bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19552: Exercise-Induced Changes in Mechanotransduction Improve Myocardial Function in a Porcine Model of Chronic Occlusion
Authors: Muthuchamy Mariappan , Chakraborty Sanjukta , Wu Xin , Sarin Vandana , Heaps Cristine L
Published: April 2024

Introduction:
Exercise training has been shown to improve cardiac dysfunction both in patients and animal models of coronary artery disease; however, the underlying cellular and molecular mechanisms have not been completely understood. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. Hypothesis: The binding probability and adhesion force between integrins-ECM, and their subsequent signaling that is cell stiffness will be increased in the myocytes from exercise-trained animals when compared to the sedentary group.

Methods:
Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult female Yucatan pigs. Twenty-two weeks postoperatively, myocardium was isolated from non-occluded and collateral-dependent regions of sedentary and exercise trained (treadmill run; 5 days/wk for 14 wks) pigs. We used atomic force microscopy for measuring cell stiffness and adhesion force between integrin and fibronectin (FN) in pig cardiomyocytes. In addition, integrins and FN expression were determined.

Results:
While exercise-trained pigs showed an increase in β1 integrin expression, β3 integrin expression was detected at an increased level in the sedentary myocardium. An increase in the amount of total FN and its fragments were found in the myocardium from collateral-dependent regions of exercise-trained and sedentary pigs when compared to the non-occluded myocardium regions. The peak bond rupture force of FN-integrin (46.4±0.3 pN vs 34.8±0.2 pN), the probability of adhesion (72% vs 54%) and cell stiffness (67.9±4.7 kPa vs 29.0±1.8 kPa) were significantly increased (p<0.05; n=10) in myocytes from exercise-trained pigs when compared to sedentary hearts, which were prevented by function blocking α5 and αv integrin antibodies, respectively.

Conclusion:
Our data demonstrate that the differences seen in adhesion force, probability and stiffness between the sedentary and exercise-trained myocytes are due to interactions of FN to different integrins, e.g., αvβ3 in sedentary and α5β1 in exercise-trained cells, suggesting potential importance of mechanotransduction pathway for therapeutic development.
Abstract 19553: Statin Therapy is Associated with Improvement of Osteoporosis, Adipose Tissue and Coronary Atherosclerosis
Authors: Ahmadi Naser , Hajsadeghi Fereshteh , Nabavi Vahid , Ramayya Sulkha , Fahmy Michael , Bhandari Ajay , Sanchez John , Choi Andrew , Ebrahimi Ramin , Budoff Matthew
Published: April 2024

Background:
There is a significant associations of osteoporosis with atherosclerosis. This study evaluates the effect of statin therapy on osteoporosis, coronary artery distensibility(CDI), vulnerable plaque composition and epicardial adipose tissue in subjects with intermediate risk for coronary artery disease.

Method:
Two hundred and forty subjects underwent computed tomography angiography (age: 61±9 years, 60% male). CDI in left anterior descending artery (LAD) was defined as: [(Early-diastole - mid-diastole lumen cross section area(CSA))/(lumen CSA in mid-diastole x central pulse pressure) x1000]. Vulnerable plaque composite score(VPS) was measured using semi-quantified plaque volume (none, localized, intermediate, or diffuse) and severity of diseased coronaries (normal, mild, moderate, or severe) in non-calcified and mixed plaques based on AHA 15-segment model. Trabecular-BMD(mg/cc) of four consecutive thoracic-vertebrae below the left-main coronary artery slice-level was assessed. EAT, adipose tissue inside pericardial sac, was measured from slice level 15 mm above to the bottom of the heart.

Results:
Osteoporosis was significant correlated with impaired CDI, VPS and EAT(p<0.05). Statin therapy was associated with increase in CDI and BMD (p<0.05). Similarly, statin therapy was associated with decrease in VPS of vulnerable plaque as well as EAT (p<0.05) (Table). Significant association between decrease in VPS of vulnerable plaque, and increase in BMD in response to statin therapy was observed, in which statin therapy was associated with 46% decrease in risk of osteoporosis and VPS (relative risk: 0.54, 95%CI:0.41-0.95, p=0.01)).

