bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14884: Variation of Immune Function Assay Within the First Year After Heart Transplantation
Authors: Ghoreshi Kayvon , Hendren Nicholas S
Published: December 2023

Introduction:
The ImmuKnow® immune function assay (IFA) is used in heart transplant recipients to measure lymphocyte-mediated cell immunity via CD4 cell ATP production. Values <225 ng/mL are associated with increased infection risk; however, serial changes in the first year after heart transplant are not well reported. We evaluated IFA trends for heart transplant recipients over the first year after transplantation.

Methods:
This is a single-center cohort study of consecutive heart transplant recipients from 1/1/2014-8/31/2022 that had an IFA obtained within 30-days of transplant and >1 subsequent IFA within the first year after transplant. We described the relative and absolute change of mean IFA in 90-day increments through the first year after transplant, including sex specific differences. Multivariable logistic regression models tested the independent association of patient-level clinical characteristics factors with IFA values <225 ng/mL.

Results:
In the study cohort, (121/315) (38%) had an IFA within 30-days prior to transplant. Most patients were white non-Hispanic (46%) and male (74%). IFA values decreased from the pre-transplant baseline with mean absolute changes of 92 ng/mL (-24%), 120 ng/mL (-31%), 121 ng/mL (-32%), and 114 ng/mL (-28%) every 90 days after transplant, respectively (panel B). The highest prevalence of an IFA value <225 ng/mL occurred 90-180 days post-transplant in 55/103 (53%) patients. Female patients had a greater absolute and relative decrease in IFA values from baseline and each 90-day period (panel C). In exploratory analysis, at the time of transplant age >60 was associated with a lower risk of IFA values <225 during days 90-180 post-transplant (OR 0.24, p=0.02). A creatinine >1.4 mg/dL was associated with IFA values <225 during 90-180 (OR 3.15, p=0.02) and 180-270 (OR 3.44, p=0.03) days.

Conclusion:
Heart transplant recipients experienced ~25% reduction in IFA value from baseline in the first-year post-heart transplant.
Abstract 14911: Effusive Constrictive Pericarditis: A Rare Complication of SARS-CoV-2 Infection
Authors: Ekpo Eson J
Published: December 2023

Background:
SARS-CoV-2 infection can result in cardiac complications, including myocarditis, left ventricular dysfunction, arrhythmias, and acute myocardial injury. Reports of effusive constrictive pericarditis (CP) are rare, and recommendations on management are limited.

Description of Case:
A 30-year-old male with recurrent episodes of effusive pericarditis after SARS-CoV-2 infection 11 months prior and anasarca presents with worsening fatigue, dyspnea, and weight gain. His echocardiogram showed pericardial thickening, annulus reversus, and interventricular septal bounce. Computed tomography showed pericardial thickening and a complex pericardial effusion. Right and left heart catheterization revealed elevated filling pressures, equalization of diastolic pressures, and ventricular discordance (Figure 1). Infection, malignancy, and autoimmune etiologies of CP were ruled out.

Decision Making:
The patient was initiated on anti-inflammatory therapy and aggressively diuresed with no improvement in his symptoms. Given recurrent episodes of pericarditis with constriction, the patient underwent a radical pericardiectomy with posterior pericardial release. The pericardium was 1 cm thick with severe fibrosis. Surgical pathology showed acute and chronic pericarditis with negative testing for Mycobacterium tuberculosis.

Conclusion:
Idiopathic, post-cardiac surgery and post-mediastinal radiation are the most common causes of CP. Acute pericarditis is a known complication of SARS-CoV-2 infection, but ongoing inflammation leading to CP is rare. CP presents with signs of heart failure and should be considered in patients with persistent symptoms of pericarditis.
Abstract 14924: SM22-Cre-Mediated SOCS3 Deficient Mice Exhibit Pericardial Fibrosis, Diastolic Dysfunction, and Increased Mortality Rates Due to Augmented Activation of STAT3 in Fibroblasts
Authors: Yanai Toshiyuki , Yamamoto Mai , Yasukawa Hideo , Shibao Kodai , Akagaki Daiki , Okabe Kota , Shibata Tatsuhiro , Nohara Shoichiro , Takahashi Jinya , Sasaki Tomoko , Shima Kanako , Fukumoto Yoshihiro
Published: December 2023

Background:
Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative regulator of STAT3 signaling pathway. Here, we aimed to determine whether SOCS3 in non-cardiomyocytes would play a role in cardiovascular pathophysiology.

Methods and Results:
To investigate the role of SOCS3 in non-cardiomyocytes, we generated conditional knockout mice by crossing SOCS3-flox mice with SM22-α-Cre mice (SM22-SOCS3-KO mice). Mortality rates in the SM22-SOCS3-KO mice was significantly higher than that in the wild-type mice (WT). Heart weight to body weight ratio was significantly increased in SM22-SOCS3-KO mice compared with WT at 12 months of age. Echocardiographic analyses revealed that SM22-SOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with WT from 12 months of age. Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in SM22-SOCS3-KO mice were markedly greater compared with WT mice at 12 months of age. Western blot analyses showed that phosphorylated STAT3 was significantly increased in SM22-SOCS3-KO hearts compared with WT mice at 12 months of age. PCR array analysis revealed that the expression of pro-fibrotic
ctgf
,
pdgf
, and TGF-beta family genes including
tgf-beta1
,
tgf-beta2
, and
tgf-beta3
, were significantly higher in SM22-SOCS3-KO hearts than those in WT at 6 months of age. We also found that circulating interleukin-6 concentration was significantly higher in SM22-SOCS3-KO mice compared with WT mice at 12 months of age. After interleukin-6 administration, in the heart tissue from SM22-SOCS3-KO mice, coimmunostaining of phosphorylated STAT3 and ER-TR7 revealed that STAT3 activation occurred in fibroblasts in the coronary arterial adventitia and pericardium.

