bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12949: Altered Fatty Acids and Oxylipins Metabolism Differentiate Isolated Post-Capillary versus Combined Pre- and Post-Capillary Pulmonary Hypertension
Authors: Tang Amber B , Alotaibi Mona , Roberts Kari , Preston Ioana R , Warburton Rod , Jain Mohit , Cheng Susan , Hill Nicholas
Published: June 2023

Introduction:
Pulmonary hypertension due to left heart disease (Group 2) is the most common type of pulmonary hypertension and has two subtypes: isolated post-capillary pulmonary hypertension (Ipc-PH) and combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Little is known about the molecular characteristics that distinguish these two subphenotypes or if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH), as has previously been suggested. Many lipid metabolites, including a diverse group of bioactive lipid mediators known as oxylipins, have been associated with cardiovascular disease and other inflammatory conditions. Therefore, we sought to characterize oxylipin and other bioactive lipid profiles among patients with Ipc-PH and Cpc-PH, as well as those with PAH.

Methods:
We studied 129 patients with Ipc-PH (n=38), Cpc-PH (n=52), or PAH (n=39) between June 2006 and March 2012. Liquid chromatography-mass spectrometry was used to assess 350 lipid metabolite analytes in each patient.

Results:
In multivariable analyses adjusting for age, sex, BMI, and pulmonary hypertension medications, we observed 34 metabolites were significantly increased and 10 were decreased in Ipc-PH compared to Cpc-PH (Figure). Among these same metabolites, only 9 were significantly different between Cpc-PH and PAH. Compared to patients with Ipc-PH, those with Cpc-PH had elevated levels of fatty acyl esters of hydroxy fatty acids and polyunsaturated fatty acids as well as lower levels of anti-inflammatory and pulmonary vascular relaxant oxylipins.

Conclusions:
Overall, these findings suggest that Cpc-PH may diverge from Ipc-PH and share some molecular similarities with PAH. Identifying key molecular targets involved in Cpc-PH pathophysiology may be critical for diagnostic purposes and in the development of novel therapeutic avenues for patients with Cpc-PH.
Abstract 12951: Electrical and Calcium-Dependent Mechanisms That Contribute to Increase the Risk for Atrial Fibrillation in Obesity
Authors: Savio-Galimberti Eleonora , Scotto Tiffany , Wasserman David , Kannankeril Prince
Published: June 2023

Obesity (OB) is an independent predictor for atrial fibrillation (AF), but mechanisms by which OB increases AF risk remain poorly characterized. We hypothesized that OB modulates AF risk through electrical remodeling and impaired Ca
2+
dynamics that can be reversed after weight loss (WL). Using transesophageal rapid pacing we characterized AF inducibility and burden in lean, OB, and OB mice that lost 20% of body weight after modified vertical sleeve gastrectomy. Local field fluorescence microscopy was used to simultaneously record action potentials (APs) (di-8-ANEPPS or glass microelectrodes) and Ca
2+
transients (CaT) (Rhod-2) in Langendorff heart preparations. We evaluated AP duration (APD) dependency of frequency from 4 to 14 Hz (1 Hz incremental steps). AP parameters analyzed included APD30, APD50, APD90 and spontaneous arrhythmogenic events. We assessed Ca
2+
dynamics by studying CaT and fractional sarcoplasmic reticulum Ca
2+
release in the absence and presence of ryanodine (Ry) and thapsigargin (Tg). Since CaT
Ry+Tg
represents sarcolemmal Ca
2+
influx, we calculated the gain of Ca
2+
induced Ca
2+
release (CICR
gain
) as the ratio between CaT in the absence and presence of Ry+Tg. Experiments were done in the presence of blebbistatin at 37° C. Mean±SE, t-test. After burst pacing, both AF prevalence and burden were higher in OB mice vs lean (94 % vs 47 %, 227±19 vs 20±1.2 s, n=16 mice/group, p<0.0001). About 76 % of OB hearts showed afterdepolarizations and fibrillation vs no events in lean. APD50 and APD90 significantly decreased as stimulation frequency increased from 4 to 14 Hz in OB hearts vs lean (n=6 mice/group, p<0.05). Peak CaT from OB hearts were significantly decreased compared to peak CaT from lean (0.3±0.05 vs. 0.8±0.06, n=9, p<0.001). CICR
gain
in OB hearts was also significantly compromised compared to lean (5.2±1 vs 23.3±1.4, n=7 mice/group, p<0.0001). After WL, OB mice showed a decreased AF burden (21.7±8 s), increased APD, increased peak CaT (0.8±0.15) and increased CICR
gain
(20±2.3) back to lean levels (n=8, p<0.001). In conclusion, shortened APs, spontaneous afterdepolarizations and impaired CICR significantly contribute to the development of AF in OB. WL reversed the electrical phenotype and the impaired Ca
2+
dynamics and prevented AF.
Abstract 12962: Circulating Biomarkers Are Associated With Left and Right Ventricular Strain Measured by Cardiac Magnetic Resonance Imaging in Repaired Tetralogy of Fallot Patients
Authors: Patel Chandni H , DiLorenzo Michael , Jones Andrea , Goldmuntz Elizabeth , Fogel Mark A , Mercer-Rosa Laura M
Published: June 2023

Introduction:
Circulating biomarkers thought to represent myocardial fibrosis and stretch are understudied in repaired tetralogy of Fallot (TOF) patients. We aim to identify associations between biomarkers and right ventricular (RV) and left ventricular (LV) function measured as strain by cardiac magnetic resonance (CMR) in repaired TOF patients.