Conclusion:
There a significant and independent association between decrease in EAT, VPS of vulnerable plaques, coronary vascular function improvement, and increase in BMD in response to statin therapy. This highlights the dual beneficial cardio- and osteoporosis-protective effects of statin therapy.
Abstract 19592: Exercise Training Prevents Obesity Normalizing Cardiac Mirna-208a and Med13 Levels in Obese Zucker Rats
Authors: Fernandes Tiago , Barretti Diego L , Soci Ursula P , Oliveira Edilamar M
Published: April 2024

Aerobic exercise training (ET) has been established as an important treatment for obesity, since it counteracts aberrant cardiac metabolism and weight gain; however, underlying mechanisms remain to be further determined. MicroRNAs (miRNAs) inhibit protein expression by base-pairing with the 3’ UTRs of mRNA targets. MiRNA-208a is a cardiac-specific miRNA that regulates β-MHC content and systemic energy homeostasis via MED13, a subunit of the Mediator complex. We investigated whether ET regulates the miRNA-208a and their target MED13 related with the weight loss in obese Zucker rats (OZR). OZR (n=10) and Lean (L, n=10) male rats were assigned into 4 groups: OZR, trained OZR (OZRT), L and trained L (LT) were studied. Swimming ET consisted of 60 min of duration, 1x/day/10 weeks, with 4% caudal body weight workload. OZR groups showed a significant augment in the body weight compared with L groups. However, ET was effective in reducing weight gain in OZRT (59%) compared with OZR group. In accordance, ET reduced 20% visceral fat weight in OZRT compared with OZR group. These alterations were accompanied by resting bradycardia (12%), reduction of triglycerides (57%) and low density lipoprotein (61%) and increased of high density lipoprotein (42%) and peak VO
2
(21%) in the OZRT compared with OZR group. No difference was observed in blood pressure and glucose between groups. Cardiac miRNA-208a levels analyzed by real-time PCR increased 57% in OZR paralleled with a decrease of 39% in MED13 protein levels analyzed by western blot compared with L group. In contrast, ET corrected the cardiac miRNA-208a and MED13 levels in OZRT compared with L group. Furthermore, ET reduced the increased cardiac mass (13%), normalized β-MHC gene and protein levels and improved the loss of diastolic function caused by obesity. These results suggest that ET can prevent weight gain via increased of cardiac MED13 and pathological cardiac hypertrophy via β-MHC reduction by regulation of miRNA-208a, indicating the heart in the systemic metabolic control and the miRNA-208a as potential therapeutic target for metabolic and cardiac disorders.
Abstract 19616: Down-Regulation of miR-23/27/24 Clusters by TGF-β1 Signalling Induces Phenotypic Switching of Vascular Smooth Muscle Cells in
vitro
and in Response to Vascular Injury in
vivo
Authors: Iaconetti Claudio , Polimeni Alberto , Sorrentino Sabato , Sabatino Jolanda , Gareri Clarice , Passafaro Francesco , Colangelo Maria , Covello Caterina , Caria Filomena , Carvelli Alessandra , Curcio Antonio , De Rosa Salvatore , Indolfi Ciro
Published: April 2024

Background:
The differentiated state of SMCs plays a key role in the pathogenesis of several major human diseases, including atherosclerosis and restenosis after vascular injury. Several miRNAs have recently been implicated in vascular smooth muscle cells differentiation and/or phenotypic switching. Members of the miR-23/27/24 clusters are highly expressed in smooth muscle cells and are involved in cell cycle control, proliferation and differentiation of various cell types. However, the role of miR-23/27/24 clusters in vascular disease is currently unknown. Thus, the aim of the present study was to evaluate the role of miR-23/27/24 cluster on SMC differentiation and proliferation
in vitro
and after vascular injury
in vivo.

Methods and Results:
To determine the expression changes of miRNAs in vascular wall with neointimal formation
in vivo
, we used the standard rat carotid artery balloon injury model. Using real-time PCR, we demonstrated for the first time that expression of miR-24 and miRNAs that are clustered with it (members of the miR-23 and miR-27 families) are consistently downregulated 3 and 7 days after vascular injury. Furthermore,
in vitro
studies showed that TGF-β1 down-regulated miR-23/27/24 clusters expression in a dose- and time-dependent manner. By using both gain-of-function and loss-of-function approaches, we found that members of the miR-23/27/24 clusters promote multiple aspects of vascular smooth muscle cell contractile phenotype and alter TGF-β1 pathway signalling. Inhibition of miR-23a/b increased gene expression of SMAD-2 and SMAD-3, while ectopic expression of miR-24 reduces the mRNA and protein levels of different genes that regulate cell-cycle progression. Also, using BrdU incorporation and cell migration assay, we demonstrate that miR-24 inhibits vascular smooth muscle cell proliferation and migration. Furthermore, systemic delivery of miR-24 mimics markedly decreased neointimal hyperplasia after balloon injury.

Conclusions:
We demonstrated that miR-23/27/24 clusters control TGF-β1 pathway signalling in vascular smooth muscle cell in
vitro
and in
vivo
. These findings suggest that members of the miR-23/27/24 clusters may have the potential to suppress neointimal hyperplasia after arterial injury.
Abstract 19637: Superiority of Calcium Sensitizer Over Beta-Adrenoceptor Agonist for Treatment of Myocardial Dysfunction after Deep Hypothermic Circulatory Arrest. Role of Calcium Desensitization
Authors: Rungatscher Alessio , Hallstroem Seth , Giacomazzi Alice , Linardi Daniele , Tessari Maddalena , Menon Tiziano , Mazzucco Alessandro , Faggian Giuseppe
Published: April 2024

BACKGROUND: Rewarming from deep hypothermic circutatory arrest (DHCA) produced a calcium desensitization by cTnI phosphorylation that results in myocardial dysfunction. This study was aimed to investigate the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan on myocardial function after rewarming from deep hypothermia.