Conclusion:
Thus, SM22-Cre-mediated SOCS3 deletion induces higher mortality rates, increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the increased activation of STAT3 in fibroblasts.
Abstract 14930: A Case of Flecainide Toxicity Causing Wide Complex Tachycardia, Unresponsiveness, Hemodynamic Instability and Pacemaker Under-Sensing
Authors: Elgwairi Emadeldeen , Friedman Brian , Lakkireddy Dhanunjaya R
Published: December 2023

Introduction:
Flecainide toxicity (FT) is an uncommon yet potentially lethal complication. We report a case of FT precipitated by acute kidney injury (AKI) in a patient with paroxysmal atrial fibrillation (AF) and a permanent pacemaker (PPM), who presented with wide complex tachycardia (WCT) and PPM under-sensing.

Case presentation:
An above 85-year-old female with paroxysmal AF and a PPM presented with an episode of unresponsiveness. While en route to the ED via ambulance, she had another episode associated with hemodynamic instability precipitated by a WCT. She regained consciousness after 1 biphasic DC shock. An EKG in the ED revealed sinus rhythm with atrial under-sensing and pacing spikes during ventricular refractory period (see picture). Laboratory data were consistent with AKI and normal electrolytes levels. PPM interrogation showed atrial under-sensing. Flecainide was discontinued and following drug washout the EKG changes resolved and the QRS normalized. She was discharged on amiodarone with no recurrence of arrhythmias on follow up.

Discussion:
Flecainide is Class 1C Antiarrhythmic drug that blocks fast the sodium channels. Prolongation of PR interval and QRS duration, in addition to supraventricular and ventricular arrhythmias, may occur with FT. Left ventricular dysfunction, myocardial scar, and high serum levels are considered risk factors for proarrhythmia. The drug half-life is prolonged in patients with renal disease/AKI. There are limited data on PPM malfunction due to FT, but it may cause increased pacing thresholds and failure to capture. Sodium bicarbonate, lidocaine, and ECMO have been used in treatment.

Conclusion:
FT can lead to lethal arrhythmias and PPM malfunction. Since flecainide serum levels are not always readily available, its diagnosis can be challenging. Therefore, physicians should be aware of the clinical presentation and EKG changes that accompany FT.
Abstract 14955: Use of Cardiac Stress Testing in Nonagenarians With Chest Pain
Authors: Ghanshani Serena , Jeong Sun Young , Wang Jiexi , Onwuzurike James , Chen Aiyu , Wu Yi-Lin , Lee Mingsum S
Published: December 2023

Background:
Nonagenarians represent a growing population in the United States. Cardiac stress testing is commonly used for risk stratification in patients with chest pain. However, there is limited evidence on the benefits of stress testing in nonagenarians.

Aims:
The goal of this study was to investigate the utilization of cardiac stress testing in nonagenarian evaluated in outpatient clinics for chest pain, and to evaluate the incremental prognostic value of stress testing in this population.

Methods:
This is a retrospective observational study that included patients 90 years and above who presented for outpatient evaluation of chest pain. Referral for cardiac stress testing was captured using electronic health records. Patients were followed for one year. The associations between cardiac stress testing and subsequent cardiac catheterization, coronary revascularization, and myocardial infarction were evaluated using logistic regression models.

Results:
Between 2017 and 2021, 11763 patients 90 years and above presented to a clinic visit with a chief complaint of chest pain. There were 50.3% male, 61.4% White, 9.0% Black, 20.0% Hispanic, and 9.3% Asian. In this group, 320 (2.7%) underwent cardiac stress testing. Patients referred for testing had fewer cardiac risk factors, with a lower prevalence of hypertension, hyperlipidemia, and diabetes. At one year of follow-up, 6.9% of patients in the stress test group underwent cardiac catheterization, compared to 2.5% of patients in the no testing group (adjusted OR 2.87, 95% CI 1.81-4.57). Revascularization occurred in 0.63% patients in the stress testing group compared to 0.78% in the no testing group (adjusted OR 0.78, 95% CI 0.19-3.21). Myocardial infarction occurred in 3.4% in the stress testing group compared to 4.4% in the no testing group (adjusted OR 1.67, 95% CI 0.79-2.9).

Conclusion:
Among nonagenarians who underwent outpatient evaluation of chest pain, cardiac stress testing was associated with a significantly increased odds of subsequent cardiac catheterization, but no difference in revascularization or myocardial infarction. These observations suggest the clinical benefits of stress testing in nonagenarians may be limited.
Abstract 14967: Branching Out: Disrupted Branched Chain Amino Acid Metabolism Exacerbates Pulmonary Arterial Hypertension
Authors: Blake Madelyn , Prisco Sasha Z , Prins Kurt W
Published: December 2023

Introduction:
Valine, leucine, and isoleucine are essential branched chain amino acids (BCAA), and recent epidemiological studies report elevated BCAAs predict worse outcomes in several cardiovascular diseases with metabolic origins such as diabetes, heart failure, and hypertension. However, the role of BCAA metabolism in pulmonary arterial hypertension pathophysiology is relatively unexplored.