Methods:
N-terminal-pro hormone BNP (NTproBNP), galectin-3 (Gal-3) and matrix metalloproteinase 1 (MMP1) were measured in serum obtained from TOF patients at the time of standard of care CMR. High and low biomarker groups were created using the median value. CMR strain analysis was performed using cvi42 (Circle Cardiovascular Imaging). CMR parameters were compared by biomarker group using two sample Student’s
t
tests (given normal distribution), and Pearson correlation coefficients were obtained.

Results:
Twenty patients were analyzed (45% male). Median age at TOF repair and CMR was 4.1 months (interquartile range [IQR] 1.6, 6.8) and 11.5 years (IQR 10, 15.5), respectively. Patients with higher Gal-3 had worse LV global longitudinal strain
(Table)
. Those with higher NTproBNP had worse RV global longitudinal and circumferential strain, and those with greater MMP1 values had worse LV global circumferential strain. Gal-3 was moderately inversely correlated with pulmonary regurgitant fraction and RV end-systolic volume
(Table)
. NTproBNP values were moderately directly correlated with RV mass. MMP1 values were moderately directly correlated with RV end-systolic volume and inversely correlated with RV ejection fraction.

Conclusions:
The three biomarkers investigated have associations with right and left ventricular strain. Gal-3 and MMP1 are potential biomarkers of LV function, while NTproBNP is a potential biomarker of RV function. Further, Gal-3 may inform more favorable RV remodeling. Future studies will determine if circulating biomarkers will identify early ventricular dysfunction after TOF repair.
Abstract 12996: Outcomes of Cardiac Resynchronization Therapy in Transthyretin Wild-Type Cardiac Amyloidosis
Authors: Sehrawat Ojasav , Alcantara Hannah P , Tan Nicholas Y , Chahal Anwar A , Kashou Anthony H , Latif Omar S , Maanja Maren , Siontis Konstantinos , Miller Wayne L , Noseworthy Peter A , Lin Grace
Published: June 2023

Introduction:
Cardiac resynchronization therapy (CRT) has known benefit for heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and dyssynchrony. However, very little is known about its benefit in infiltrative cardiomyopathies such as cardiac amyloidosis (CA) due to relative rarity of these conditions.

Methods:
This retrospective case series (2003-2021) comprised patients with HF due to transthyretin wild-type CA with (case) or without (control) CRT implant. Only controls with an indication for CRT or LVEF <40% were included. To further match disease severity, cases were 1:1 matched (propensity score tolerance 0.04) to controls for age, NYHA class, and CA stage (UK Staging). Primary outcome was MACE (major adverse cardiac events) which included stroke, myocardial infarction, HF hospitalization and cardiac mortality during a 3-year follow-up. Loss to follow-up was censored as per last visit date. LVEF and NYHA were noted closest to 1-year follow-up. Survival analysis for MACE was performed with Kaplan-Meier (KM) and multivariable cox regression models.

Results:
Study Cohort (n=160) had a mean age of 75.5 (SD 7.8) years and 97.5% were males. A majority had NYHA class 2 or 3 (92.3%) and CA stage 2 (42.2.%). Notably, median LVEF at baseline was lower in controls (33.5 vs 36.5;
P
= .001) and 77.5% of controls had an indication for CRT device. A total of 79 MACE events occurred, most frequent being HF hospitalization (n=45). KM curves were comparable for MACE events in the two groups (log-rank test;
P
= .059). Even after adjusting, as in table, CRT device was not associated with MACE events (adjusted HR 0.66; 95% CI 0.40-1.09;
P
= .106). Lastly, change in LVEF (
P
= .84) and NYHA (
P
= .86) at follow-up was similar in cases vs controls.

Conclusions:
The findings of this largest yet observational study to examine this question suggest that CRT in patients with transthyretin wild-type CA does not favorably impact outcomes for MACE events, improve LVEF or NYHA functional class.
Abstract 13028: Associations Between White Matter Microstructure, Resting and Peak Exercise Oxygen Saturations, and Cognitive Function in Adolescents and Adults With a Fontan Circulation; A Diffusion Brain MRI Study
Authors: Verrall Charlotte E , Chen Jian , Yeh Chun-Hung , Tran Derek , Laohachai Karina , MacKay Mark T , d'Udekem Yves , Winlaw David S , Iyengar Ajay J , Ayer Julian , Gentles Thomas L , Yang Joseph , Cordina Rachael
Published: June 2023

Introduction:
Adolescents and adults with a Fontan circulation demonstrate broad cognitive dysfunction. Neurological alterations and risk factors associated with worse outcomes are poorly characterized. Persisting hypoxemia and reduced exercise tolerance are also common and are associated with long-term morbidity and mortality. This study investigated white matter (WM) microstructure in adolescents and adults with a Fontan circulation and associations with CPET data and cognitive functioning.

Methods:
Ninety-two participants with a Fontan circulation (aged 13-49 years) underwent diffusion brain MRI. Diffusion tensor imaging MRI metrics were computed for 34 WM tracts of interest; Lower FA and higher MD and RD typically infers WM axonal injury and/or demyelination. Resting

SaO
2,
peak exercise SaO
2
, and % predicted peak VO
2
(%pred VO
2
) were measured during CPET. Processing speed and executive function were assessed using Cogstate.

Results:
Mean resting and peak SaO
2
were 93.1% (± 3.81) and 90.1% (± 4.71) respectively and mean %pred VO
2
was 62.7% (± 18.5); all were significantly lower for participants with a patent fenestration compared to those without (p < 0.05). Mean processing speed and executive function z-scores were -0.72 (± 1.44) and -0.43 (± 1.09), respectively. Significant associations were identified between i) resting SaO
2
and the left corticospinal tract (CST) and bilateral superior longitudinal fasciculus I (SLF-I) ii) peak SaO
2
and bilateral CST, frontopontine tract, and SLF-I and -II, and the right SLF-III, and iii) %pred VO
2
and the right cingulum and left uncinate fasciculus (p < 0.05), whereby lower resting and peak SaO
2
and %pred VO
2
were associated with lower FA and/or higher MD and RD. Paradoxical associations were identified between processing speed and executive function and WM tract metrics (p < 0.05).