METHODS AND RESULTS Forty male Wistar rats (400-500 g) underwent cardiopulmonary bypass and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After 15 minutes of DHCA, they were randomly assigned to treatment with levosimendan (0.1 μg/kg/min) (n=15) or epinephrine (0.1 μg/kg/min) (n =15) or saline as control (n =10). The rewarming lasted 60 minutes. Systolic and diastolic function was evaluated at different preloads with a conductance catheter. Levosimendan produced a significantly better recovery of the slope of the left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than ephinephrine (as percentage of baseline respectively 85+9 vs 51+11, p=0.003 and 78+5 vs 48+8, p=0.005). Levosimendan and not ephinephrine compared to control reduced left ventricular stiffness expressed by end-diastolic pressure volume relationship (EDPVR) and improved ventricular relaxation described by Tau. Levosimendan preserved high-energy phosphates content and energy charge and reduced lactate plasma concentration. Ephinephrine (E) determined a significant cTnI phosphorylation during normothermia (N) and enhanced cTnI phosphorylation after DHCA (H/R). On the contrary levosimendan (L) prevent cTnI phosphorylation that was not different from normothermic control (Fig. 1).

CONCLUSIONS: Levosimendan is more effective than epinephrine for treatment of myocardial dysfunction after DHCA. Ephinephrine has a detrimental effect on calcium desensitization that has a key role in myocardial dysfunction after rewarming from DHCA.
Abstract 19679: Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Ameliorates Angiotensin II-Induced Cardiac Remodeling and Myocardial Dysfunction through Inhibition of Mitochondrial Oxidative Stress and Induction of Autophagy
Authors: Zhang Yingmei , Ren Jun
Published: April 2024

Angiotensin II-induced cardiac damage is associated with oxidative stress, mitochondrial injury, cardiac remodeling and contractile dysfunction. ALDH2, a mitochondrial enzyme governing mitochondrial and cardiac function, displays distinct polymorphism and predisposes increased prevalence of hypertension. This study was designed to evaluate the role of ALDH2 in angiotensin II-induced myocardial remodeling and contractile dysfunction. Echocardiographic, cardiomyocyte contractile and intracellular Ca
2+
properties were examined in WT and ALDH2 transgenic mice with or without angiotensin II perfusion. Cardiac histology and autophagy, a process governing hypertrophy and oxidative stress, were evaluated. Myocardial contractile function and intracellular Ca
2+
handling were compromised in angiotensin II-perfused WT mice, the effects of which were significantly attenuated by ALDH2. H&E and Masson trichrome staining revealed cardiomyocyte hypertrophy and interstitial fibrosis associated with greater echocardiographic LV mass and wall thickness. ALDH2 ameliorated angiotensin II-induced cardiomyocyte hypertrophy, cardiac interstitial fibrosis, cardiomyocyte apoptosis, and cardiac atrial natriuretic peptide mRNA levels. The beneficial effect of ALDH2 was independent of blood pressure regulation and was linked to decreased ER stress, autophagy, and 5' AMP-activated protein kinase phosphorylation. Myocardial ER stress and autophagy were facilitated by angiotensin II associated with higher phosphorylation of AMPK. Mitochondria from angiotensin II perfused WT hearts showed clustered mitochondrial patterns, decreased numbers, and volume fractions but increased trans-sectional areas. All of these effects were reduced in ALDH2 mice. The ALDH2 activator Alda-1 ameliorated angiotensin II-induced mitochondrial injury and autophagy induction. Human study also revealed a positive correlation between high blood pressure prevalence and ALDH2 gene mutation. In summary, ALDH2 may provide a blood pressure-independent protection against angiotensin II-induced mitochondrial remodeling and cardiac contractile dysfunction, possibly through modulation of mitochondrial oxidative stress and autophagy induction.
Abstract 19681: Endothelial PGC-1alpha Mediates Vascular Dysfunction in Diabetes
Authors: Sawada Naoki , Jiang Aihua , Takizawa Fumihiko , Croce Kevin , Manika Andre , Tesmenitsky Yevgenia , Kang Kyu-Tae , Bischoff Joyce , Kalwa Hermann , Michel Thomas , Kamei Yasutomi , Benjamin Laura , Sata Masataka , Ogawa Yoshihiro , Arany Zolt
Published: April 2024

[Background] Endothelial dysfunction and aberrant angiogenesis is a hallmark of diabetes. How metabolic perturbations deteriorate endothelial function, however, still remains elusive. The transcriptional coactivator PPARgamma-coactivator-1alpha (PGC-1alpha) is a powerful regulator of metabolism in numerous cell types and is involved in the development of diabetes, but its role in endothelial cells remains poorly understood.