Hypothesis:
BCAAs are elevated in human PAH and reduction of BCAAs via small molecule activation of BCAA catabolism and dietary interventions combats PAH severity in preclinical PAH.

Methods:
Literature search of human PAH metabolomics studies was conducted. For rodent studies, male Sprague Dawley rats were divided into three groups: control (saline injection), monocrotaline (MCT) vehicle (MCT-V), or MCT-BT2, a small molecule inducer of BCAA catabolism. BT2 was administered at 20mg/kg/day. A low BCAA dietary intervention was implemented, with male Sprague Dawley rats divided into two groups: MCT-standard chow diet and MCT-low BCAA diet. To assess exercise capacity, rodents underwent a maximal exercise testing protocol before echocardiographic and hemodynamic assessments of PAH. Proteomic analysis of lung mitochondrial extracts was performed to define the molecular effects of BT2.

Results:
Of 11 studies evaluating human PAH metabolomics, 7 studies reported elevated BCAAs or BCAA metabolites in PAH. BT2 treatment improved exercise performance, reduced PA pressures, and augmented RV function. Moreover, the MCT-BT2 group possessed a distinct lung proteomic signature with changes in inflammatory and metabolic pathways. Finally, the low BCAA diet intervention modestly combatted PAH severity.

Conclusions:
BCAA metabolism is disrupted in human PAH and interventions that reduce circulating BCAAs display therapeutic potential in rodent PAH.
Abstract 14969: Association Between Apolipoprotein A-I and Ischemia Risk at Different Diabetes Statuses in Patients Undergoing Percutaneous Coronary Intervention: A Large-Scale Real-World Study
Authors: Yan Kailun , Li Jiawen , Li Yulong , Yuan Jinqing , Zhao Xueyan
Published: December 2023

Introduction:
Recently, growing attention has shifted to apolipoprotein A-I (ApoA-I), revealing compelling relationship between low ApoA-I and ischemia risk. Diabetes mellitus (DM) frequently coexists with abnormal ApoA-I levels. However, the association between ApoA-I and ischemia risk under different diabetes statuses in patients undergoing percutaneous coronary intervention (PCI) remains unclear.

Hypothesis:
We hypothesized that diabetes status could modify the relationship between ApoA-I levels and ischemia risk in PCI patients.

Methods:
This prospective study included consecutive 10724 patients treated with PCI throughout 2013. Patients were categorized into 3 subgroups: DM, pre-DM, and normal group. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE, including all-cause death, myocardial infarction, stroke, and revascularization).

Results:
Among 10232 PCI patients finally included, 2139 (20.9%) MACCEs occurred at 5-year follow-up. There was a significant interaction between ApoA-I and diabetes status (P for interaction = 0.044). In the DM group, an L-shaped curve was observed (Figure 1A), and multivariate Cox regression analysis revealed that only the lowest quintile level of ApoA-I exhibited an increased risk of MACCE (hazard ratio [HR], 1.336; 95% CI, 1.101-1.620; P = 0.003) (Figure 1B). However, neither the normal group nor pre-DM groups could observe the association between ApoA-I and MACCE (both P >0.05). Further sensitivity analysis, stratifying ApoA-I into two groups based on median level, also indicated the highest MACCE in those combined with lower ApoA-I levels and DM (Figure 1C).

Conclusions:
In a large-scale 5-years follow-up study, we were the first to demonstrate that diabetes status modified the ischemia risk of low ApoA-I levels, highlighting the clinical importance of low ApoA-I levels for risk stratification and focusing on diabetes status in future therapy targeting ApoA-I.
Abstract 14974: Spontaneous Coronary Dissection: A Challenging Case of Young Weightlifter
Authors: Du Yimeng Lina , Soares Andrea , Atreja Surabhi M
Published: December 2023

A 26-year-old weightlifter with no significant past medical history presented with chest pain while performing his routine exercise. ECG showed anterior ST elevation myocardial infarction with subsequent angiography revealing 99% occlusion in the proximal LAD with extensive thrombus burden along with a 100% occluded distal RCA with left to right collaterals present, indicating an RCA subacute/chronic lesion (see image). An intra-aortic balloon pump was inserted, and the patient was transferred to UC Davis Medical Center. Repeat angiography revealed thrombus and dissection in the proximal LAD and RCA, stabilized with heparin drip and Gp2b3a inhibitor. Transthoracic echocardiogram showed a severely reduced ejection fraction of 15%. After heart team discussion, the patient was deemed high risk for surgery, so he underwent percutaneous coronary intervention with balloon angioplasty and deployment of drug eluting stents to the LAD and RCA with resulting TIMI-3 flow. He was initiated on guideline directed medical therapy and discharged home with LifeVest. Unfortunately, he presented with ventricular tachycardia (VT) after LifeVest shock on the following day. Repeat angiogram did not show any in-stent restenosis or thrombus. Implantable cardioverter-defibrillator (ICD) was implanted, and the patient was started on amiodarone. The patient continued to have recurrent VT. Lidocaine was added and MRI was done, which showed a large scar burden. Left ventricular assist device Impella 5.5 was placed, and the patient eventually underwent successful cardiac transplant. This case report highlights weightlifting causing spontaneous coronary dissection. It is rare but has devastating complications with limited options for acute management. Revascularization options have limited success in a patient with such an extensive scar burden and a severely reduced ejection fraction.
Abstract 14990: A Propensity Score Analysis of Five-Year Outcomes After Coronary Thrombus Aspiration in Acute Myocardial Infarction: Insights From the FAST-MI Real-Life Registry
Authors: Weizman Orianne , Hauguel-Moreau Marie , Cayla Guillaume , Lemesle Gilles , Ferrieres Jean , Schiele François , Simon Tabassome , Danchin Nicolas
Published: December 2023

