bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18919: Race/Ethnic Differences in Mortality Among Patients Hospitalized with Intracerebral Hemorrhage
Authors: Xian Ying , Holloway Robert G , Smith Eric E , Schwamm Lee H , Reeves Mathew J , Cox Margueritte , Olson DaiWai M , Hernandez Adrian F , Lytle Barbara , Fonarow Gregg C , Peterson Eric D
Published: April 2024

Background:
Despite higher burden of stroke in minorities, limited data exists in comparing mortality for patients with intracerebral hemorrhage of different racial and ethnic background.

Methods:
Data from 123,736 patients (83,280 white, 22,165 black, 10,541 Hispanic, and 7,750 other race) with intracerebral hemorrhage admitted to 1,199 Get With The Guidelines-Stroke hospitals between 2003 and 2012. Multivariate logistic regressions with generalized estimating equations were performed to evaluate the association between race and in-hospital mortality.

Results:
Compared with white patients, black, other race, and Hispanic patients were younger (median 75, 59, 67, and 64), had less comorbidities except for diabetes mellitus and hypertension, and had more severe stroke (National Institutes of Health Stroke Scale [NIHSS], median 9, 10, 11, and 10; all p<0.001). Black (23.0%, adjusted OR 0.91, 95% CI 0.87-0.95), Hispanic (22.8%, adjusted OR 0.85, 95% CI 0.79-0.91), and other racial/ethnic patients (25.3%, adjusted OR 0.87, 95% CI 0.81-0.93) were less likely to die in hospital than white patients (27.6%) after adjustment for patient and hospital characteristics. The mortality differences remained consistent after further adjustment for NIHSS in NIHSS complete records (N=47,436). To determine whether race/ethnic differences in mortality varied by age, we examined the interaction between race and age (p <0.009). The survival advantage was observed in older age groups but was not evident in younger age groups (Table). In contrast to lower mortality, minorities had longer length of stay than white patients (median 6, 6, 6, and 5 days for black, Hispanic, other, and white respectively, p<0.001).

Conclusion:
Among patients hospitalized with intracerebral hemorrhage, black, Hispanic, and other race/ethnic groups have lower risk of in-hospital mortality compared to white patients, though these race/ethnic differences were confined to patients age 60 and older.
Abstract 18926: Serum Resistin is not Associated with the Response to Lipid-Lowering Therapy in Non-Diabetic Patients with Coronary Artery Disease
Authors: Lee Sahmin , Kim Yoon-Ki , Kwon Yoo-Wook , Yang Han-Mo , Cho Hyun-Jai , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: April 2024

Background :
Resistin is an adipokine that mediates insulin resistance in obese mice. In human, however, circulating resistin levels are not associated with obesity or insulin resistance. Although the function of human resistin is enigmatic, it has recently been reported that human resistin plays a role in hepatocyte low-density lipoprotein (LDL) receptor suppression.

Objectives :
Aim of this study was to determine if serum levels of resistin are associated with the response to lipid-lowering therapy and the prognosis in coronary artery disease (CAD).

Methods :
One hundred and eighty two patients without diabetes who underwent percutaneous coronary intervention for CAD participated in this study. We measured pre-procedural serum resistin levels. After procedures, we treated the patients with atorvastatin 20mg and evaluated response to the statin therapy at 6-month follow-up. We also performed 6-month follow-up coronary angiography (CAG) in all patients and quantitative coronary angiographic analysis was conducted.

Results :
After adjusting age, sex, BMI, hypertension and smoking, serum levels of resistin had positive correlation with total cholesterol (Pearson’s partial correlation coefficient (r)=0.170,
p
=0.015) and LDL (r=0.159,
p
=0.023) at baseline. However, there was no correlation between baseline serum levels of resistin and the decrement of LDL after statin therapy (r= 0.07,
p
=0.36). Although, serum resistin (odds ratio 1.714, 95%CI 1.266-2.319) and hypertension (odds ratio 4.617, 95%CI 1.535-13.887) were independent predictors of coronary artery disease in multivariate logistic regression analysis, we found no relationship between baseline serum levels of resistin and decrement in minimal lumen diameter of target vessel at follow-up CAG (r=0.003,
p
=0.96).

Conclusions :
Higher baseline serum resistin levels and the positive correlation between serum resistin and baseline LDL in CAD patients suggest that resistin may affect coronary atherosclerosis via lipid metabolism pathway. However, serum resistin is not associated with the response to lipid-lowering therapy and the prognosis in CAD. The different mechanism of restenosis after DES implantation might explain the irrelevance of resistin level and restenosis.
Abstract 18928: Cardiac Soluble Guanylate Cyclase Protects Against Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice
Authors: Vandenwijngaert Sara , Swinnen Melissa , Pokreisz Peter , Gillijns Hilde , Caluwé Ellen , Bartunek Jozef , Bloch Kenneth D , Janssens Stefan P
Published: April 2024

Background - The chemotherapeutic use of doxorubicin (DOX) is limited by cardiotoxicity. Growing evidence suggests a protective role for cyclic guanosine monophosphate (cGMP) in pathological LV remodeling. We therefore tested the hypothesis that reduced cGMP bioavailability in cardiac myocytes worsens myocardial dysfunction in mice after chronic DOX treatment.