Conclusion:
Persisting hypoxemia and exercise intolerance may have long-term detrimental impact on WM microstructure in people with a Fontan circulation. Paradoxical associations between cognitive functioning and DTI-based metrics could be suggestive of compensatory WM remodeling. Longitudinal investigations are required to investigate the mechanisms and trajectory of altered WM microstructure in this cohort.
Abstract 13035: Mechanical Circulatory Support is a Viable Solution for Adults With Failing Fontan Circulation
Authors: Soghoyan Kengo Z , Cook Stephen , Guglin Maya
Published: June 2023

Mechanical circulatory support (MCS) is rarely used in adults with congenital heart disease and even more uncommon among those with single ventricle (e.g. Fontan) circulation. As survivorship among Fontan patients increases, evaluation for MCS is warranted. This systematic review’s objective is to study the outcomes of adult Fontan patients supported by MCS. METHODS We searched the literature in English in PubMed and Google Scholar in May 21 & 2, 2022 using MeSH terms: "VAD," "Fontan," and "circulatory assist device." The search yielded 2785 results. After screening for title, abstract, patient age (>18 y/o), and extractable individual patient data, 23 reports met the criteria. Ultimately, 15 full texts were reviewed and included in this report. RESULTS We identified 18 patients on MCS, including 7 on short-term devices (Impella), 4 on paracorporeal pulsatile devices (PPDs), and 7 on durable continuous flow ventricular assist devices (VADs). Short-term pumps were used for cardiogenic shock (5, with 3 survivors) or support of high-risk ablation procedures. PPDs were used as a bridge to transplantation, mean patient age of 23.5±3.4 years old; all survived after a mean time on MCS of 172±158 days.In the VAD cohort (7 patients, 85.7% males, age 25.1±4.0), 5 received Heartmate 3, one received Heartmate II, and one Heartware (Table 1). Indications for VAD included cardiogenic shock (4 patients, 2 on VA ECMO) or heart failure. VADs dramatically increased cardiac index from 1.6±0.14 to 3.6±0.1 L/min/m2, p=0.0003, and decreased Fontan pressure from 21.4±3.3 to 13.0±1.4 mmHg, p=0.02. Heartmate 3 mean speed was 6460±568.3 rpm. All patients survived, with mean time on VAD lasting 459.5±452.2 days. CONCLUSIONS Implanted mostly for catastrophic indications, adult Fontan patients demonstrated improved hemodynamics and excellent survival following MCS use. These improvements are promising, and earlier implantation prior to catastrophic events may lead to better outcomes.
Abstract 13051: Comparative Antiplatelet Effects of Chlorthalidone and Hydrochlorothiazide
Authors: Palicherla Anirudh , Ismayl Mahmoud , Bashir Khalid M , Burns Tammy , Pirruccello Samuel J , Aurit Sarah , Hilleman Daniel E
Published: June 2023

Introduction:
The ACC/AHA hypertension guidelines recommended chlorthalidone (CTD) over hydrochlorothiazide (HCTZ) due to its longer half-life and proven reduction in major adverse cardiovascular events. The mechanism of the potential benefit of CTD compared to HCTZ has not been established. Unlike other thiazide diuretics, studies suggest that CTD may affect platelet aggregation, gene transcription, angiogenesis, and vascular permeability. We aimed to compare the antiplatelet effects of CTD versus HCTZ.

Methods:
We conducted a prospective, double-blind, randomized, three-way crossover study comparing the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers ≥ 19 years of age. ASA was included in the study as a known control for inhibition of platelet aggregation. Whole blood aggregometry was used to assess the impact of treatments on platelet activation and aggregation.

Results:
Of the 40 subjects, 34 (85%) completed the 3-way crossover comparison. Six subjects were excluded due to non-compliance and adverse effects. Compared to ASA, both CTD and HCTZ had no antiplatelet effects (Table 1). There was no statistically significant difference between CTD and HCTZ in terms of platelet function.

Conclusions:
Although recent studies showed increased cardiovascular benefit with CTD compared to HCTZ, CTD and HCTZ do not have antiplatelet effects. Larger studies are needed to confirm our findings.
Abstract 13063: Clonal Hematopoiesis Associated With TET2 and DNMT3A Gene Driver Mutations Accelerates Aortic Valve Calcification in vitro and in vivo
Authors: Abplanalp Wesley T , Schuhmacher Bianca , Mas-Peiro Silvia , Zuriaga María A , Matesanz Nuria , Fuster Jose J , John David , Muhly-Reinholz Marion , Vasa-Nicotera Mariuca , Merten Maximilian , Hoffmann Jedrzej , Zeiher Andreas M , Dimmeler Stefanie
Published: June 2023