Introduction:
Though previous trials and registries have shown no short-term benefit of thrombectomy in acute myocardial infarction (AMI), data on long-term outcomes are lacking.

Hypothesis:
Use of coronary thrombectomy in real-life conditions does not affect 5-year outcome.

Methods:
FAST-MI program consists of 3 nationwide French surveys (2005, 2010, 2015), including consecutive AMI patients over a 1-month period. This analysis focused on patients undergoing percutaneous coronary intervention (PCI, N=9,731). Five-year follow-up is >96%.

Results:
Thrombectomy was used in 1,781 patients (18%; 2005: 7%, 2010: 27%, 2015: 18%), 87% of them had STEMI. They were younger (61±13 vs 65±14 yo), mostly men (81% vs 74%, p<0.001), with less multivessel coronary artery disease (47% vs 55%, P<0.001) and a culprit lesion mostly on the right coronary artery (40% vs 31%, P<0.001). Crude in-hospital death was higher with thrombectomy (3.1% vs 2.0%, P=0.005) but 5-year death lower (13% vs 17%, P<0.001; crude HR 0.74 [95%CI 0.66-0.82]). After adjustment on the propensity score (PS) for getting thrombectomy, OR for in-hospital death was 1.24[95%CI 0.82-1.87] and HR for 5-year death: 0.95 [95%CI 0.79-1.14], P=0.58. In hospital survivors, Cox multivariate adjustment including discharge medications yielded similar results (HR 0.96, 95%CI 0.76-1.21, P=0.73). After PS matching, the two cohorts (N=1,430 each) had even distributions for all baseline characteristics and medications. In-hospital death was similar (2.7% vs 2.6%, P=0.91) but stroke was numerically higher (0.8% vs 0.3%, P=0.13) with thrombectomy. Five-year survival was similar in the 2 cohorts: HR 0.93, 95%CI 0.75-1.14, P=0.46. (Figure)

Conclusions:
These real-world data show that the use of thrombectomy has increased until 2010 and declined thereafter, in keeping with international guidelines, and suggest that thrombectomy has no beneficial nor detrimental effect on long-term survival compared to PCI alone.
Abstract 14998: Assessment of Microcirculatory Dysfunction by Measuring Subcutaneous Tissue Oxygen Saturation Using Near-Infrared Spectroscopy in Patients With Circulatory Failure
Authors: Sato Jun , Sakurai Atsushi , Kinoshita Kosaku
Published: December 2023

Background:
Patients with circulatory failure have been treated with the goal of normalizing systemic hemodynamic parameters such as blood pressure, central venous pressure, urine output, and central venous oxygen saturation. However, microcirculatory dysfunction remains even after improvement of these indices, suggesting a loss of hemodynamic coherence between the macrocirculation and the microcirculation. Recently, the usefulness of near-infrared spectroscopy (NIRS) in assessing the microcirculation has been reported.

Aim:
We measure regional tissue oxygenation saturation (rSO
2
) at 3 - 5 mm subcutaneously in patients with circulatory failure using a finger-mounted tissue oximeter with the NIRS technique (Toccare: Astem Co., Ltd., Kawasaki, Japan) to investigate its relationship with microcirculation.

Methods:
This is a single-center prospective observational cohort study of patients with circulatory failure (systolic blood pressure ≤ 90 mmHg or lactate ≥ 2 mmol/L at presentation) transported to the emergency department of Nihon University Hospital from 15 June 2020 to 31 March 2022. We measured rSO
2
in the forehead, thenar eminence, thumb and knee using Toccare and assessed the relationship between rSO
2
and blood pressure, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score and mottling score.

Result:
In patients with circulatory failure (n = 38), rSO
2
at each site showed no correlation with blood pressure, a negative correlation with SOFA score and APACHE II score and a positive correlation with mottling score. These significant correlations were also best observed in the knee.

Conclusion:
In patients with circulatory failure, rSO
2
measured with Toccare showed no correlation with blood pressure but a significant negative correlation with the severity of organ damage. The knee is possibly the optimal measurement site for monitoring microcirculatory dysfunction and determining the effectiveness of treatment.
Abstract 15003: Risk Factors Associated With the Initiation and Progression of Mitral Annular Calcification: A Two-Step Process
Authors: Kim Kyung An , Lee Soyoung , Ahn Yuran , LEE DONGHYEON , Jung Hae-Ok O
Published: December 2023

Background:
Mitral annular calcification (MAC) is hypothesized to be a representation of atherosclerosis and is associated with adverse outcomes. However, the pathophysiology and risk factors associated with MAC are not completely understood.