Methods and Results - We generated mice with an inducible (Tet-Off) cardiac myocyte-specific expression of a dominant-negative soluble guanylate cyclase (dnsGC) mutant, which inhibits sGC signaling selectively in the heart. Cardiac cGMP levels, measured using an enzyme immunoassay, were lower in dnsGC mice (n=10) than in WT littermates (n=20) 5 minutes after administration of the NO-donor GSNO (1mg/kg) (0.99±0.34 vs 1.85±0.17 nmol/mg protein, respectively, P<0.05). At baseline, transthoracic echocardiography (TTE) demonstrated similar LV dimensions and function in dnsGC and WT (data not shown). Heart to body weight ratio was also comparable (HW/BW; 4.3±0.2 mg/g in dnsGC, n=13, vs 3.9±0.1 mg/g in WT, n=21). After 12 weeks DOX (2 mg/kg weekly), LV function was significantly reduced and LV diameters significantly enlarged as compared to saline-treated WT (Table). The impact of DOX on cardiac function and dimensions was more marked in dnsGC than in WT (P<0.05 for both, Table). Survival was similarly impaired in DOX-treated dnsGC (67%, n=30) and WT (59%, n=24) compared with saline-treated WT (100%, n=25). HW/BW was similar in DOX-treated dnsGC and WT (4.3±0.1 vs 4.2±0.1 mg/g), as was the % bromodeoxyuridine (BrdU)-positive cardiac myocytes or cardiac progenitor cells (0.8±0.4%, n=7 vs 1.6±0.7%, n=9, respectively, P=NS).

Conclusions - Reduced myocardial cGMP results in increased LV dysfunction and dilatation in doxorubicin-treated mice. Stimulation of sGC activity in cardiac myocytes may represent a promising therapeutic approach for doxorubicin cardiotoxicity.
Abstract 18949: Socioeconomic Patterning of Hypertension in Grenada
Authors: Roberts Eric T , Quarles Leigh , Fuster Valentin , Boden-Albala Bernadette
Published: April 2024

Over 80% of cardiovascular disease deaths occur in low and middle income countries with approximately two-thirds of stoke and one-half of ischemic heart disease estimated to be due to non-optimal blood pressure. Much is known about the social epidemiology of hypertension in “Western” contexts but less is known about these associations in developing or “non-Western” contexts. The island nation of Grenada, located off the Northeast coast of Venezuela with a population of approximately 110,000 persons, presents an instructive case study. This study describes the socioeconomic patterning of hypertension in a population of Grenadians. The Grenada Heart Project surveyed 2827 persons regarding the clinical, biological and psychosocial determinants of cardiovascular health between 2008 and 2010. We explored the association between education, income, occupation, nativity, residing in either the United States or Europe at one point in time, and parish of residence with definitive hypertension (≥140/90 mmHg) in separate logistic regression models adjusting for age and sex. The sample was 57.5% female with a mean age of 44.8 (sd = 17.1)., Participants that did not complete primary school [OR=2.04, 95%CI 1.37, 3.02)], participants that only completed primary school [OR=1.82, 95%CI 1.29, 2.58)], and participants that attended or completed secondary school [OR=1.48, 95%CI 0.99, 2.21)] had increased odds of having hypertension compared to those with more than a secondary education. Compared to government employees, homemakers [OR=2.45, 95%CI 1.52, 3.95)], retired persons [OR=2.40, 95%CI 1.69, 3.42)], and unemployed persons that are unable to work [OR=2.85, 95%CI 1.59, 5.11)] had increased odds of having hypertension whereas non-government employees [OR=1.09, 95%CI 0.79, 1.50)], self-employed persons [OR=1.09, 95%CI 0.96, 1.85)], and unemployed persons that are able to work [OR=1.09, 95%CI 0.68, 1.69)] did have significantly different odds of hypertension. We found significant differences in the prevalence of hypertension by parish. Income, nativity, and history of residing in western countries was not associated with hypertension. This work documents the importance of social variables in low and middle income countries in predicting hypertension.
Abstract 18955: VSMC-Targeted Aptamer-siRNA Chimeras as Inhibitors of Intimal Hyperplasia
Authors: Thiel William H , Bair Thomas , Peek Andrew S , Stanic Bojana , Takapoo Maysam , Streeter Jennifer , Liu Xiuying Y , Behlke Mark A , Miller Francis J , Giangrande Paloma H
Published: April 2024

Arterial revascularization by stenting is associated with restenosis due to proliferation of vascular smooth muscle cells (VSMCs) and intimal hyperplasia. Although the use of cell cycle inhibitors in drug eluting stents (DES) has reduced the rate of in-stent restenosis, this approach also inhibits re-endothelialization, thereby requiring prolonged antithrombotic regimens to prevent stent thrombosis. Delivery of nucleic acid aptamers by DES is a potential novel approach due to their high specific binding affinity and potential for modification by medicinal chemistry. The goal of this study was to identify RNA aptamers that (1) internalize into VSMCs and/or (2) specifically inhibit VSMC activation. Using an
in vivo
compatible RNA aptamer library, VSMC-specific aptamers were selected using a cell-internalization SELEX (systematic evolution of ligands by exponential enrichment) process with iterative rounds of positive selection using VSMCs and negative selection using endothelial cells (ECs). The top candidate aptamers demonstrated 15-20-fold specificity for internalization into cultured VSMCs
vs
. ECs. Specificity of these aptamers was confirmed by
ex vivo
studies that demonstrated preferential internalization into denuded, but not endothelium-intact, aortic segments. In addition, several of the VSMC-targeting aptamers exhibited differential effectiveness in inhibiting VSMC migration as measured by Boyden chamber assays. In proof-of-concept delivery studies, we next engineered aptamer-siRNA chimeras using siRNAs targeting Nox1 NADPH oxidase, which has been implicated in intimal hyperplasia. These VSMC-targeting aptamer-siRNA chimeras retain specificity for VSMCs and are being evaluated for efficacy in reducing intimal formation in a murine model of vascular injury. In conclusion, we developed novel VSMC-targeting aptamers that may serve as a platform technology to selectively deliver therapeutics to VSMCs over ECs. The aptamers that inhibited cell migration present an opportunity for dual-action VSMC-targeted therapeutic agents. Future refinement of this panel of VSMC-directed aptamers will enable broader application of targeted therapies for vascular-proliferative diseases.
Abstract 18965: Monitoring the Asymptomatic Patient with Severe Mitral Regurgitation: Do Measuring LV Volumes Make a Difference in Predicting Mortality?
Authors: Penesetti Sunil , Costa Salvatore , Chin Ronald , Sidhu Mandeep
Published: April 2024

Background:
The ACC/AHA Valvular Heart Disease Guidelines include a class I recommendation for surgery in asymptomatic patients with chronic severe mitral regurgitation (MR) if the EF is ≤ 60% and/ or the end-systolic diameter (ESD) > 40 mm. However, the ESD has inherent limitations because it only detects changes in one dimension while LV volume can detect subtle changes in LV geometry in multiple dimensions. We sought to measure the impact of shifting from ESD to end systolic volume (ESV) in predicting mortality.