Calcific aortic valve disease (CAVD) is the most common age-related heart valve disease, with no medical therapy to halt progression. Age is associated with the enrichment of somatic mutations in hematopoietic stem cells leading to clonal hematopoiesis (CH). CH mutations promote inflammation, occur in more than 30% of patients with severe CAVD and CAVD patients harboring CH mutations have a worse prognosis. Single-cell RNA-sequencing of immune cells (n=127120 cells) of CAVD patients with CH-mutations showed strong proinflammatory and M1-like macrophage gene signatures (CD38, CXCL10) along with genes associated with calcification (S100A9, RUNX2, Oncostatin M=OSM) suggesting that CH might be causally involved in CAVD. Indeed, silencing of TET2 or DNMT3A in macrophages in vitro induce the prototypic osteoblastic transcription factor RUNX2 and paracrine acting genes such as OSM and S100A9, which can promote vascular calcification. Secreted factors from TET2 or DNMT3A-silenced macrophages induced osteoblastic differentiation as demonstrated by elevated calcium deposition and genes involved in the RUNX2 signaling pathway (COL1A2, ALP), which could be ablated by silencing of OSM in CH-macrophages. Atheroprone Ldlr
-/-
mice receiving TET2
-/-
bone marrow transplants mice showed increased total calcified area along (1.49-fold) with increased numbers of calcification deposits (2.33-fold) as evidenced by von Kossa staining. Increased myeloid derived OSM and S100A9 was found in the valves of TET2
-/-
BMT mice with S100A9 strongly co-occurring with OSM. This study provides insights into the development of incident CAVD for patients with CH mutations and therefore yields plausible interventions for nearly one third of CAVD cases to slow or stop disease progression.
Abstract 13075: Hemodynamic Estimation of Personalized Initial Target Heart Rate in Patients With Atrial Fibrillation With Rapid Ventricular Response
Authors: Kim Chee Jeon
Published: June 2023

Introduction:
Rate control in atrial fibrillation (AF) has played a pivot role in clinical setting even though recent advances in rhythm control. There are few evidences for target heart rate in either acute or chronic situations.

Hypothesis:
This study tried to estimate personalized initial target heart rate based on hemodynamic assessment in patient with AF with rapid ventricular response.

Methods:
A total of 72 patients with AF were included. From the equation between preceding RR interval and left ventricular peak ejection velocity adjusted by pre-preceding RR interval, the relationship between cardiac performance representing cardiac output and heart rate was calculated, and heart rate showing maximal cardiac performance (HRmax) was obtained (Left Figure).

Results:
Mean HRmax was 126±21.8/min (from 75/min to 188/min). Three-fourth patients had HRmax >120/minute (Right Figure). The relationship between Vpe and preceding RR interval showed two types, biphasic or monophasic resulting in similar patterns between cardiac performance and heart rate (Left Figure). HRmax <100/min was found in 7 patients in whom left ventricular dilatation, dysfunction, and/or aortic regurgitation were observed (Left Figure C). Lower HRmax was independently associated with larger aorta size (r=0.48, p<0.001), the absence of mitral regurgitation (r=0.43, p<0.005), prescription of angiotensin converting enzyme inhibitor or angiotensin receptor blocker (r=0.39, p=0.001), and a history of heart failure (r=0.21, p=0.019).

Conclusions:
In most AF patients, hemodynamic approach suggested that tachycardia of 120/min or more is tolerable. The method of this study may be useful to deliver individually designed management by identifying patient that strict rate control is mandatory. In other patients, management of underlying causes for tachycardia is enough without medications for mechanical heart rate control to avoid adverse effects without clinical benefits.
Abstract 13122: Exome Sequencing Reveals Novel Genetic Variants Predisposing to Sudden Cardiac Death Due to Primary Myocardial Fibrosis
Authors: Junttila Juhani , Pakanen Lasse , Skarp Sini , Doedens Anne
Published: June 2023

Introduction:
Sudden cardiac death (SCD) is one of the most common modes of death in Western countries. In post-mortem investigations, myocardial fibrosis is a common finding, as more than 90% of the SCD victims have fibrotic accumulation in the myocardium.

Hypothesis:
Our aim was to identify novel candidate genes and variants predisposing to the development of myocardial fibrosis in SCD victims.

Methods:
Whole exome sequencing was performed for 127 nonischemic SCD cases with primary myocardial fibrosis as the only pathological finding. We searched for rare variants with minor allele frequency <0.005 estimated to be pathogenic and present in three or more cases. A computational approach was used to identify protein interactions for candidate genes in cardiomyocytes. Associations of the identified variants with cardiovascular disease endpoints were investigated in the Finnish national genetic study (FinnGen) dataset.

Results:
We identified 21 missense and one nonsense variant in SCD victims with primary myocardial fibrosis. Most variants locate in genes participating in extracellular matrix (ECM) formation, inflammation, mitochondrial function, cardiomyocyte contractility or hypertrophy. Heart enhanced protein interactions were identified for 16 candidate genes. Ten variants were significantly associated with SCD and primary myocardial fibrosis (adjusted p-value <0.05). Sixteen variants were also associated with cardiac diseases in Finnish general population. Four missense variants were highly likely to be pathogenic, significantly associated with sudden cardiac death due to primary myocardial fibrosis and were also associated with cardiac diseases in general Finnish population. These variants locate in cartilage acidic protein 1 (
CRATC1
), the calpain 1 (
CAPN1
), unc-45 myosin chaperone A (UNC45A) and unc-45 myosin chaperone B (UNC45B).

Conclusions:
We identified novel variants and candidate genes predisposing to sudden cardiac death due to primary myocardial fibrosis. Our results highlight the importance ECM pathways as well as cardiomyocyte function and survival in the pro-fibrotic process.
Abstract 13145: Mixed Digital Model of Care in Real-Time for Mexican Patients With Heart Failure
Authors: GUIZAR CARLOS , Alvarez Amada , JORDAN ANTONIO , Mendez Arturo , DE LA FUENTE MANCERA JUAN CARLOS , BARANDA FRANCISCO , RODRIGUEZ DANYA , VELAZQUEZ ARANTXA , Cacelin Rafael , LOPEZ NANCY , DALI LUIS , ZURITA THANIA , GOMEZ ALVAREZ ULISES , Aguilar Serrano Maria del Refugio , JUAREZ SONIA , RODRIGUEZ ARELI , Collado Juan , TEJADO LUIS
Published: June 2023

Introduction
Decompensated heart failure (DHF) is the main cause of cardiovascular hospitalization. During 1-year follow-up (FU), at least one rehospitalization occurred in 56.6% of patients with HF. In Mexico, HF places great burden on patients, caregivers, and healthcare systems. New strategies are essential for early diagnosis and treatment of DHF.