Methods:
From the KOrea Initiatives on Coronary Artery calcification registry, 738 asymptomatic individuals who underwent health screening with echocardiography and serial cardiac computed tomography (CT) scans were included for analysis. MAC was identified on CT and measured using Agatston units (AU). Risk factors associated with the initiation of MAC were identified with multivariable logistic regression, and risk factors associated with the progression of MAC were determined using multivariable linear regression on the annualized progression of the MAC AU.

Results:
The initial prevalence of MAC was 7.0%, and the median rate of progression was 3.4 AU/year (IQR 0.2-14.7 AU/year) during a median interscan duration of 36.4 months. In addition, 4.3% of the participants developed new MAC between the first and last examinations. The factors associated with the initiation of MAC were age (p<0.001), body mass index (p=0.046), history of smoking (p=0.048), HbA1c (p=0.011), and left atrial volume index (p=0.034). Meanwhile, the factors associated with MAC progression were initial MAC Agatston score (p<0.001), male sex (p=0.005), and calcium-phosphorus product (p=0.002).

Conclusion:
Traditional cardiovascular risk factors and increased hemodynamic stress seem to be more important in the initiation of MAC, while initial MAC severity and calcium-phosphate metabolism seem to be a major determinant in the later phase of MAC progression.
Abstract 15024: Immunomodulatory Effects of Human Embryonic Stem Cell-Derived Epicardial Cells in Myocardial Infarct Healing
Authors: Yang Huang-Tian , Luo Xiaoling , Jiang Yun , Li Qiang , Yu Xiu-Jian , Ke Min-Xia , Zhang Peng , Tan Ji-Liang , Gao Ling
Published: December 2023

Background:
Acute myocardial infarction (AMI) causes excessive myocardium damage, including epicardium. Cell therapy by implantation of human pluripotent stem cell (hPSC)-derived cardiovascular cells has been tested in the infarcted hearts of preclinical models and clinical studies. However, whether hPSC-derived epicardial cells (hEPs) can be a therapeutic approach for infarcted hearts remains unclear. AMI induces inflammatory cascades, leading to multifaceted processes of myocardial injury and healing, whereas it is unknown whether hEPs regulate immune responses, especially macrophage plasticity at the acute phase of MI.

Aims:
to determine whether hEP implantation promotes myocardial infarct healing and modulates inflammatory response.

Results:
intramyocardial injection of hEPs at the acute phase of MI ameliorated functional worsening (p<0.001 vs. MI control) and scar formation of adult male NOD-SCID mouse hearts (p<0.05 vs. MI control) at day 28 post-MI, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis (p<0.05 vs. MI control). Mechanistically, hEPs suppressed AMI-induced increases of type I interferon (IFN-I) response, infiltration and cytokine-release of inflammatory cells, and promoted polarization of reparative macrophages. These effects were blocked by a IFN-I receptor agonist RO8191 in mouse model of MI. Moreover, hEP abundantly secreted intelectin 1 (ITLN1), which interacted with IFN-β and mimicked the effects of hEP-condition medium in the suppression of IFN-β-stimulated responses in macrophages and promotion of reparative macrophage polarization. However, ITLN1 downregulation in the hEPs canceled beneficial effects of hEPs in anti-inflammation and anti-IFN-I response, and in cardiac repair of infarcted hearts.

Conclusions:
our resutls demonstrate the reparative effects of hEP implantations in the infarcted hearts and reveal hEPs as an inflammatory modulator in promoting infarct healing via paracrine factor-mediated cell-cell communications. These findings provide new knowledges for the functions and mechanisms of hEPs for cardiac repair and suggest a therapeutic option of hEPs for ischemic myocardial repair.
Abstract 15045: Anti CTLA-4 and PD-1 Monoclonal Antibodies Increases Systemic SDF-1 and Galectin-3 Levels and Reduces Myocardial Strain Through NLRP3 and MyD-88 Pathways
Authors: Maurea Nicola , De Lorenzo Claudia , Passariello Margherita , Di Mauro Annabella , Bisceglia Irma , Iovine Martina , Merola Alessia , Bruzzese Francesca , Luciano Antonio , Palma Giuseppe , Gabrielli Domenico , Maurea Carlo , Canale Maria Laura , Quagliariello Vincenzo
Published: December 2023

Background:
Immune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed.

Methods:
Firstly, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100,Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs, MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β and IL-6 were analyzed before, during and after ICIs therapy.

Results:
Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs.

Conclusions:
Short therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues after ICIs therapy.
Abstract 15049: Combinatorial Immune Checkpoint Blockade Increases Myocardial Secretion of H-FABP, NT-Pro-BNP, NLRP-3 Inflammasome, Interleukin-1β and Interleukin-6: Biochemical Implications in Cardio-Immuno-Oncology
Authors: Maurea Nicola , Passariello Margherita , Bisceglia Irma , Paccone Andrea , Inno Alessandro , Maurea Carlo , Gabrielli Domenico , Merola Alessia , Iovine Martina , Scherillo Marino , Lembo Rapuano , Manna Lorenzo , Ascierto Paolo Antonio A , De Lorenzo Claudia , Quagliariello Vincenzo
Published: December 2023

Background:
Immune checkpoint blockade alone or in combination with chemotherapy or radiotherapy or other immune checkpoint blocking agents have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) human monoclonal antibody, Relatlimab, has been approved by FDA for combinatorial treatment with Nivolumab for metastatic melanoma. Moreover, anti PD-L1blocking agent Atezolizumab is actually under study in association with Ipilimumab as innovative thearpy for metastatic lung cancer. Cases of cardiotoxicity such as myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies and the use of new targets in immunotherapy could expose patients to more adverse cardiovascular events.