Methods:
We performed a retrospective search of our single center echocardiography database over a 5 year period for all cases with severe (4+) MR. From this list of 240 patients, we reviewed the medical records to identify the subgroup of patients who remained asymptomatic at the time of echo evaluation (N = 61). Since the ACC/AHA Guidelines recommend surgical referral for asymptomatic patients with an EF ≤ 60%, these patients were also excluded in order to isolate the impact of LV size on mortality. This resulted in a total of 31 study subjects. Study subjects were classified according to 2 different methods: “classic” LV size criteria (ESD > 40mm) or “volume” LV size criteria (ESV ≥ “mildly dilated” per ASE Chamber Quantification Guidelines). Volumes were obtained using a biplane Simpson.

Results:
As compared to classic LV size criteria using ESD, a change to volume criteria using ESV would significantly increases the percentage of patients identified with abnormal LV geometry (61% vs 25%, p < 0.01). However, despite identifying a larger number of patients with abnormal LV geometry, the difference in mortality using volume criteria or classic criteria was not significant.

Conclusion:
Although there are conceptual advantages to the assessment of LV size using LV volumes rather than 2D linear measurements, the difference in the two methods for predicting mortality in the context of asymptomatic MR with normal EF was not significant. Further refinements in the assessment of LV volumes, larger studies, and inclusion of additional end-points such as CHF admissions may be needed to further understand the relationship between changes in LV geometry and adverse events in this population.
Abstract 19063: TGF-β Levels Are Associated with Aortic Root Dilatation, Aortic Root Growth Rate and Clinical Events in Patients with Marfan Syndrome
Authors: Franken Romy , Engele Leo J , den Hartog Alexander W , Timmermans Janneke , Scholte Arthur J , van den Berg Maarten P , Zwinderman Aeilko H , Mulder Barbara J , Groenink Maarten
Published: April 2024

Background:
Marfan syndrome (MFS) is a connective tissue disorder with variable aortic root dilatation. Recently, increased transforming growth factor beta (TGF-β) signalling emerged as a new potential biochemical pathway leading to aortic disease. The aim of this study was to investigate whether TGF-β is correlated with aortic root dilatation, exploring the role of TGF-β as a prognostic biomarker in MFS.

Methods:
In this correlation study between aortic root diameters and TGF-β, 86 MFS patients were included. Twenty-five patients had previously undergone aortic root replacement. Total plasma TGF-β was assessed at baseline in patients and 22 healthy controls. Aortic root diameters were measured by means of echocardiography with a mean follow-up of 32 months. Clinical events, including aortic dissection and aortic root replacement were evaluated.

Results:
At baseline TGF-β levels were higher in MFS patients as compared to controls (112.6 vs 33.5 pg/ml, p=0.019). Patients with previous aortic root replacement had significantly higher TGF-β levels compared to patients without aortic root repair (168.7 vs 89.7 pg/ml, p=0.008). Higher plasma TGF-β levels correlated with larger aortic root diameter at baseline (p=0.047) and at follow-up (p=0.006). Moreover, there is a correlation between higher TGF-β levels and faster aortic root growth rate (p=0.022). After 32 months of follow-up 17 events were observed: aortic root replacement in 13 patients and type b dissection in four patients. Patients with an event had higher aortic root diameters at baseline (45.6 vs 39.6 mm, p=<0.0001) and higher TGF-β levels (160 vs 100 pg/ml, p=0.014) compared to patients without event.

Conclusion:
TGF-β levels are higher in MFS patients than in healthy controls. Higher TGF-β plasma levels were correlated with larger aortic root diameters, faster aortic root growth and aortic root replacements or type b dissections. Plasma TGF-β might serve as a prognostic biomarker in Marfan syndrome.
Abstract 19071: Impact of Angiotensin Receptor Blocker on Development of Glucose Intolerance and New-onset Diabetes Mellitus in Asian Population
Authors: Park Ji Young , Rha Seung Woon , Choi Jae Woong , Ryu Sung Kee , Choi Byoung Geol , Choi Se Yeon , Im Sung Il , Kim Sun Won , Na Jin Oh , Han Seong Woo , Choi Cheol Ung , Lim Hong Euy , Kim Jin Won , Kim Eung Ju , Park Chang Gyu , Seo Hong Seog , Oh Dong Joo
Published: April 2024

Background;
Angiotensin receptor blocker (ARB) is being extensively used to control hypertension. But, there have been limited data whether ARB is associated with increased incidence of new-onset diabetes mellitus (DM) or impaired glucose intolerance (IGT).

Methods;
We investigated total 13,561 patients (pts) that was glycerate hemoglobin level < 6.0% and fasting glucose level < 124 mg/dL (ARB therapy group=3421 and control group=9808) from January 2004 to February 2012. To adjust potential confounders, a propensity score matched analysis was performed using the logistic regression model. The primary end-point was the cumulative incidence of new-onset DM, IGT, and impaired fasting glucose (IFG). Also, multivariable cox-regression analysis by adjusted by aforementioned variables was performed to determine the impact of statin therapy on the incidence of new-onset DM, IGT, and IFG.

Results;
Mean follow-up duration was 534±604 days in all-pt group, and 608±607 days in propensity score matching group. After propensity score match, total 5632 pts (ARB group=2816 and control group = 2816) were enrolled for analysis. Baseline characteristics was similar between the two groups except the more use of diuretics (38% vs. 35.5%, p=0.047). In Kaplan-Meyer curve, there was no difference between the two groups (p=0.428, figure A). Also, in cox-regression analysis performed in all pts, ARB therapy was not associated with the increased incidence of primary end-point (figure B).

