To investigate the underlying mechanism of CV protection, we evaluated the effects of SOTA on platelet activation and thrombus formation, in both
in vivo
and
ex vivo
models, to understand its effects on MI and stroke.

Washed human platelets treated with SOTA were stimulated with various agonists and platelet activation was assessed via lumi-aggregometry and flow cytometry. In whole blood, SOTA was evaluated for its potential to reduce platelet adhesion and thrombus formation in the perfusion flow chamber and Total Thrombus formation Analysis System (TTAS) assays.
In vivo
, mice dosed with SOTA were assessed for thrombus formation at the site of injury in real-time in the cremaster arteriole injury model. To determine the effect of SOTA on hemostasis, we assessed coagulation parameters
ex vivo
in human whole blood using thromboelastography. Finally, bleeding time was measured
in vivo
in mice dosed with SOTA using the tail bleeding assay.

In washed platelets, SOTA inhibits platelet activation and aggregation in a dose-dependent manner. Similarly, a dose-dependent decrease in platelet adhesion and thrombus formation was observed in whole blood assays.
In vivo
, platelet accumulation and fibrin formation were decreased in mice dosed with SOTA, however no effect is observed in coagulation parameters or bleeding time.

SOTA inhibits platelet activation and thrombus formation with no impact on coagulation parameters or bleeding potential. These findings highlight a potential mechanism through which SOTA reduces the risk of stroke and MI in patients with T2DM and CKD, underscoring the importance of further investigation into the role of SOTA in CV protection, particularly in patients suffering from both T2DM and CKD at high risk of thromboembolic events.
Abstract 4134396: Trends and Disparities in Ischaemic Heart Disease Mortality in the United States: An Analysis of CDC WONDER Database, 1999-2020
Authors: Ali Farman , Ahmed Faizan , Naveed Muhammad Abdullah , Ali Ahila , Azeem Bazil , KASHAN MUHAMMAD , Iqbal Rabia , Ishaq Syed Muhammad , Abdul Basit Salman , Akbar Usman , HARFOUCH BADR
Published: November 2024

Backgrounds:
Ischemic heart disease (IHD) remains a leading cause of mortality globally and has a high prevalence in the United States, necessitating an understanding of long-term trends to inform interventions. This study examines IHD-related mortality trends among US adults from 1999 to 2020, considering demographic and geographic disparities.

Aim:
This study aimed to evaluate patterns and geographical variations in mortality associated with IHD among adults in the United States.

Methods:
Death certificates from the CDC WONDER database spanning from 1999 to 2020 were analyzed to investigate mortality related to IHD among adults aged 35 years and above. Age-adjusted mortality rates (AAMRs) per 100,000 persons and annual percent change (APC) were calculated, stratified by year, sex, race/ethnicity, and geographic region.

Results:
Ischemic Heart Disease (IHD) caused 12,756,359 deaths among U.S. adults aged 35 and above from 1999 to 2020. Annual trends in age-adjusted mortality rates (AAMRs) showed a decline from 48.7 in 1999 to 28.9 in 2020, with notable fluctuations. Men consistently had higher AAMRs than women. NH Black or African American individuals exhibited the highest AAMRs. Geographically, significant disparities existed among states and regions, with the Northeast having the highest mortality. Nonmetropolitan areas consistently had higher AAMRs compared to metropolitan areas, showing varying trends over the study period.

Conclusion:
Fluctuations in mortality trends among IHD patients were observed over the study duration, revealing significant disparities across demographic and geographic parameters. Targeted interventions are imperative to alleviate the burden of IHD and mitigate mortality rates in the United States.
Abstract 4134449: Increasing Histidyl dipeptides in Skeletal Muscle Preserves Muscle Mass and Function During Heart Failure.
Authors: Chaudhari Mamata , Doelling Benjamin , Hoetker David , Nong Yibing , Brittian Kenneth , Bhatnagar Aruni , baba Shahid
Published: November 2024

Background:
In heart failure patients muscle wasting is a serious comorbidity. Oxidative stress and inflammatory cytokines, which cause muscle wasting, are increased in the skeletal muscle of heart failure patients. Oxidative stress leads to oxidation of lipids, generating toxic lipid peroxidation products, such as acrolein, which activates TNFa. Whether lipid peroxidation products accumulate in muscle and their removal from muscle influences muscle atrophy during heart failure has not been studied. In the muscle there are histidyl dipeptides, such as carnosine, ranging between 5-10 mM, synthesized via enzyme carnosine synthase (CARNS) that bind lipid peroxidation products. We examined whether intramuscular histidyl dipeptides influences heart failure-induced muscle wasting.

Hypothesis:
Histidyl dipeptides, alleviates intramuscular inflammation, preserves muscle mass and function during heart failure.

Methods:
Wild type (WT) and muscle-specific CARNS transgenic (Tg) mice were subjected to sham and transverse aortic constriction (TAC) surgeries. Cardiac function, muscle strength, atrophic and inflammatory markers, aldehyde modified protein, CARNS, and histidyl dipeptides were measured after 12 weeks.