[Objective] We hypothesized that PGC-1alpha may mediate endothelial dysfunction and aberrant neovascularization associated with diabetes.

[Methods and Results] PGC-1alpha mRNA was upregulated by two to fivefold in cultured endothelial cells (ECs) following high glucose stimulation as well as in the ECs isolated from distinct diabetic mouse models (streptozocin-induced type I DM, high fat diet (HFD) feeding, and ob/ob mice). Forced expression of PGC-1alpha abolished VEGF and S1P-induced EC migration, and diminished the capacity of EPCs to undergo vasculogenesis. Conversely, pro-angiogenic factors like VEGF, sphingosine 1-phosphate (S1P) and NO rapidly downregulated PGC-1alpha in ECs, suggesting a role for PGC-1alpha in angiogenic signaling. Consistently, deletion of PGC-1alpha caused pronounced EC migration to a level comparable to that provoked by VEGF. Mechanistically, the angiostatic effect of PGC-1alpha was mediated through inhibition of Rac1 and Akt/eNOS pathway. Transgenic overexpression of PGC-1alpha in ECs in vivo recapitulated multiple diabetic phenotypes, including aberrant reendothelialization in response to carotid injury, wound healing, and blood flow recovery in response to hindlimb ischemia. Conversely, deletion of PGC-1alpha in ECs rescued wound healing dysfunction in type I and II diabetic animals, and restored blood flow recovery in type I diabetic animals with hindlimb ischemia.

[Conclusion] Our data identify EC PGC-1alpha as a critical negative regulator of endothelial function and angiogenesis. Upregulation of PGC-1alpha by hyperglycemia renders ECs unable to properly undergo angiogenesis, and thus constitutes a critical mechanism underlying vascular dysfunction in diabetes.
Abstract 19694:
Etv2-
Regulated Micrornas are Essential for Endothelial Development
Authors: Singh Bhairab N
Published: April 2024

Precise regulation of the fate of endothelial precursors is critical for vascular development. Currently, no known microRNAs have been shown to have a functional role in the specification of the endothelial progenitor cell fate during early embryogenesis. To decipher the requirement of miRNAs during endothelial and vascular development, we disrupted Dicer in a tissue-specific manner, utilizing the
Etv2
-Cre transgenic mouse model that we engineered to ablate microRNA biogenesis in endothelial progenitors. Using this strategy, we determined that miRNA biogenesis is essential for vasculogenesis as Etv2-Cre:Dicer
F/F
embryos are lethal by E11.5-12.5. Histological analysis reveals that the Dicer conditional knockout embryos have severe vascular defects and hemorrhage compared to the wildtype littermates. We have previously reported enrichment of a Pdgfr-α

+

cell population in the Etv2 mutant embryos, however the mechanism is unclear. In the present study, we have identified miR-27a and miR-130a as Etv2 downstream target genes. Using transcriptional assays, we observed that Etv2 transactivated both miR-27a and miR-130a in a dose-dependent manner. Further, we have identified and mapped the miR-27a and miR130a binding sites on the Pdgfr- α 3’-UTR. Our transcriptional assays indicate that miR-27a and miR-130a attenuate the expression of Pdgfr- α. Collectively, these findings identify novel microRNA-mediated mechanisms that govern lineage decisions of mesodermal progenitors and ultimately impact cardiovascular development.
Abstract 19698: Altered Dendritic Cell Network in Chronic Heart Failure - Implications for Chronic Inflammation
Authors: Mohamed Ismahil Mohamed Ameen , Hamid Tariq , Zhou Guihua , Kingery Justin R , Prabhu Sumanth D
Published: April 2024