Conclusions;
In the present study, there was no clear association between ARB therapy and IGT or new-onset DM in a series of cardiovascular pts in Asian population.
Abstract 19105: Response in Left Ventricular Twist During Dobutamine Stress Echocardiography After ST-segment Elevation Myocardial Infarction Predicts Reverse Remodeling
Authors: Joyce Emer , Leong Darryl P , Hoogslag Georgette E , Van Herck Paul L , Debonnaire Phillipe J , Holman Eduard R , Schalij Martin J , Bax Jeroen J , Delgado Victoria , Ajmone Marsan Nina
Published: April 2024

PURPOSE
Left ventricular (LV) twist, an emerging marker of global LV function, has not been evaluated during full-protocol dobutamine stress echocardiography (DSE) in patients following ST-segment elevation myocardial infarction (STEMI).

HYPOTHESIS
We aimed to evaluate if the response of LV twist during DSE could predict follow-up LV reverse remodeling.

METHODS
Consecutive patients admitted with first STEMI undergoing primary percutaneous coronary intervention, standard protocol DSE at 3 months and 2-dimensional echocardiographic studies at baseline (48 hours) and follow-up (6-months) were selected. DSE studies positive for ischemia were excluded. Speckle-tracking analysis was used to calculate LV twist - defined as the net difference (in degrees) between apical and basal rotation at isochronal time points -at each stage. LV reverse remodeling was defined as a ≥10% decrease in LV end-systolic volume at follow-up.

RESULTS
In total, 82 patients (mean age 61 ± 12 years, 85% male, mean LVEF 49 ± 9%) had complete DSE studies feasible for speckle-tracking. Overall LV reverse remodeling occurred in 28 (34%) patients, who showed significantly higher peak-stress LV twist (8.51° versus 6.69°, p=0.01) (Figure). On univariate analysis, baseline LVEF (p=0.03), family history of CAD (p=0.05) and the increase in LV twist from rest to peak stress (p=0.005) were significantly related to LV reverse remodeling; however only LV twist increase remained independently related on multivariate analysis (OR 1.3, 95% CI 1.1-1.5, p=0.005). The ability of LV twist increase to predict reverse remodeling remained significant for subgroup analysis of patients with LV ejection fraction <50%. (OR 1.62, 95% CI 1.1 - 2.3, p=0.01).

CONCLUSIONS
The increase in LV twist from rest to peak-stress on 3-month DSE in post-STEMI patients independently predicts 6-month LV reverse remodelling, suggesting a novel, clinical use for LV twist as a marker of contractile reserve.
Abstract 19124: Detection and Prevalence of Systemic Atherosclerosis: Results from the High-Risk Plaque (HRP) Initiative
Authors: Baber Usman , Sartori Samantha , Mehran Roxana , Muntendam Pieter , Garcia Mario J , Sillesen Henrik , Falk Erling , Fuster Valentin
Published: April 2024

Background
Most studies examining the burden of atherosclerosis involve a single anatomic territory. Such approaches, however, underestimate the true prevalence of vascular disease as atherosclerosis is a systemic, rather than focal, process. We sought to determine the prevalence and clinical correlates of systemic polyvascular atherosclerosis in an asymptomatic US population.

Methods
In the High-Risk Plaque (HRP) Initiative, 5823 asymptomatic adults underwent multimodality non-invasive imaging for evaluation of subclinical atherosclerosis in the carotid and coronary arteries using duplex ultrasound and computed tomography (CT). Subclinical atherosclerosis was defined as presence of any coronary calcification (score > 0) or any focal carotid plaque. Patients were categorized by number of vascular territories with atherosclerosis (0, 1 or 2) and by quartiles of carotid atherosclerotic burden.

Results
Any subclinical atherosclerosis was common, detectable in 87.8% (n=5113) of participants. While 1772 (30.4%) of individuals had involvement of either the coronary or carotid arteries alone, 3341 (57.4%) had involvement of both territories. Significant clinical correlates of polyvascular atherosclerosis included male gender, older age, diabetes mellitus, white race, smoking status and systolic blood pressure (p <0.001). The positive predictive value (PPV) for detecting any carotid plaque with an abnormal calcium score was 85% while the PPV for any coronary calcium with carotid plaque was 74%. In addition, the prevalence of coronary calcification increased in a step-wise fashion with greater carotid atherosclerotic burden (Figure).

Conclusion
In the HRP Initiative, traditional risk factors correlated strongly with greater prevalence of subclinical atherosclerosis. Testing in one territory is strongly associated with probability of disease in the remaining vascular bed, highlighting the systemic nature of atherosclerosis.
Abstract 19129: Clinically Important Human Leukocyte Antibody Production is Uncommon in a Large Series of Pediatric Patients Supported with the Berlin Heart EXCOR Ventricular Assist Device
Authors: O'Connor Matthew J , Harville Terry O , Rhodes Bobbie , Pye Sherry E , Knecht Kenneth R , Imamura Michiaki , Frazier Elizabeth A , Morrow W R
Published: April 2024

Background:
Ventricular assist device (VAD) support is associated with human leukocyte (HLA) antibody production. This process, known as sensitization, has not been evaluated in pediatric patients supported with the Berlin Heart EXCOR VAD. Furthermore, the impact of sensitization in the era of single antigen assays for the detection of HLA antibodies is unclear.

Methods:
The records of all patients supported with a Berlin Heart EXCOR VAD at our institution from 4/2005-8/2011 were reviewed. Class I and II HLA antibodies were identified by fluorescence methods pre-/post-VAD, with antibody titer reported as median fluorescence intensity (MFI). MFIs were summed to derive a total MFI for each patient post-VAD. To determine changes in HLA antibodies pre-/post-VAD, MFIs pre-VAD were compared with those ≥14 days post-VAD, but prior to transplant, using Wilcoxon matched-pairs sign-rank test. Sensitization was present if MFI for any antibody was > 1000 (threshold for a positive flow cytometric crossmatch).