Methods:
human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays.

Results:
Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. Biomarkers of cardiotoxicity, such as NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy with respect to monotherapies. NLRP3 inflammasome, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies.

Conclusions:
Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype.
Abstract 15057: miR-132 Inhibitor CDR 132L Attenuates Cardiac Remodeling by Exhibiting Anti-Fibrotic Effects
Authors: Batkai Sandor , Genschel Celina , Viereck Janika , Rump Steffen , Hauke Wilfried , Gyongyosi Mariann , Traxler Denise , Hinkel Rabea , Kupatt Christian , Levin Arthur A , Thum Thomas
Published: December 2023

Introduction:
Increased cardiac expression levels of miRNA miR-132 have been associated with pathological cardiac remodeling including cardiac fibrosis. As a selective inhibitor for miR-132, the synthetic antisense oligonucleotide CDR132L, is capable to reverse cellular pathology and restore normal heart function. Pharmacological inhibition of miR-132 as well as genetic knockout has been shown to protect mice from transverse aortic constriction induced cardiac remodeling including interstitial fibrosis.

Methods and Results:
Treatment effects of CDR132L were investigated in several different pig models of ischemic and non-ischemic heart failure (HF) with the aim to further elucidate CDR132L’s mode of action and confirm species-independent effects on fibrotic remodeling. In a pig model of subacute post myocardial infarction (MI) induced HF, CDR132L was administered on day 3 and day 28 by intravenous (IV) or intracoronary (IC) infusion at doses of 1, 5 and 10 mg/kg and followed until day 56. In a chronic post-MI HF large animal model, beneficial effects were confirmed in a 6-month study comparing 5 monthly and 3 monthly repeated IV administrations of 5 mg/kg CDR132L starting one month post-MI. Further, CDR132L was tested in a porcine model of percutaneous aortic constriction by implantation of a reduction stent in the thoracic aorta and two IC injections of CDR132L on day 0 and day 28 followed for 56 days. As part of the pharmacodynamic analyses in these models, paraffin sections of cardiac tissue from the left ventricular remote region were stained with picrosirius red (PSR) and fibrosis was assessed based on collagen quantity. Analysis of fibrosis in PSR-staining revealed that the degree of interstitial fibrosis was significantly reduced in CDR132L treatment groups compared to placebo between 22% and 61%. Moreover, results of the first-in-human safety and tolerability study of CDR132L in patients with stable HF of ischemic origin (NCT04045405) showed encouraging positive trends for relevant cardiac fibrosis biomarkers.

Conclusion:
By blocking aberrant miR-132 expression, CDR132L is capable to halt and reverse pathological cardiac remodeling partly due to its anti-fibrotic effects.
Abstract 15076: Long-Term Recurrence Free Survival in Second Generation Cryoballoon Ablation for Persistent Atrial Fibrillation: It’s All About the Autonomic Nervous System
Authors: Guckel Denise , El Hamriti Mustapha , Fink Thomas , Sciacca Vanessa , Imnadze Guram , Braun Martin , Khalaph Moneeb , Isgandarova Khuraman , Sommer Philipp , Sohns Christian , Nölker Georg
Published: December 2023

Introduction:
Cryoballon (CB)-guided pulmonary vein isolation (PVI) is an accepted treatment option for atrial fibrillation (AF). The cardiac autonomic nervous system (ANS) plays a crucial role in the regulation of AF.

Hypothesis:
ANS modulation has an impact on patients’ AF free survival following CB-ablation. The aim of this observational clinical trial was to analyze the impact of vagal reactions (VRs), as a surrogate parameter for ANS modulation, on the long-term outcome of CB-ablation in patients with persistent AF (PERS AF).

Methods:
Data from consecutive PERS AF patients treated with a CB-guided PVI for symptomatic drug refractory AF between 2013-2023 were analyzed. VRs were defined as bradycardia < 40 beats/min, asystole or higher-degree atrioventricular block. All patients were continuously followed up in our outpatient clinic. AF-recurrence was defined as AF lasting > 30 seconds beyond a 3-month blanking period.

Results:
A total of 250 consecutive patients (mean age 63.9 ± 10.0 years, 70% male) were included. VRs were recorded in 61 patients (24%). The mean follow-up duration amounted to 84±14 months. Within this observation period 101 patients (40%) developed AF recurrence a mean of 1.75 ± 0.80 times. Re-ablation procedures were performed in 61 patients (60%) a mean of 1.28 ± 0.55 times. Reconnected PVs were documented in 41 cases (67%). An additional substrate modification was performed in 34 procedures (42%). Patients with procedure associated VRs presented with a significantly higher estimated AF-free survival rate compared to those without (log-rank p-value=0.016) (Figure1). Multivariate analyses revealed the days to first AF recurrence following primary CB-ablation as an independent predictor for AF-free survival (CI 0.841-0.928, HR, 0.883, p<0.01).