Although activation of Th1 inflammatory pathways is a hallmark of chronic heart failure (HF), underlying changes in immune effector cells are poorly understood. Dendritic cells (DCs) are orchestrators of T-cell polarization, and thereby can regulate Th1 and Th2 responses. We hypothesized that alterations in the local and systemic DC network, and tissue DC trafficking, underlie the pro-inflammatory state in HF. Post-infarction HF was studied in adult C57BL/6 mice 8 wks following left coronary ligation; sham operated mice served as controls. Pathological remodeling and HF were verified by echocardiography, hemodynamics, gravimetry and histology. Cardiac interstitial cells were isolated by collagenase digestion of the heart followed by density gradient centrifugation; standard isolation procedures were used to isolate splenic, BM, and PB cells. We characterized two major DC subsets using flow cytometry: 1) classical DCs (cDCs, CD11c+B220-) that initiate adaptive immune responses and enhance interferon production from T cells, and 2) plasmacytoid DCs (pDCs, CD11c+B220+) that upon proper stimulation can produce pro-inflammatory cytokines that polarize T cells to a Th1 phenotype or, alternatively, suppress adaptive immunity. Compared with sham-operated mice, HF mice exhibited significantly (p < 0.05) increased cDCs in PB (3.65±0.34 vs 1.36±0.27%), spleen (3.65±0.41 vs 2.35±0.22%), and heart (4.22±0.15 vs 3.1±0.40%), but no changes in BM. A major cDC subset, CD11c+B220-CD8+ cells, preferentially endocytose dying cells and stimulate Th1 CD4+ T cell responses. In HF mice, these cDCs significantly (p < 0.01) increased in PB (0.17±0.018 vs 0.053±0.017%) and spleen (0.35±0.035 vs 0.21±0.027%). Additionally, there were significant (p < 0.05) increases in pDCs in the heart (2.55±0.44 vs 0.60±0.30%), spleen (2.32±0.40 0.90±0.11%) and BM (1.30±0.10 vs 1.02±0.08%), but no changes observed in PB as compared with sham. Hence, we conclude that in HF, there are augmented cDCs and pDCs locally in the heart and selective alterations in the PB, spleen, and BM that together support the development of systemic Th1 responses. A better understanding of DC networks in HF can elucidate the mechanisms of pathological inflammation and lead to novel therapeutic approaches.
Abstract 19723: Randomized Comparison of Bosentan in Intermittent Claudication in Peripheral Arterial Disease : The Clinical and Endotelial Function Assessment after Endothelin Receptor Antagonism (CLAU) Randomized Controlled Trial
Authors: De Haro Joaquin , Bleda Silvia , Varela Cesar , Esparza Leticia , Lopez de Maturana Ignacio , Acin Francisco
Published: April 2024

INTRODUCTION
There is evidence that endothelin-1 (ET-1) is involved in the etiopathology of Peripheral Arterial Disease (PAD) due to its capacity to induce impairment of the endothelial function, its vasoconstrictor effects, its pro-inflammatory cytokine action, fibrosis and induction of cell proliferation. Bosentan is a dual ET-1 receptor antagonist, administered orally with antifibrotic, antiinflamatory, antihipertrophic properties and the capacity to vasodilate selectively the damaged vascular bed.

MATERIAL AND METHODS
A prospective, randomized, controlled, parallel groups, simple blind,
proof-of-concept
trial was performed in 30 male patients (50-60 years old) with Intermittent Claudication (Rutherford category 1-2) recently diagnosed, and clinical manifestations not exceeding 6 months, with hypertension and/or dyslipidemia as unique cardiovascular risk factors burden permitted. After a 2-weeks period of stabilization of the claudication distance verified in two consecutive treadmill test (12.5%,3.2 km/h), patients were randomized 1:1 to the experimental arm (Bosentan 62.5 mg twice daily/four weeks and 125mg twice daily/eight weeks) or control group.

RESULTS
After six months of treatment there was an increase in the Absolute Claudication Distance (ADC) of 549% (p=0.003), the Flow-Mediated Artery Dilation (FMAD) of 768% (p=0.001), the Ankle-Brachial Index (ABI) 24% (p<0.001) and a decrease in the C Reactive Protein (CRP) of -22,7%(p<0.019) vs. control group (22%,-16%,-8%,21%, respectively). The patient subjective claudication assessment corroborated the improvement in the ability to walk (589%, p <0.001) in the treatment group. No severe adverse events were reported in the experimental group.

CONCLUSIONS
Bosentan improves significantly the Claudication Distance, the endothelial function, inflammatory and the hemodynamic status in patients with incipient PAD.
Abstract 19728: Translesional Time to Determine Complete Bidirectional Block Across the Cavotricuspid Isthmus
Authors: Thomas George
Published: April 2024

Introduction:
The goal of ablation of typical atrial flutter is to create complete bidirectional block across the cavotricuspid isthmus (CTI). The purpose of this study was to document whether there was a transisthmus time that is associated with complete bidirectional isthmus block (CBIB).

Methods:
Thirty consecutive patients who had CTI ablation procedures were assessed. A circular right atrial mapping catheter, coronary sinus catheter, and electroanatomical mapping were used in all patients. Before ablation, points were marked medial and lateral to the planned line and bidirectional conduction times were assessed. Post ablation bidirectional conduction times were assessed again at the points medial and lateral to the line. The translesional time (TL) was defined as the difference in bidirectional conduction time recorded lateral to the line from medial to the line. CBIB was verified by reversal of activation of the right atrium on the circular mapping catheter and/or documentation of widely spaced double potentials.