Results:
The Berlin Heart EXCOR VAD was used in 36 patients; 20 met inclusion criteria and 13 had complete MFI data. Median duration of support was 56 (21 - 131) days; all survived to transplant. For the entire group, changes in total MFI for class I and class II HLA antibodies were not significant over the course of VAD therapy. For class I antibodies, 6/13 (46%) were sensitized pre-VAD, and 7/13 (54%) were so for class II antibodies; sensitization was maintained for the same antibodies in 4/6 for class I antibodies and 5/7 for class II antibodies.
De novo
sensitization, including new antibodies in presensitized patients, occurred in 9/13 (69%) for class I antibodies and 4/13 (31%) for class II antibodies. Only one patient, however, had a positive flow cytometric crossmatch at transplant to one class II HLA antibody that developed on VAD. No patient was denied an acceptable donor heart on the basis of elevated HLA antibodies.

Conclusions:
Using single antigen techniques, HLA sensitization is seen in approximately 50% of pediatric patients prior to initiating support with the Berlin Heart EXCOR VAD; nearly 70% developed
de novo
class I HLA antibodies on VAD. The clinical impact of such antibodies, however, appears to be limited in this population.
Abstract 19164: Products of Murine Cytochrome P450 Cyp2j Locus Regulate Pulmonary Vascular Response to Alveolar Hypoxia
Authors: Zhou Guo Ling , Beloiartsev Arkadi , Yu Binglan , Baron David M , Zhou Weihua , Niedra Rasma , Lu Naifang , Zapol Warren M , Seed Brian , Bloch Kenneth D
Published: April 2024

Epoxyeicosatrienoic acids (EETs) are eicosanoids with potent vasoactive effects. Multiple cytochrome P450 enzymes, including CYP2J2, synthesize EETs in humans. However, genetic analysis of the contributions of CYP2J2 to physiologic processes in humans has been confounded by the allelic expansion in rodents: mice have 8 Cyp2j genes that encode epoxygenases similar to CYP2J2. To investigate the role of CYP2J2, we created mice bearing a 626 kb deletion spanning the murine Cyp2j locus using a combination of homologous and site-directed recombination strategies. Two bacterial artificial chromosomes (BACs) covering the 2 ends of murine Cyp2j locus were modified to allow an integrase-mediated site-specific recombination event to fuse the BACs and form a deletion replica that could be propagated in E. coli. The replica was introduced into mouse ES cells to ultimately enable generation of Cyp2j-null mice (Cyp2j-/-). RT-MLPA (Multiplex Ligation-independent Probe Amplification) revealed that the 8 Cyp2j genes were expressed in wild-type (WT) but not in Cyp2j-/- mice. A mouse strain in which the Cyp2j locus deletion was complemented by transgenic delivery of BAC sequences encoding human CYP2J2 was also created (Cyp2j-/-tg). Systemic and pulmonary hemodynamic parameters did not differ in anesthetized WT, Cyp2j-/-, and Cyp2j-/-tg mice at baseline. Hypoxic pulmonary vasoconstriction (HPV) was monitored by measuring left pulmonary vascular resistance (LPVR) and systemic arterial oxygenation (PaO2) before and during left main stem bronchial occlusion (LMBO). LMBO did not alter systemic arterial pressure in any genotype. LMBO increased LPVR 2.0- and 2.3-fold in WT and Cyp2j-/-tg mice, respectively, due to HPV (P<0.05 for both). LMBO did not change LPVR in Cyp2j-/- mice. During LMBO, PaO2 was greater in WT and Cyp2j-/-tg mice than in Cyp2j-/- mice (P<0.05 for both) demonstrating that Cyp2j deficiency impairs matching of ventilation with perfusion (V/Q). Administration of MS-PPOH, a selective inhibitor of CYP450 epoxygenase, to WT mice also blocked the ability of LMBO to increase LPVR. These data suggest that products of Cyp2j epoxygenase activity contribute to the pulmonary vasoconstriction produced by alveolar hypoxia and preservation of V/Q matching.
Abstract 19189: Aldosterone and Diabetic Heart Disease: Relevance to Diffuse Myocardial Fibrosis and Coronary Microvascular Dysfunction
Authors: Shah Ravi , Rao Ajay , Garg Rajesh , Jerosch-Herold Michael , Kwong Raymond , Perlstein Todd , Di Carli Marcelo , Adler Gail
Published: April 2024

BACKGROUND:
Early diabetic heart disease is characterized by expansion of the cardiac interstitial matrix and impaired myocardial blood flow. Aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury. We hypothesized that aldosterone is associated with interstitial expansion and microcirculatory dysfunction in Type 2 diabetes mellitus (T2DM).

METHODS:
We studied 53 subjects with T2DM (68% male; age [mean±SD] 53±7 years, body mass index 32.2±4.3 kg/m2) without evidence of infarction or ischemia by cardiac magnetic resonance (CMR) and PET. After ≥3 months ACE inhibition (enalapril 20 mg daily ± amlodipine for BP control) and optimal glycemic and lipid control, subjects consumed 5 days of high salt diet. 24-hr urinary aldosterone excretion and angiotensin II-stimulated increase in serum aldosterone were measured. CMR to assess extracellular volume fraction (ECV), cardiac PET to assess coronary flow reserve (CFR) and echocardiography were performed. RESULTS: T2DM subjects (HbA1c 6.8±0.7%, BP-systolic 126±14, diastolic 76±9 mmHg) had normal left ventricular structure by CMR and normal diastolic function (transmitral E/A 1.13±0.28, tissue Doppler e’ 0.11±0.03 m/s). CFR (2.51±0.83) was not associated with aldosterone. Myocardial ECV (0.36±0.05) was positively associated with 24-hr urinary aldosterone excretion (r=0.37, P=0.01) and angiotensin II-stimulated increase in aldosterone (r =0.35, P=0.02). In a best-overall stepwise multivariate model (with age, BMI, HbA1c, systolic BP and CFR as covariates), 24-hr urinary aldosterone excretion was still associated with myocardial ECV (P=0.004).