Conclusions:
CB-ablation procedure associated VRs seem to be associated with a favorable long-term outcome in PERS AF. Thus, our findings may influence future CB-ablation strategies.
Abstract 15077: Mitochondrial LonP1 Upregulation in End Stage Heart Failure
Authors: Soliman Saifullah , Ibrahim Ayman Maher M , Wagdy Dr. Kerolos , Selwanos Peter , Khedr Hadir , MOSTAFA MOSTAFA SABER , Shah Ajay M , Yacoub Magdi , Aguib Yasmine
Published: December 2023

Introduction:
Mitochondrial dysfunction is a hallmark of heart failure (HF), where correct mitochondrial proteins’ folding is challenged under mitochondrial stress. To restore mitochondrial proteostasis and homeostasis, the mitochondrial unfolded protein response (UPR
mt
) is activated, a mechanism not fully elucidated in HF.

Purpose:
We here investigate the UPR
mt
induction in advanced/end-stage HF patients requiring Left Ventricular Assist Device (LVAD). In addition, we analyzed the potential influence on clinical outcome.

Methods:
RNA was extracted from 44 Left Ventricular discs excised during implantation of LVAD from end-stage HF patients and from 5 control LV tissues. Quantitative PCR was performed to assess the relative expression levels of UPR
mt
machinery (
ATF5, CHOP, mtDNAj, HSP60/10, CLpP
and
LonP1
). Immunoblotting was performed to validate mRNA levels. LonP1 subgrouping was performed in reference to LVAD patients’ 3
rd
quartile of pre-LVAD Lonp1 mRNA levels. The primary outcome for the Kaplan-Meier survival analysis was all-cause mortality post-LVAD intervention.

Results:
Gene expression analysis revealed a significant increase in mRNA levels of CHOP and LonP1. Immunoblotting validated the upregulation of CHOP & LonP1 in end-stage HF tissue in comparison to controls. In High-LonP1 patients, we observed a significant increase in left ventricular ejection fraction and blood sodium levels while serum levels of ST-2 and blood urea levels were significantly decreased. High-LonP1 patients had a significantly higher probability of survival post-LVAD intervention and potential to recover myocardial function.

Conclusion:
This study suggests LonP1 as a potential marker of myocardial recovery and clinical outcome in end-stage heart failure patients treated by LVADs.
Abstract 15129: Applying Magnetocardiography to Identify Asymptomatic Ischemic Heart Failure at an Early Stage
Authors: Dong Yiming , Han Xiaole , Yin Xiaofei , Li Ruochuan , Xu Yansong , Fan Jiaxin , Xie Fei , Xu Feng , Xiang Min , Yu Dexin , Ning Xiaolin , Pang Jiaojiao , Chen Yuguo
Published: December 2023

Introduction:
Asymptomatic cardiac dysfunction (ACD) has management implications, and been shown to have special cardiac electrical signal features, magnetocardiography (MCG) can be used in a range of cardiovascular diseases by tracing subtle changes of the cardiac electromagnetic activity.

Hypothesis:
MCG could be used to identify ACD in patients with heart failure (HF) risk factors.

Methods:
This study was a subcohort of a prospective MCG study (NCT05392712), in which patients hospitalized with ischemic heart disease (IHD) were all underwent MCG examination. Patients with asymptomatic HF, according to the American Heart Association Heart Failure Guideline, were divided into “at risk for HF” (stage A) or “pre-HF” (stage B, namely ACD). Supervised machine-learning were undertaken to select specific MCG features and establish MCG recognition model for pre-HF (MCG-HF model), which was further tested in an independent test set. In the end, we compared the performance of MCG-HF model with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the optimized Atherosclerosis Risk in Communities (ARIC) HF risk score for identifying pre-HF.

Results:
A total of 420 inpatients with IHD, of which 111 were in stage A and 309 in stage B, were included in this study. In an independent test set (n= 126), the MCG-HF model for identifying patients at stage B demonstrated 95.7% sensitivity and 66.7% specificity (area under the receiver-operating characteristic curve [AUC]: 0.904; 95% confidence interval [CI]: 0.800 to 0.957). The AUC for optimized ARIC model and NT-proBNP model were 0.631 (95% CI:0.572 to 0.690) and 0.761 (95% CI:0.716 to 0.807), respectively. Conventional methods for pre-HF recognition showed inferior discriminative ability.

Conclusions:
The MCG based on machine learning shows valuable performance in identifying ACD, the cardiac magnetic signal detection technology provides a rapid and optimized screening tool in patients at risk for HF.
Abstract 15164: The Different Prognostic Values of T1 Mapping in Patients With Hypertrophic Cardiomyopathy
Authors: Wang JIE , Zhang Jinquan , Pu Lutong , Qi Weitang , Xu Yuanwei , Han Yuchi , Chen Yucheng
Published: December 2023

Objectives:
This study aimed to determine the impact of T1 mapping on cardiovascular magnetic resonance (CMR) on long-term adverse outcomes in patients with hypertrophic cardiomyopathy (HCM).

Background:
In patients with HCM, the prognostic value of native T1 and extracellular volume fraction (ECV) for sudden cardiac death (SCD) has not been well defined.

Methods:
Consecutive 663 participants with HCM who underwent CMR were recruited. The follow-up endpoints included heart failure (HF)-related death and SCD or aborted SCD.