Results:
CBIB was achieved in 29/30 patients. The average baseline counterclockwise (CCW) conduction time across the CTI was 43 +/- 22 msec The average baseline clockwise (CW) conduction time was 42 +/- 16 msec. The average baseline TL was 10 msec CCW, and 9 msec CW. The longest baseline TL was 52 msec CCW and 28 msec CW . Post ablation, the average CCW conduction time was 149 msec, and CW was 150 msec in patients with CBIB. The average TL in patients with CBIB was 116 msec CCW and 111 msec CW. The shortest TL associated with CBIB was 90 msec CCW and 91 msec CW. The maximum TL associated with incomplete block was 68 msec.

Conclusions:
A bidirectional TL of greater 90 msec was predictive of CBIB after typical atrial flutter ablation, and could be used simplify assessment of CBIB during CTI ablation.
Abstract 19748: Predicting Outcome in Adult Congenital Heart Disease: Correlating the Seattle Heart Failure Model with peak VO2 from Cardiopulmonary Exercise Testing
Authors: Stefanescu Ada , Macklin Eric , Lin Elaine , Dudzinski David , Defaria Yeh Doreen , Lui George , Bhatt Ami
Published: April 2024

Background

: The adult congenital heart disease (ACHD) population continues to grow and has increased risk of mortality and morbidity, including heart failure. Currently, no model exists to identify high risk patients. Cardiopulmonary exercise testing (CPET) is used in risk stratification with peak VO2 (pVO2) as a surrogate marker for outcomes in ACHD. This measurement requires specific equipment and expertise, not widely available outside of tertiary centers. The Seattle Heart Failure Model (SHFM) is a validated prediction model that estimates total mortality in patients with heart failure by using commonly obtained clinical, laboratory, medication, and device variables.

Hypothesis

: The SHFM predicts CPET pVO2 in moderate and complex ACHD.

Methods

: We performed a retrospective IRB approved study of 106 individuals (>18 years of age) with transposition of the great arteries (TGA), Ebstein anomaly, tetralogy of Fallot (TOF), double outlet right ventricle (DORV) and single ventricle (SV) with a clinically indicated CPET at the Massachusetts General Hospital (MA, USA) and Montefiore Medical Center (NY, USA) between 2008 and 2012. Clinical/laboratory data (within one year of CPET) were obtained for SHFM calculation.

Results

: Mean age was 35.6 years (range 18-64), 55.7% are female, average systemic ventricle ejection fraction was 56.3% (18-83%). Medication use: 9.4% of individuals on ACE-I/ARB, 34% beta-blockers, 23.6% diuretics. The mean SHFM 1 year survival was 93.9% (72.5-99.0%); mean pVO2 was 21.2 cc/kg/min (10.2-41.6). The SHFM 5-year model was able to predict an outcome of pVO2<20 in the group as a whole with a C statistic of 0.69. In individuals with TGA (systemic right ventricle) and Ebstein, the predictive ability of the SHFM 5-year model had a C statistic of 0.86 and 0.87, respectively. Peak VO2 and SHFM predicted survival correlated strongly among TGA and Ebstein patients (r=0.65 and 0.57, p < 0.03), but not among SV or TOF patients (r.= -0.02 and 0.12, p > 0.4).

Conclusion

: The SHFM is able to offer an increased ability to discriminate among ACHD patients who have a pVO2 < or > 20cc/kg/min. This model is easily created using clinically obtained data. Targeted application of SHFM in the community may have predictive value and guide care in select populations.
Abstract 19764: Cardiac Disease Modeling of Familial Left Ventricular Noncompaction Cardiomyopathy Using Induced Pluripotent Stem Cells
Authors: Bui Yen K , Cordes Kimberly R , Hastie Samantha , Srivastava Deepak
Published: April 2024

Left ventricular noncompaction cardiomyopathy (LVNC) is thought to arise from developmental arrest of the normal compaction of ventricular heart muscle, sometime between weeks 4-8 of gestation. In normal heart development, a network of muscle bands (trabeculations) compact fully, resulting in a dense muscle and a smooth inner surface. Failure of trabecular compaction results in a muscle wall consisting of a spongy myocardium with a meshwork of trabeculations that can lead to thin dilated heart muscle and impaired muscle function. Although several disease-causing genes have been implicated in LVNC, the genetic cause remains unknown in more than 50% of patients. We hypothesize that LVNC arises from developmental arrest of the embryonic ventricular myocardial compaction process and that LVNC patients will have expression profiles reflective of this. We have identified a family with LVNC affecting 4 individuals. Through whole exome sequencing we identified a mutation in a cardiac developmental gene that was associated with the LVNC phenotype and was fully penetrant in this family. Using dermal fibroblasts from members of this family, we generated induced pluripotent stem (iPS) cells from affected and unaffected family members to identify transcriptome and functional consequences in cardiomyocytes harboring the genetic mutation. We will present our results from this genetic and cellular approach to LVNC, which allows study of the physiologic consequences of genetic mutations in relevant human cells.
Abstract 19817: Influence of the Purkinje Conduction System on the Ekg: A Modeling Study
Authors: Krishnamoorthi Shankarjee , Ajijola Olujimi , Perotti Luigi E , Klug William S , Garfinkel Alan , Ennis Daniel B
Published: April 2024