Hypothesis:
Use of a digital tool is effective for remote monitoring of patients with CHF to reduce the number of hospitalizations and/or unscheduled visits to the ER.

Methods:
A mixed digital model of HF (MDM-HF) care has been developed. It included an app in patient’s mobiles (CardioEnlace) that allowed real time monitoring of key parameters. These data were transferred into HF Unit portal and integrated into the patient's clinical file. CardioEnlace allowed detection of decompensation events through 1) alerts by patient′s text messages and 2) system alerts when variables were out of security limits on three or more consecutive days. If a patient showed signs of DHF, he/she was reached to provide medical instructions and/or scheduled an early appointment.

Results:
MDM-HF care was deployed in July 2021. Up to date 131 patients have been included. The median of age is 58 years (interquartile range 47.5-65.5) and 77.1% were male. Cardiovascular risk factors (CVRF) frequencies are shown in Table 1. HF was secondary to ischemic condition in 44.5% of the patients. At least one hospitalization in the previous 2 years was reported in 73.5% of the subjects. Cardio Enlace parameters are shown in Fig 1. A blood pressure <140/90 mmHg was reported in 89.5% of patients and the average exercise time was 32 min/day. CardioEnlace alerts from January 2022 to date, were 82. Reasons are shown in Table 2. Adjustments to the treatment were done immediately and none of the patients had been hospitalized.

Discussion:
MDM-HF care model supports an early detection of DHF and monitorization of CVRF treatment which affect around 50% of the patients. Follow-up evaluations would allow to assess its impact on hospitalizations/emergency admissions. MDM-HF care model is part of the HF National Mexican Registry that will integrate data-driven solutions to reduce lead times from diagnosis to therapy adjustments and reduce the economic burden of DHF.
Abstract 13147: Formate Stimulates S-Nitrosylation and Mitochondrial Activity to Induce Cardioprotection
Authors: Kabir Raihan , Garbus Haley , Ebenebe Obialunanma V , Taube Nicole , Ashok Deepthi , O'Rourke Brian , Kohr Mark J
Published: June 2023

Formate (FM) is a substrate in one-carbon metabolism, and recent studies implicate its function in both health and disease, but a role in the heart remains unexplored. Research from our group demonstrates that the loss of formaldehyde dehydrogenase, which oxidizes formaldehyde into FM, ameliorates sex-dependent cardioprotection against ischemia-reperfusion (I/R) injury in the female mouse heart. Considering that FM depletion may be detrimental, we tested the hypothesis that FM yields cardioprotective benefit in a model of I/R injury. Hearts from male and female mice (n=5-10/group) were subjected to ex vivo I/R injury with or without FM via Langendorff perfusion. FM significantly enhanced post-ischemic functional recovery in male hearts (27.1%, 95% CI 10.8 to 45.9, p=0.0023; females: 9.5%, 95% CI -6.9 to 27.8, p=0.2020) and decreased infarct size (males: -24.6%, 95% CI -35.1 to -12.2, p<0.0001; females: -3.7%, 95% CI -9.6 to -0.3, p=0.1128), indicating that FM protects the myocardium against I/R injury. Although FM had a greater protective effect in male hearts than in female hearts, plasma FM levels were greater in female mice, suggesting that FM-mediated cardioprotection may already exist near steady state in females. Mechanistically, cardiomyoblasts stimulated with FM exhibited a significant increase in total protein S-nitrosylation (SNO) without changing nitric oxide synthase (NOS) phosphorylation or protein expression; this was suppressed by NOS inhibition, suggesting that FM contributes to NOS-dependent NO cycling in the heart. FM-treated cardiomyocytes and cardiomyoblasts also exhibited significant increases in mitochondrial marker protein expression, metabolic activity, and maximal oxygen consumption, demonstrating an enhanced respiratory capacity to respond to increased energetic demand. Furthermore, FM treatment significantly increased phospho-activation of the energy regulator AMPKα and the protein expression of PGC-1α targets, indicating a potential upregulation in mitochondrial biogenesis. Taken together, these data suggest that FM may stimulate protein SNO and mitochondrial activity to protect the heart against I/R injury.
Abstract 13157: Workplace Culture and Biomarkers of Sympathetic Activation
Authors: hart joy , walker kandi , Shuck Brad , Rai Shesh N , Rai Jayesh , Srivastava Shweta , Srivastava Sanjay , Rai Shesh N , Bhatnagar Aruni , Keith Rachel J
Published: June 2023

Workplace environment can impact health, but most research has focused on toxic chemicals. Recently, workplace culture—experiences, values, and behaviors unique to a workplace—is studied for its impact on overall health risk; however, connections with robust biologic markers of health remain to be established. Therefore, we examine associations between work environment and urinary levels of catecholamines and their metabolites as biomarkers of sympathetic activation.

In 2018-19, we recruited participants (n=219) from an ongoing CV risk cohort to investigate workplace culture, overall well-being, and stress. Participants completed 7 questionnaires. Clean catch urine samples were used to measure catecholamines and their metabolites. To estimate associations between work and health scales and log or logit-transformed outcomes we used Pearson correlation and linear regression models adjusting for demographics and creatinine.