CONCLUSIONS:
Aldosterone is associated with CMR measures of interstitial matrix expansion in individuals with T2DM without evidence of epicardial coronary artery disease or diastolic dysfunction and on chronic ACE inhibition. These results implicate aldosterone in early myocardial remodeling in T2DM.
Abstract 19198: Adult Human Heart Contains Two Populations of C-kit-Oct-4+SSEA-4+ Very Small Embryonic-Like Stem Cells (Isl-1- and Isl-1+)
Authors: Wojakowski Wojciech , Zuba-Surma Ewa K , Syzdol Marcin , Kowalowka Adam , Kamycka Elzbieta , Kargul Tomasz , Drukala Justyna , Bachowski Ryszard , Wos Stanislaw , Ratajczak Mariusz Z , Tendera Michal
Published: April 2024

Very small embryonic-like cells (VSELs) express pluripotent stem markers (Oct-4,Nanog, SSEA-4). and in adult mice may be expanded and differentiatiated into three germ layers. In humans VSELs were found in cord blood and peripheral blood (PB). AIM: Comparison of VSELs isolated from human myocardium with cardiac stem cells (CSC) and to measure the mobilization into PB after cardiac surgery. METHODS: 32 patients undergoing CABG were enrolled. Right atrial appendage (RAA), left ventricle (LV) were collected. PB samples were drawn before and immediately after surgery, 24 hrs and 5-7 days after weaning from cardiopulmonary bypass. Tissue samples (0.5-1.0 cm3) were cut, digested in collagenase, passed through 70um cell strainer, centrifugated, resuspended and stained with antibodies CD34 FITC/CD133 APC/SSEA-4PE/CD45 APC-Cy7. Analyses were carried out on Image Stream System which is a combination of FACS and immunofluorescent microscope. RESULTS: VSELs and CSC were identified in LAA. VSELs had markedly smaller diameter (4.7 ± 0.2µm vs. 7.7 ± 0.4µm), were c-kit negative, expressed markers of pluripotent cells (Oct-4, SSEA-4) and CD133. Two populations of VSELs - both Isl-1 negative and positive were identified. Subpopulation of Oct-4+SSEA-4+Isl+ VSELs contained cells of intermediate size (5.7 ± 0.7µm) and might form more mature population of VSELs progenitors. VSELs undergo significant mobilization into PB following the CABG. CONCLUSION: Human myocardium in adults contains two subpopulations of Oct-4+SSEA4+ VSELs which are distinct from CSC. Cardiac surgery with cardiopulmonary bypass induced mobilization of VSELs into peripheral blood.
Abstract 19262: Hexokinase-2-Mediated Protection Against Cell Death is Dependent Upon Voltage-Dependent Anion Channels 2&3
Authors: McCommis Kyle S , Baines Christopher P
Published: April 2024

It is well known that tumor cells, which by definition do not die easily, have high rates of glycolysis. Hexokinase (HK), the first enzyme in glycolysis, is often overexpressed in these tumor cells, and is thought to be driving these high glycolytic rates. As HK is localized partly to the outer mitochondrial membrane (OMM), it has been proposed that HK may also be playing a role in these tumor cells’ resistance to death. Cardiomyocytes and murine embryonic fibroblasts (MEFs) express both HK1 and HK2 isoforms, both of which are capable of localizing to the OMM mainly through interaction with Voltage-Dependent Anion Channels (VDACs). Therefore, the purpose of this study was to assess whether overexpression of HK1 or HK2 could protect cultured cardiomyocytes or MEFs against H
2
O
2
-induced cell death. Additionally, HK2-mediated protection was also investigated in MEFs with genetic deletion of VDAC1 or VDAC3, or WT MEFs treated with a VDAC2 siRNA to significantly reduce VDAC2 protein levels. HK1 or HK2 protein expression and enzymatic activity was increased 2-3 fold by infection of cells with HK1 or HK2-encoding adenovirus. Control cells were infected with adenovirus encoding Β-Galactosidase. Cell death was induced by 50 μM H
2
O
2
in cultured neonatal rat cardiomyocytes (NRCM), or by 500 μM H
2
O
2
in MEFs. Overexpression of HK1 or HK2 reduced H
2
O
2
-induced death by ∼50% in both NRCMs and WT MEFs. Interestingly, overexpression of HK2 also protects MEFs devoid of VDAC1 by ∼50%. However, in MEFs with reduced VDAC2 expression or MEFs with deletion of VDAC3, HK2-mediated protection against H
2
O
2
-induced death is completely lost. Thus, it appears that the minor VDAC isoforms 2 & 3 are essential, while the main VDAC1 isoform is dispensable for HK2-mediated protection against cell death.
Abstract 19269: Impact of Recommedations of Guidelines in Patients with Atrial Fibrillation Submitted for Coronary Stenting
Authors: Mutuberria Maria , Sambola Antonia , Bosch Eduard , Bruno Garcia Del Blanco , Alfonso F , Cequier Angel , Bueno Hector , Rodriguez Oriol , Zueco Javier , Zueco Javier , Llavero Nadia , Garcia Dorado David
Published: April 2024

Objetive:
to assess the impact of dual antiplatelet therapy (DAT) with clopidogrel and ASA vs. DAT with warfarin (triple therapy: TT) in patients with nonvalvular AF submitted to coronary stenting and the impact of CHADS2 and CHA2DS2VASc scores.

Methods:
a retrospective multicenter study was conducted from 2007 to 2011 to identify patients with nonvalvular AF who undergoing PCI with stenting. Patients basic characteristics, CHADS2 score, CHA2DS2VASc score, PCI details, antithrombotic therapy at discharge and its duration were recorded. Follow-up was 1 year. All bleeding events, stroke, thromboembolism, death, acute myocardial infarction or target revascularization were recorded.