Introduction -
Computational modeling of cardiac electrophysiology (EP) is important for exploring the mechanisms that underlie fatal arrhythmias. Methods are limited for anatomically mapping the Purkinje conduction system (PCS) in whole hearts, and incorrect definition of the PCS geometry and/or conduction velocity leads to incorrectly modeled activation wavefronts, fractioned QRS, and T-wave inversion. The objective of this study was to design a PCS that resulted in the best simulated six-lead electrocardiogram (ECG), while maintaining consistency with known anatomy.

Methods -
Diffusion tensor (DT) MRI was used to define gross anatomy and fiber orientations, combined with a cell model to build a finite element model of rabbit cardiac EP, from which the six-lead ECG was simulated. An in vivo six-lead rabbit ECG served as a reference for the computed ECG. The number and distribution of Purkinje-muscle junctions (PMJ) and the conduction velocity in RV, LV, and septal branches were varied. Whole-heart activation wavefronts and the resultant ECG were compared to the normal rabbit ECG. Parameters assessed included activation wavefront timing and QRS/T-wave morphology in a six-lead ECG.

Results -
Forty combinations of PCS geometry and conduction speed were implemented. Increasing the density (from 34 to 399), uniformly distributing the PMJs, and a PCS with branches for earlier septal activation (3.0m/s) and a faster Purkinje conduction speed in the LV (3.0m/s) compared to the RV (2.1m/s) was necessary to produce the correct activation sequence, eliminate QRS fractionations, and produce the best T-wave morphology. The figure shows the comparison of the ECG output from V3 for three different iterations.

Conclusion -
The reported Purkinje conduction speed is 0.8-2m/s, but a heterogeneous Purkinje conduction speed distribution combined with a high PMJ density is needed to produce computationally accurate ECGs.
Abstract 213: Physiogenomic Response to Prolonged Cardiac Arrest and Resuscitation: Hyporesponders Fail to Upregulate Certain Genes
Authors: Menegazzi James J , Salcido David D , Housler Greggory J , Hollingshead Deborah J , Shi Haiwen , Lyons-Weiler James
Published: April 2024

Background: In our porcine laboratory studies of prolonged cardiac arrest and resuscitation we have observed that approximately one out of every four animals appears to be hyporesponsive to vasopressor drug therapy during CPR. These hyporesponsive animals fail to generate an increase in coronary perfusion pressure (CPP) sufficient to attain a return of spontaneous circulation (ROSC) and cannot be resuscitated. Some humans unexplainably fail resuscitation despite promising conditions (age, witnessed arrest, bystander CPR, rapid EMS response). We conducted this natural experiment in order to compare the physiogenomic responses of animals that were hyporesponsive, to those that responded as expected to vasopressor therapy. Hypothesis: We hypothesized that we would identify genes that were differentially expressed between the two groups (hyporesponders and normal responders).

Methods: We sedated, anesthetized, and instrumented 14 female swine (mean mass 28.6 kgs). Micro-manometer tipped catheters were placed to measure CPP for determination of response status. Ventricular fibrillation (VF) was induced and untreated for 10 minutes, then CPR was begun. Two minutes later pressors were given (epinephrine 0.1 mg/kg and vasopressin 0.6 U/kg). At minute 15 the first rescue shock was delivered. Twenty-eight minutes after the induction of VF, femoral artery samples were harvested and snap-frozen. Gene expression was assessed on the Affymetrix Porcine Genome Array, and affected pathways were ordered with Pathway Express (with Impact Analysis of p<0.05 considered significant).

Results: We compared 4 hyporesponsive pigs to a sample of 5 normal responders. There were 213 differentially expressed genes affecting 10 pathways shown in the Table (with the apoptosis pathway at p=0.056).

Conclusion: Hyporesponders differentially express genes that affect vasoregulation, myocardial contractility, calcium regulation and 7 other pathways.
Abstract 215: First Shock Success Rates Across Waveforms and Energy Levels in Adult Cardiac Arrest: A Systematic Review and Meta-analysis
Authors: Morrison Laurie J , Henry Rowan , Ku Vivien , Nolan Jerry P , Morley Peter T , Deakin Charles D
Published: April 2024

Objectives: Current guidelines advise a single biphasic shock followed by chest compressions; however, it is unclear if this applies to all waveforms and energy levels. We conducted a systematic review and meta-analysis of the literature to determine the comparative success rates for single-shock defibrillation across waveforms evaluated in out-of-hospital cardiac arrest patients presenting in Ventricular Fibrillation.