Participants reporting higher well-being had lower levels of dopamine (DA) (
r
= -0.28), serotonin (5HT) (
r
= -0.17), and 3-methoxytyramine (3MT) (
r
= -0.31), a product of dopamine breakdown. Participants reporting a more engaged workplace had lower levels of DA (
r
= -0.20) and 3MT (
r
= -0.22). Those reporting more positive workplace culture had lower levels of DA (
r
= -0.17) and 3MT (
r
= -0.26) and higher levels of norepinephrine (
r
= 0.19) and 5-hydroxyindole-3-acetic acid (HIAA) (
r
= 0.22). When participants identified more workplace isolation, they had higher levels of DA (
r
= 0.19) and 3MT (
r
= 0.19). Positive workplace culture was correlated with lower levels of DA (
r
= -0.22) and 3MT (
r
= -0.28) and higher levels of HIAA (
r
= 0.22) and homovanillic acid (
r
= 0.20). Given high correlations between catecholamines, we used 3MT for linear regression. In fully adjusted models we found in more positive work cultures, levels of 3MT remained significantly lower (β = -0.065 ±0.025,
p
= 0.01), accounting for 23% of the variance, and a significant positive association between workplace isolation and 3MT (β= 0.064 ±0.030,
p
= 0.04), accounting for 22% of the variance with 3MT, which may reflect greater dopamine degradation. These findings suggest an important relationship between how we work and sympathetic nervous system activity.
Abstract 13180: Trans-Valvular Unloading Reduces Anaerobic Glycolysis Before Reperfusion and Preserves Energy Substrate Utilization After Reperfusion in Models of Acute Myocardial Infarction
Authors: Swain Lija , QIAO Xiaoying , Reyelt Lara A , Zweck Elric , Everett Kay , Majumdar Monica , Mahmoudi Elena , Bhave Shreyas , Diakos Nikolaos , Kapur Navin K
Published: June 2023

Background:
The impact of mechanical left ventricular (LV) unloading before reperfusion on myocardial energetics in acute myocardial infarction (AMI) is unknown. We hypothesized that LV unloading reduces anaerobic glycolysis in models of ischemia reperfusion injury (IRI).

Methods:
Myocardial ischemia was induced by percutaneous occlusion of the left anterior descending (LAD) artery for 90 minutes in adult swine. In Groups A and B, an additional 120 minutes of LAD occlusion without reperfusion was performed in the presence or absence of a trans-valvular pump (TVP). In Group C and D, an additional 120 minutes of reperfusion was performed in the presence or absence TVP (Fig. 1A). Untargeted Metabolomics was performed on the tissues from the infarct zones.

Results:
Compared to Group A, infarct size normalized to the area at risk (IS/AAR) was significantly smaller with LV unloading after ischemia alone (Group B; Fig 1B) and reperfusion (Group D; Fig 1B). Principal component analysis analysis of 800 metabolites identified 5 distinct clusters corresponding to the 4 study groups and sham controls (Fig 1C). LV unloading without reperfusion reduced lactate by 30±4% (p<0.006), glucose by 25±5% (p<0.02), and intermediates of glucose metabolism, Fructose 1,6-diphosphate by 9.3%, p<0.008) and ATP by 14±5% (p<0.04) consistent with decreased anaerobic glycolysis and reduced myocardial oxygen demand (Fig 1D Groups A and B). LV unloading followed by reperfusion increased lactate and glucose levels by 30±5% and 75±30% (p<0.05). Consistent with reduced glycolytic metabolites during ischemia with unloading, we observed significantly reduced levels of genes and proteins associated with glycolysis including mRNA expression of Glut1 and PDK1 within the infarct zone.We report for the first time that LV unloading during coronary occlusion reduces anaerobic glycolysis, energy substrate utilization and ATP production before reperfusion.
Abstract 13182: Inhibition of Microrna-466 and Microrna-200 Accelerates Wound Healing by Decreasing Endothelial Cell Permeability
Authors: Li Hainan , Kujawa Marisa , O'Meara Megan , Xu Liping , Wang Jie-Mei
Published: June 2023

Introduction:
Endothelial cell (EC) permeability is essential to vascular homeostasis in diabetes. MicroRNAs (miRs) are critical gene regulators whose roles in the EC permeability have yet to be elucidated. It remains unclear whether miR-200 and miR-466 regulate EC permeability. We hypothesized that the inhibition of miR-466 and miR-200 can restore vascular integrity and accelerate wound healing via targeting Claudin-5.

Methods and Results:
Human dermal microvascular ECs from healthy subjects and type 2 diabetic patients at passages 5-7 were cultured in vitro. The EC permeability was significantly increased by high glucose (25mM)or silencing Claudin-5 as measured by FITC-Dextran Transwell assay (n = 5, p<0.05). Claudin-5 protein levels were significantly reduced in diabetic ECs and healthy ECs exposed to high glucose. The reduction of Claudin-5 protein was restored by the inhibition of miR-466 (Western Blot, n = 5, p<0.05), though both miR-200 and miR-466 are directly bound with the 3’ UTR of Claudin-5 mRNA (luciferase 3’UTR reporter assay). Furthermore, silencing Claudin-5 diminished the protection of miR-200/miR-466 inhibition on EC permeability damaged by high glucose (n = 5, p<0.05). In the in vivo study, the topical application of miR-200 and miR-466 inhibitors showed enhanced efficacy in accelerating the closure of a 7-mm full-thickness excisional wound in a type 2 diabetic (db/db) mouse model, with concomitant robust wound capillary formation (CD31 immunochemistry), compared with the topical application of miR-200 inhibitor alone (n = 5, p<0.05). Claudin-5 levels were increased in the wounds receiving miR-466 inhibitor alone or both miR-200 and miR-466 inhibitors (n = 5, p<0.05).