Results:
We identified 489 patients with AF (74.8% male, 73.11±8 years); 307 (62.8%) received TT and 182 (37.2%) received DAT. Duration of DAT and TT was: 5.15±4 and 4.49±2.85 months, respectively. Baseline characteristics were similar in both groups, except for a higher rate of previous stroke (9.6% vs 16.8%, p=0.018) and previous PCI (44.5 % vs 25.4%, p=0.0001) in TT group. Patients treated with TT showed a trend to a higher rate of CHADS2 score ≥2 (64.8% vs 35.2%, p=0.17) and for CHA2DS2VASc ≥2 (64.3% vs 35.2%, p=0.25). Major bleeding and cardiovascular death were more frequent in patients with TT (6.7% vs 1.7%, p=0.01; 7% vs 2.9%, p=0.042, respectively). Stroke rate was more frequent in patients with DAT (5.7% VS 1.3%, p=0.008). In these patients CHADS score was median 2 (range 1-4) and CHA2DS2VASc median 4.5 (range 3-5). 44 patients (9.2%) died during follow-up.13 (29.2%) of them had had a bleeding event; 3 of them had CHADS2=1. Multivariate analysis identified as independent predictors for cardiovascular death: previous stroke (OR 5.7; 95% CI 0.9-34.6, p=0.05), drug eluting stent (OR:0.35; 95% CI 0.13-0.96, p=0.03) and TT (OR 0.35; 0.12-1.00, p=0.05). CHADS2 and CHA2DS2VASc scores were not predictors (OR 1.86: 95% CI 0.93-1.77, p=0.076; OR 1.32; 95% CI 0.92-1.89, p=0.123, respectively).

Conclusions:
In patients with nonvalvular AF who undergo PCI with stenting, the decisions of treatment with DAT or TT is not always influenced by CHADS or CHA2DS2VASc. There is a high incidence of bleeding with TT and a high incidence of stroke with DAT.
Abstract 19278: The Impact of Chronic Kidney Disease on Clinical Outcomes in Patients Admitted with Acute Myocardial Infraction in an Australian Setting
Authors: Kotwal Sradha S , Ranasinghe Isuru , Gallagher Martin P , Cass Alan
Published: April 2024

Background:
International data suggests the presence of chronic kidney disease (CKD) increases morbidity and mortality following acute myocardial infarction (AMI) and reduces the likelihood of revascularisation. However, the impact of CKD on longer term clinical outcomes and health resource usage remains unclear. Aim: To assess the impact of CKD upon clinical outcomes for patients admitted with AMI.

Methods:
New South Wales (NSW) is Australia’s most populous state with an estimated population of 7.2 milllion, representing 32.3% of the total Australian populaton. The NSW admitted patient data collection (NSW APDC) is an administrative coding dataset collecting data on all admissions to NSW hospitals. Coding uses the International Classification of Disease 10 Australian Modification (ICD10 AM). All patients admitted to a NSW hospital with a principle diagnosis of AMI (ICD10 codes: I21.0-I21.3 and I21.4) between 2004 and 2008 were extracted from NSW APDC and linked to the NSW Registry of Births Deaths and Marriages. We analysed outcomes of 30 day, 1 year and medium term (median follow up) all cause mortality, length of stay (LOS) and revascularisation crude rates based on the presence or absence of a diagnostic code of CKD (N18, N19, Z49).

Results:
A total of 40,482 patients with AMI were analysed, including 1565 with a CKD code, to a median follow up 3.5 years. Unadjusted analyses of patients coded as having CKD showed higher 30 day mortality (15% versus 7%, p<0.001), 1 year mortality (40% versus 14.5%, p<0.001), 3.5 year mortality (67% versus 25%, p<0.001), LOS (mean 10.4 days versus 7.5 days, p < 0.001) and lower revascularisation rates (14% versus 35%, p< 0.001) compared to those without a CKD code.

Conclusions:
Patients admitted to NSW hospitals with an AMI and coding history of CKD have lower rates of intervention, despite significantly higher mortality and length of stay. CKD coding was used infrequently and further research is required to explore the utilisation of CKD diagnostic codes and the poorer outcomes they portend.
Abstract 193: Transthoracic Impedance Patterns During Systole Reveal Changes in Cardiac Hemodynamics Using External Defibrillators
Authors: Didon Jean-philippe , Jekova Irena , Ménétré Sarah , Trendafilova Elina , Krasteva Vessela
Published: April 2024

BACKGROUND: This study aims to test the Automated external defibrillators (AED) transthoracic impedance cardiogram (EICG) as a potential sensor for detection of compromised hemodynamics in different arrythmias (atrial fibrillation (AFIB), atrial flutter (AFL), ventricular tachycardia (VT)) vs. sinus rhythm (SR).

METHOD: ECG and ICG recordings via pads in antero-apical position from 106 patients with AFIB, AFL, VT, who received external cardioversion (ECV) with external cardioverter/defibrillator are retrospectively processed. EICG patterns are accumulated to compute EICG measures (maximal EICG velocity (dZ/dt-PEAK), ventricular ejection time (VET), ventricular ejection ratio (VER=VET/ RR interval)), static impedance (Z). Hemodynamical indices are collected: heart rate (HR), HR variability (HRV), systolic and diastolic blood pressure (SYS, DIA).

RESULTS: ANOVA test indicates that EICG measures significantly differ in AFIB, AFL, VT vs. SR (Table 1). Multiple linear regression shows that EICG measures are significantly dependent on hemodynamical indices (HR, HRV, SYS, DIA) with multiple correlation coefficient R=0.49 (VET), 0.54 (dZ/dt-PEAK), p<0.001, whereas Z is not correlated. Linear discriminant analysis (LDA) shows that a combination of dZ/dt-PEAK, VET, VER is able to discriminate either AFIB, or AFL, or VT from SR with respective accuracy of 92.8%, 93.9%, 99.1%.