Results:
In heart failure mice, weight of gastrocnemius (sham: 18.64 ± 1.73 vs TAC: 14.10 ± 0.90 mg, p=0.005), soleus (sham: 6.06 ± 0.82 vs TAC: 4.14 ± 0.70 mg, p=0.001), and tibialis anterior (sham:10.76 ± 1.62 vs TAC: 6.22 ± 1.83 mg, p=0.003), were decreased. Muscle strength was diminished (sham: 2.81 ± 0.36 vs TAC: 1.52 ± 0.27 N, p=0.004). Atrophic marker, atrogin1, aldehyde protein adducts and TNF-a were increased in the gastrocnemius muscle of TAC mice (~2-3-fold vs sham, p<0.05). CARNS expression and carnosine was decreased in different muscles of TAC mice (gastrocnemius; sham: 43.38 ± 20.46 vs TAC: 24.48 ± 6.49 nmoles/mg protein, p=0.03; soleus; sham: 22.04 ± 11.36 vs TAC: 11.02 ± 4.69 nmoles/mg protein, p=0.03; and tibialis; sham: 27.9 ± 11.70 vs TAC: 15.50 ± 3.48 nmoles/mg protein, p=0.01). Gastrocnemius muscle weight (WT TAC: 14.38 ± 1.08 vs Tg TAC: 17.30 ± 1.32 mg, p=0.004) and muscle strength (WT TAC: 3.06 ± 0.32 vs Tg TAC: 3.98 ± 0.41 N) were preserved, atrogin and TNFa expressions were decreased in gastrocnemius muscle of Tg TAC mice (~2-3-fold, p=0.04).

Conclusion:
Increasing intramuscular histidyl dipeptides alleviates muscle inflammation, preserves muscle mass, and function during heart failure.
Abstract 4134456: Hybrid Cardiac Targeting Peptide Ameliorates HFpEF Phenotype in Mice
Authors: Lopuszynski Jack , Sahagun Daniella , Wang Jingyu , Zahid Maliha
Published: November 2024

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure which is rapidly rising in incidence in the US today. Despite this, no therapies with mortality benefit exist for this syndrome. Previous work with our novel hybrid cardiac targeting peptide (hCTP), a cardiomyocyte-specific cell penetrating peptide, has shown multiple beneficial biological effects (improved calcium handling, anti-inflammatory properties) beyond its transduction abilities. Therefore, we hypothesized that treatment with hCTP in a mouse model of HFpEF would ameliorate the pathophysiology of this disease.

Methods:
To establish a HFpEF model, 6-week-old, C57BL/6NJ mice were placed on a high-fat diet (HFD), 60% kCal from lard, and water with 0.5 g/L of an iNOS inhibitor (N-Nitro-L-arginine methylester) to induce hypertension. After 5 weeks of the diet, HFD mice and their littermate controls underwent baseline exercise testing and echocardiograms. Exercise capacity was measured after 2 days of exercise training with 2 days of rest in between; mice were placed on a treadmill at a 10-degree angle and made to run at increasingly fast speeds (5-30 m/min) until exhaustion. Echocardiograms were performed under 1.5% inhalational isoflurane. After baseline testing, the mice were treated with vehicle, or either 2.5 or 5 mg/Kg hCTP, either 3 or 5 days a week (five groups, n = 3 per group). After four weeks of treatment, the mice were again subjected to the same battery of tests and euthanized. Data was compared using two way ANOVA with Sidak’s test to compare measurements pre- and post-treatment.

Results:
Treatment with hCTP at either concentration for five days/week led to an increase in running distance from 39.8 m to 116.3 m (p = 0.03, n = 6), compared to changes in control distance from 208.4 m to 157.8 m (p = 0.399). Running distance did not correlate with weight (R
2
< .001). Treatment with 5 mg/Kg hCTP for 5 days/week led to a normalization of the E/e’ ratio, from 43.3 to 26.9 (p = 0.004, n = 3) compared to a change in the control of 34.7 to 26.1 (p = 0.312). Ejection fractions remained consistent (>55%) across all groups.

Conclusions:
Our data suggests that hCTP appears to be a promising treatment in ameliorating some of the physiological effects in a murine model of HFpEF. Gene and protein expression studies in heart tissue are underway. Further work is warranted with a larger sample size.
Abstract 4134483: How succesfully can we presribe the 'four pillars' of medications for patients with heart failure with reduced LV systolic function?
Authors: Bain Robert , Walters Mark , Wickham Keeley , Jones Rachel
Published: November 2024

Introduction:
European, American and UK guidelines all endorse the prescription of the 'four pillars' of treatment (ACE/ARBs, b-blockers, MRAs and SGLT2 inhibitors) for heart failure with reduced LV systolic function (HFrEF). Many doctors believe that it is difficult to initiate and maintain patients on all these medications. We have studied 162 consecutive patients referred to our service as outpatients from primary care, subsequently diagnosed as having HFrEF, and our ability to establish them on these medications.

Methods:
Patients referred with potential heart failure (signs, symptoms and raised BNP) were identified as having HFrEF by echocardiography using British Society of Echocardiography (BSE) criteria. Patients attended regular outpatient appointments with a consultant cardiologist and specialist heart failure nurse and were prescribed and uptitrated all appropriate medications with any contraindications and intolerances noted.

Results:
Table 1 shows the number of patients sucessfully established on maximally tolerated doses of each class of medication. Reasons for not prescibing or discontinuing were: CKD 6, severe aortic stenosis 5, asthma 3, symptomatic bradycardia 5, hypotension 3, type1 diabetes 2, syncope 1, Raynauds 1, patient choice 8 and 6 patients died before all appropriate medications could be initiated. In 10 cases no clinical reason could be identified.

It can be seen that a high proportion of patients were successfully established on each individual class of medication and more than two thirds of patients were able to be maintained on all four classes of therapy.

Table 2 shows the breakdown of prescribing success according to the severity of LV dysfunction. It can be seen that prescribing success appears to be higher in those with the more severe LV dysfunction.

Conclusions:

1. The majority of patients can be established and maintained on appropriate polypharmacy for the treatment of LV systolic dysfunction.

2. The severity of LV systolic dysfunction is not a negative predictor of success in prescribing.