Conclusions:
Our study demonstrated the potentially effective approach of miR-200/miR-466 cocktail inhibition to restore vascular integrity and tissue repair in hyperglycemia. This may provide a novel therapeutic strategy targeting miRs for the treatment of wound healing in diabetes.
Abstract 13192: The Influence of Posture and Steps on Daytime Ambulatory Blood Pressure
Authors: Barone Gibbs Bethany , Muldoon Matthew F , Conroy Molly B , Paley Joshua L , Perera Subashan
Published: June 2023

Introduction:
Ambulatory blood pressure (BP) monitoring (ABPM) provides data beyond clinic BP. Yet, free-living activity prior to measurements may add variability and obscure clinical interpretation. The influence of posture and ambulation on ABPM is unclear.

Hypothesis:
Posture and ambulation will partially explain variability in daytime ABPM.

Methods:
This study used baseline data from RESET BP (NCT03307343), a randomized clinical trial testing a sedentary behavior reduction intervention among inactive desk workers with elevated, unmedicated BP. ABPM was measured 2 x per self-reported waking hour over 24 hours with a SunTech Medical
®
Oscar 2
TM
ambulatory BP monitor. Upright posture and step count were concurrently captured with an activPAL
TM
thigh-worn accelerometer. Upright time and steps were summed for the 1-, 5-, 10-, and 15-minute intervals prior to each ABPM measurement. Percentage of BP variability explained (R
2
) by upright time, steps, and both was calculated within-subject using linear regression. Additional models considered quadratic terms for upright time and steps.

Results:
Participants (n=256) were 59% female, with mean±SD age of 45.2±11.6 years, resting systolic BP (SBP) of 130±10 and diastolic BP (DBP) of 84±7, and provided 32.5±3.9 daytime ABPM measurements. Upright time and steps were directly associated with BP. Upright time and steps explained the most variability (highest R
2
) using the 1-minute interval prior to ABPM measurement; R
2
gradually declined with increasing interval length. From 1-minute prior, upright time explained 12% of the variability in SBP and 10% of DBP, on average. Adding an upright time quadratic term increased R
2
(SBP: 16%; DBP: 13%). Steps in the minute prior explained 12% and 7% of the variability in SBP and DBP, respectively, and increased to 16% and 11% with the addition of a quadratic term. A final model including upright time, steps, and quadratic terms explained 25% and 20% of the variability in SBP and DBP, respectively.

Conclusions:
Posture and steps, especially in the minute prior, explained a substantial amount of individual variability in ABPM. These findings advance our understanding of BP variability and may have implications for the quantification and interpretation of daytime ABPM data.
Abstract 13196: Inter-Stage Infants With Single Ventricle Heart Disease Show Prominent Dysregulation in Multiple Metabolic Pathways: A Targeted Metabolomics Analysis
Authors: Frank Benjamin S , Khailova Ludmila , Dekermanjian Jonathan , Mitchell Max B , Morgan Gareth J , Twite Mark , Christians Uwe , Di Maria Michael V , Klawitter Jelena , Davidson Jesse
Published: June 2023

Objectives:
To evaluate the circulating metabolome of interstage infants with single ventricle heart disease (SVHD) and determine whether metabolite levels were associated with pulmonary vascular inadequacy.

Background:
Infants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between metabolite levels and pulmonary vascular readiness for staged SVHD palliation.

Methods:
Prospective cohort study of 52 infants with SVHD undergoing Stage 2 palliation and 48 healthy infants. Targeted metabolomic phenotyping (n=175 metabolites) performed by tandem mass spectrometry on SVHD pre-Stage 2, post-Stage 2, and control serum samples. Clinical variables were extracted from the medical record.

Results:
Random Forest analysis readily distinguished between cases and controls (Figure), and pre-op and post-op samples. Seventy-four of 175 metabolites differed between SVHD and controls. Twenty-seven of 39 metabolic pathways were altered including pentose phosphate and arginine metabolism. Seventy-one metabolites differed in SVHD patients between timepoints. Thirty-three of 39 pathways were altered post-operatively including arginine and tryptophan metabolism. We found trends towards increased pre-operative methionine metabolites in patients with higher pulmonary vascular resistance and higher post-operative tryptophan metabolites in patients with greater post-operative hypoxemia.

Conclusions:
The circulating metabolome of interstage SVHD infants differs significantly from controls and is further disrupted after Stage 2. Several metabolites showed promising trends towards association with adverse outcomes. Metabolic dysregulation may be an important factor in early SVHD pathobiology.
Abstract 13205: Mitigating Alarm Fatigue and Improving the Care Provider, Patient, and Family Experience Through Reduction in Non-Actionable Bedside Alarms
Authors: Yang Jeffrey K , Su Felice , DeSousa Carlos , Graber Anna , Hedlin Haley , Feehan Shannon , Graves Angela , Palmquist Andrew , Madsen Nicolas , Cable Rhonda , Kipps Alaina
Published: June 2023

Introduction:
The burden of bedside alarms is a well-established patient safety hazard with >85% of alarms in ICU settings considered non-actionable or “false alarms”. Healthcare providers risk developing alarm fatigue with potential for prolonged response times and silencing of clinically meaningful alarms. Additionally, alarms disrupt care and cause stress for patients and families.

Hypothesis:
Creating conditional alarm triggers for bedside monitors can decrease the frequency of non-actionable alarms without compromising safety. The decreased burden of alarms on nurses, patients, and families may promote increased satisfaction.