Results:
During the median follow-up time of 44 months (interquartile range [IQR]: 23 to 65.5 months), 55 (8.3%) participants reached the endpoint including 37 (5.6%) with SCD or aborted SCD and 18 (2.7%) with HF-related death. On Cox proportional hazards regression multivariable analyses, native T1 but not ECV was independently associated with CD (hazard ratio [HR]: 1.00; 95% confidence interval[CI] : 1.00 to 1.01;
P
= 0.02), while native T1 (HR: 1.01; 95%CI: 1.00 to 1.01;
P
= 0.008) and ECV (HR:1.15 for every 1% increase; 95%CI: 1.05 to 1.26;
P
= 0.003) were both independently associated with HF-related death after the adjustment for left ventricular ejection fraction (LVEF) and LV late gadolinium enhancement (LGE) extent. Conversely, native T1(HR: 1.00; 95% CI: 1.00 to 1.01;
P
= 0.40) and ECV (HR: 1.01; 95% CI: 0.94 to 1.08;
P
= 0.81) were not associated with SCD after the adjustment for non-sustained ventricular tachycardia, history of syncope and LV LGE extent.

Conclusions:
In this study of patients with HCM, T1 mapping had distinct prognostic associations; native T1 and ECV were both independently associated with HF-related death, whereas T1 mapping was not independently associated with SCD or aborted SCD. These findings may indicate distinct implications for the management of left ventricular fibrosis in HCM.
Abstract 15167: The Use of Echocardiography in Patients With Advanced Peripheral Arterial Disease
Authors: Jamil Yasser , Huttler Joshua , Alameddine Dana , Zhuo Haoran , Mena-Hurtado Carlos , Velazquez Eric J , Guzman Raul J , Ochoa Cassius I
Published: December 2023

Introduction:
Patients with peripheral arterial disease (PAD) are at high risk of concomitant cardiac diseases. Transthoracic echocardiography (TTE) is a common imaging modality to assess cardiac function and is used as a screening tool, especially for patients with advanced PAD undergoing lower extremity revascularization (LER). The current study evaluates the incidental use of TTE in patients undergoing LER.

Hypothesis:
Patients with a perioperative TTE have improved outcomes compared to patients who do not undergo TTE.

Methods:
The electronic records of patients undergoing LER between 2013-2020 were reviewed. All TTE within 6 months of initial LER were captured. Patient characteristics and outcomes were compared between patients who underwent TTE and those who did not.

Results:
A total of 1,988 patients underwent LER, and 69.3% (N=1,377) had TTE. Patients in the TTE group were more likely to be African American and have diabetes mellitus, chronic kidney disease, and coronary artery disease. Patients with TTE were more likely to be on aspirin and undergo open/hybrid revascularization. There was no significant difference between the 2 groups in perioperative MI, major amputation, or mortality. Furthermore, patients with TTE had higher MALEs. (Table) However, there were no differences in MALE-free survival between the two groups (Figure 1)

Conclusion:
TTE was obtained in 69.3% of patients with advanced PAD undergoing LER but did not seem to be associated with outcomes in this institutional series. Further research is warranted to identify PAD patients that would benefit from TTE prior to LER.
Abstract 15183: Diabetes is Associated With Worse Postoperative Mortality and Morbidity in Bariatric Surgery, Regardless of the Procedure
Authors: Khalil Omar , Dargham Soha , Jayyousi Amin , Al Suwaidi Jassim , Abi Khalil Charbel
Published: December 2023

Introduction:
Bariatric surgery is an efficient treatment for obesity.

Objectives:
We aimed to assess the impact of diabetes on postoperative outcomes of bariatric surgery. Further, we compared the outcomes of different techniques in patients with diabetes.

Methods:
We used data from the National Inpatient Sample (2015-2019) to identify patients who underwent either sleeve gastrectomy, Roux-en-Y, or gastric banding. Outcomes included postoperative mortality (primary outcome), major bleeding, atrial fibrillation, and acute renal failure.

Results:
Patients with diabetes had an overall increased risk of perioperative complications when compared to non-diabetic ones for all three types of bariatric surgery. Among patients who underwent sleeve gastrectomy, diabetes was associated with a higher adjusted risk of mortality [aOR 2.07 (1.36-3.16)], atrial fibrillation [aOR 1.07 (1.02-1.11)], and acute renal failure [aOR 1.51 (1.39-1.64)] but a similar risk of major bleeding. Among patients who underwent Roux-en-Y, diabetes did not increase the risk of mortality and bleeding. Still, it was associated with a higher risk of atrial fibrillation [aOR 2.24 (1.25-4.02)] and acute renal failure [aOR 1.36 (1.21-1.62)]. Among patients who underwent gastric banding, diabetes was only associated with a higher risk of major bleeding [aOR 2.94 (1.42-5.88)]. When comparing the 3 techniques in diabetes patients, Roux-en-Y was significantly associated with a higher mortality rate (1.05%, 0.06%, 0%), atrial fibrillation (7.04%, 3.35%,3.48%), and acute renal failure (6.32%, 1.29%, 3.48%) (Roux-en-Y, sleeve, gastric banding; respectively). Major bleedings were more common in Roux-en-Y (1.05%) than in Sleeve (0.5%) (p<0.001).

Conclusions:
Diabetes is associated with worse postoperative outcomes regardless of the type of bariatric surgery performed. Among diabetes patients, Roux-En-Y was associated with higher mortality and morbidity.