CONCLUSION: EICG measures are significantly correlated to hemodynamical indices and are altered in AFIB, AFL, VT compared to SR. EICG is a potential sensor for compromised cardiac hemodynamics in AFIB, AFL, VT with a discrimination ability for VT vs. SR of 99.1%, but lower for AFIB and AFL vs. SR (around 93%).
Abstract 19318: Value of a Combined Epicardial-Endocardial Ablation Strategy for Ventricular Tachycardia Storm
Authors: Tung Roderick , Yu Ricky , Hayase Justin , Boyle Noel , Shivkumar Kalyanam
Published: April 2024

Background:
Epicardial mapping and ablation has been shown to be a useful adjunct in the setting of ventricular tachycardia (VT) storm. The aim of this study is to report ablation outcomes in 53 consecutive VT storm cases in patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM), and compare the results of an combined epicardial-endocardial (epi-endo) versus endo-only ablation strategy.

Methods:
Patients with VT storm referred for ablation between 6/04-6/11 were analyzed into two groups: ICM and NICM. Six month freedom from VT recurrence was compared between patients who underwent combined epi-endo with those who underwent endocardial-only ablation strategy.

Results:
53 patients (ICM=26, NICM=27) underwent ablation for VT storm. In the ICM group, there was significantly higher freedom from VT recurrence at 6 months in the epi-endo group compared to the endo-only ablation group (80% vs. 38%, p = 0.03). In the NICM group, there was no difference in freedom from VT recurrence at 6 months in the epi-endo group compared to the endo-only ablation group (25% vs. 31%, p = 0.75).

Conclusion:
A combined epi-endo ablation resulted in significantly better outcomes compared to endo-only ablation in patient with ICM. No difference was seen for the NICM group. A combined epi-endo should be considered initially in patients with ICM presenting with VT storm.
Abstract 19322: Cardiac Function and Beta-Adrenergic Response in Mice with Genetic Ablation of Two Major Phosphorylation Sites in the Cardiac Ryanodine Receptor
Authors: Camors Emmanuel , Loaiza Randall , Alvarado Francisco , Powers Patricia , Valdivia Héctor H
Published: April 2024

Despite intensive research, the functional consequences of cardiac ryanodine receptor (RyR2) phosphorylation remain highly controversial. Two major phosphorylation sites, S2808 and S2814, are respective targets for PKA and CaMKII and form a RyR2 “phosphorylation hot spot”. We previously showed that genetic ablation of S2808 has no structural or functional consequences for cardiac function. Here we generated a novel double knock-in mouse with genetic ablation of S2808 and S2814 (S2808A/S2814A) and tested the hypothesis that preventing the “hot spot” phosphorylation has discernible impact in cardiac function. Echocardiography and intraventricular pressure measurements revealed that, under basal conditions, S2808A/S2814A mice have higher heart rate (553±33
vs.
460±28 bpm,
p
<0.05, n= 8/group) and decreased ejection fraction (55±3
vs.
65±2%,
p
<0.05, n=12/group) compared to WT. In addition, ventricular myocytes isolated from the S2808A/S2814A hearts displayed a significant increase in Ca
2+
transient amplitude (357±27
vs.
257±31 nM,
p
<0.05, n=13 cells/group), a trend towards higher Ca
2+
spark frequency (0.51±0.14
vs.
0.30±0.17 sparks.100 μm
-1
.sec
-1
, n=7 cells/group) while the sarcoplasmic reticulum (SR) Ca
2+
load was comparable to that of WT cells (107±7
vs.
97±4 μmol/L cytosol). Surprisingly, β-adrenergic stimulation eliminated the differences between the two groups: Langerdorff-perfused hearts displayed a robust increase in the amplitude of contraction in response to 200 nM isoprenaline (51±4
vs.
62±14% above control in double knock-in and WT mice, respectively; n=5/group) and in isolated ventricular myocytes, 100 nM isoproterenol significantly increased the Ca
2+
transient amplitude (1.99±0.18
vs.
1.47±0.15 μM, n= 7 cells/group) and SR Ca
2+
load (175±12
vs.
183±14 μmol/L cytosol) in double knock-in and WT mice, respectively. Thus, ablation of the “phosphorylation hot spot” has discernible effects on cardiac function at baseline, but under β-adrenergic stimulation other RyR2 phosphorylation sites appear to normalize Ca
2+
transient and cardiac contraction. This is compatible with a multi-phosphorylation site model of RyR2 where the β-adrenergic stimulation response is dictated by a complex interplay of phosphorylations.
Abstract 19328: Postnatal Formation of Myocardial Laminar-Sheet Architecture in New Born Pig Hearts
Authors: Chen Junjie , Zhang Lei , Zhang Huiying , Lanza Gregory M , Wickline Samuel A
Published: April 2024

Myocardial fiber and laminar sheet architecture is a critical determinant of coordinated cardiac contractile function. We hypothesized that myofiber and sheets may reorganize after birth to accommodate programmed perinatal adaptations of cardiac function. Isolated fixed pig hearts at postnatal day 1, day 5, day 14, and adulthood (n = 5 for each group) were acquired for diffusion-weighted magnetic resonance imaging to determine cardiomyocyte fiber angle and sheet structure in the left ventricular free wall using previously reported methods. Finally, hearts were prepared for histology analysis of sheet architecture. A progressive increase in left ventricular wall thickness occurred from day 1 (4.8±0.2 mm) to adulthood (22±4 mm, p < 0.05). However, the transmural distribution of helix angle (fiber architecture) was comparable at all ages (p = N.S.). In contrast, fractional anisotropy decreased progressively from day 1 (0.71±0.05) to adulthood (0.28 ±0.29, p < 0.05), which was caused by increased cross-fiber water diffusivity (0.25 ± 0.04 μm2/ms at day 1 vs. 0.55±0.05 μm2/ms at day 5, p < 0.05). The expected laminar sheet cleavage (white spaces) was not detectable at day 1, but became visually appreciable after day 5 (Figure ). In summary, the helical myofiber architecture appeared well developed at birth but unchanged thereafter. However, the higher order laminar sheet architecture did not emerge until after birth. The postnatal formation of laminar sheets appears to play a critical role in physiological remodeling of new born hearts to accommodate the an abrupt increase of left ventricular workload after the closing of patent ductus arteriosus and foramen ovale, which bypassed the right ventricular output to systemic circulation in prenatal hearts. .