Methods:
Single center, quality improvement initiative in a 26-bed cardiac acute care unit and 36-bed pediatric ICU, modeled after successful iterative effort at another tertiary children’s hospital. After 1 month pre-intervention observation of bedside monitor alarm burden, monitors were programmed with hierarchical time delay and conditional pulse oximetry, respiratory rate, and premature ventricular contractions alarm triggers. Bedside alarms were tallied for 1-month follow-up. The primary outcome was alarms per monitored patient day (MPD).

Results:
A total of 1394 and 776 MPD were evaluated in the pre- and post-intervention periods, respectively. The median number of cardiorespiratory monitor alarms per MPD decreased by 73% (15 to 4, p < 0.001) in both acute care and ICU. Alarm burden in RR, SpO2, and PVC categories also decreased. No increase in frequency of rapid response or code events occurred in either unit. Nursing surveys (n=253) reported positive trends of more manageable alarm burden and decreased perceived number of alarms. Family surveys (n=160), however, reported decreased sleep quality and increased perceived alarms.

Conclusions:
Implemented changes to bedside monitor alarm conditions decreased total alarm frequency in both cardiac acute care and pediatric ICU without compromising safety.
Abstract 13214: Circulating Progenitor Cells Are Associated With Bioprosthetic Aortic Valve Deterioration
Authors: Kanaji Yoshihisa , Ozcan Ilke , Toya Takumi , Gulati Rajiv , Young Melissa , Kakuta Tsunekazu , Lerman Lilach O , Lerman Amir
Published: June 2023

Introduction:
Mechanisms underlying bioprosthetic valve deterioration (BVD) are multifactorial and incompletely elucidated. Reparative circulating progenitor cells (CPCs), and conversely calcification-associated osteocalcin expressing CPCs (CPC-OCN), have been linked to native aortic valve deterioration. However, their role in BVD remains elusive. This study sought to evaluate the contribution of different subpopulations of CPCs in BVD.

Methods:
This prospective study enrolled 121 patients who had peripheral blood mononuclear cells (PBMC) isolated prior to bioprosthetic aortic valve replacement (surgical 104, transcatheter 17) and had an echocardiographic follow-up ≥2 years after the procedure. Using flow cytometry, fresh PBMC were analyzed for the surface markers CD34, CD133, and osteocalcin (OCN). BVD was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30mmHg and/or at least moderate intraprosthetic regurgitation. Multivariable models were constructed to evaluate the association of each subpopulation of CPCs and other clinical characteristics with HVD.

Results:
Sixteen patients (13.2%) developed HVD during follow-up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34
+
CD133
+
cells and higher levels of OCN
+
cells than those without HVD (CD34
+
CD133
+
cells: 125 [80, 210] vs 270 [130, 420], P=0.002; OCN
+
cells: 3060 [523, 5528] vs 670 [180, 1930], P=0.005 respectively). Decreased level of CD34
+
CD133
+
cells was a significant predictor of HVD.

Conclusions:
Circulating levels of CD34
+
CD133
+
cells and OCN
+
cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. CPCs might play a vital role in the mechanism, risk stratification and a potential therapeutic target for patients with bioprosthetic valve deterioration.
Abstract 13265: Soluble Klotho Captures FGF23 to Mitigate Aortic Valve Inflammocalcification Associated With Chronic Kidney Disease
Authors: The Erlinda , Zhai Yufeng , Yao Qingzhou , Ao Lihua , Fullerton David , Meng Xianzhong
Published: June 2023

Calcific aortic valve disease (CAVD) is prevalent in the elderly people, particularly those with chronic kidney disease (CKD). Klotho (KL), an anti-aging protein, is expressed mainly in the kidney and the cardiovascular system as soluble and membrane forms. CKD patients have reduced levels of KL and increased levels of fibroblast growth factor 23 (FGF23), a pro-inflammatory mediator that may interact with soluble KL. We have reported that KL reduces the osteogenic response to high phosphate levels, a condition seen in CKD, in human aortic valve interstitial cells (AVICs). This study tested the
hypothesis
that soluble KL captures FGF23 to prevent aortic valve inflammocalcification induced by CKD.

Methods and Results:
We developed a novel CKD-CAVD model in old C57 mice (20 months) on AIN-76A diet and treated with adenine and calcitriol. Histology and immunostaining revealed tubular damage and monocyte/macrophage accumulation in kidney tissue of CKD mice. Aortic valve lesions, thickening and calcification, were evident in CKD mice. Serum FGF23 levels were increased while serum KL levels decreased. In addition, KL expression in the aortic valve was reduced. Recombinant FGF23 (0.04 mg/ml) elevated the inflammosteogenic activity in human AVICs. Treatment with recombinant KL (0.5 μg/ml) markedly decreased FGF23-induced inflammosteogenic activation in AVICs. Systemic analysis revealed that FGF23 upregulates YAP/SMAD3 signaling, and inhibition of YAP and SMAD3 reduced the effect of FGF23 on the inflammosteogenic activity in AVICs. In addition, recombinant KL suppressed the activation of this signaling mechanism in AVICs, and treatment of CKD mice with recombinant KL attenuated aortic valve lesions. However, denaturation of KL protein resulted in a loss of its effect on FGF23-induced AVIC inflammosteogenic activation. Further, incubation of FGF23 with recombinant KL not only resulted in the formation of complexes of these two proteins, but also markedly decreased the pro-inflammosteogenic effect of FGF23 in AVICs.

Conclusion:
This study demonstrates that CKD induces KL insufficiency and FGF23 accumulation that promote aortic valve lesions. Recombinant KL is capable of binding to FGF23 to suppress its pro-inflammosteogenic effect in the aortic valve.