Methods: A comprehensive search strategy was used across Embase, Medline, Cochrane libraries, dissertation abstracts and clinicaltrials.gov, and unpublished data was sought. Two investigators independently reviewed titles, abstracts and full texts in a hierarchical manner for study eligibility with a quadratic kappa score at each level. Two authors abstracted data independently, and the quality of the articles was assessed using the Jadad scale. Outcomes were termination of fibrillation to any rhythm (TOF), return of organized rhythm (ROOR) and return of spontaneous circulation (ROSC).

Results: A total of 3,281 potentially relevant citations were identified and of these 7 RCTs were selected with Kappa values of titles 0.53, abstract 0.71, and article 0.94. Mean quality scores varied from 1-2.5/3. First-biphasic shock success (pooled mean) for TOF were similar: Biphasic Truncated Exponential (BTE) 200J 90.5%, BTE 150J 89.9%, Rectilinear Biphasic (RLB) 120J 84.9% but were lower and divergent for both ROOR BTE 200J 43%, BTE 150J 38%, RLB 23% and ROSC; BTE 200J 39%, BTE 150J 78%, RLB 46%. Median time to first shock (min) varied across trials (5.1 BTE 200/150J, 10.4 RLB) and may contribute to observed differences.

Conclusion: First shock success rates as measured by the industry standard of TOF do not significantly differ across biphasic waveforms and energy levels.
Abstract 218: Cerebral Oximetry as a Post-ROSC Predictor of Neurologic Outcome After OOHCA
Authors: Medado Patrick , Thomas Craig J , Scott Timothy , Kessler Justin , O’Neil Brian
Published: April 2024

No reliable early predictors of neurological outcome exist for patients resuscitated from an OOHCA.

Objectives: We investigated the prognostic utility of cerebral oximetry (rSO2) obtained after Return of Spontaneous Circulation (ROSC) on neurological outcome after OOHCA.

Methods: This IRB approved, observational trial collected data on a convenience sample of patients presenting to an academic, urban Emergency Department with OOHCA. Cerebral Oximetry uses near infrared spectroscopy to measure oxygen in the brain independent of pulse using adhesive rSO2sensors that were placed on patient’s forehead upon ED arrival and data recorded for at least 4 hours post ROSC. We followed Utstein criteria for demographics and data recording. Blinded investigators abstracted CPC scores for all patients. Outcome measure defined as good CPC (≤ 2) at hospital discharge. We analyzed data with descriptive statistics and logistic regression.

Results: We analyzed 32 patients: 69% were male, mean age 62.5 years (52 to 75), 30 (93.8%) witnessed and 23 (71.9%) had bystander CPR. Initial rhythm was VF/VT 19%, PEA 40%, Asystole 34% and 2 unknown. There were 7 (22%) with good CPC at hospital discharge. Univariate analysis showed only the average rSO2 during first 4-hours post ROSC predictive of good outcome (p<0.003). Initial Mean Arterial Pressure (MAP) was a good prognosticator (p<0.087). Logistic regression revealed only average rSO2 4-hours post ROSC as indicative of good outcome (p<0.086).

Conclusion: The average cerebral oximetry in the first 4 hours post ROSC was an excellent predictor of good neurological outcome at hospital discharge. This study is limited by small sample size and observational nature.
Abstract 219: Prognostic Significance of Serum Albumin on Long-Term Mortality in Survivors of Out-of-Hospital Cardiac Arrest
Authors: Park In Won , Lee Jae Hyuk , Kim Joonghee , Kim Kyuseok , Jo You Hwan , Kang Kyeongwon , Kang Changwoo , Lee Soohoon , Rhee Joong Eui
Published: April 2024

Introductions:

Hypoalbuminemia is known as a reliable predictor of mortality in patients with various illnesses. However, the prognostic value of serum albumin on out of hospital cardiac arrest (OHCA) patients has not been established. The purpose of study is to investigate whether serum albumin concentration on hospital arrival may be useful in predicting the long-term mortality in survivors from OHCA.

Methods:

Retrospective analysis of emergency departments OHCA registry from January 2008 to December 2011 has been conducted. The individual medical records were reviewed for the data including Utstein predictors of OHCA, underlying disease, and initial laboratory finding including serum albumin. Primary outcome was survival at 6 months. The secondary outcome was CPC (Cerebral Performance Category) at 6 months. Albumin was categorized as quartiles as < 2.7g/dL, 2.7 to 3.2g/dL, 3.2 to 3.9 g/dL and > 3.9g/dL. Hazard ratios (HRs) were estimated using Cox-proportional hazard models in both univariate and multivariate analysis. All prognostic variables with their p value < 0.1 in univariate analysis were used in multivariate analysis for adjustment.

Results:

Of 546 OHCA patients, 139 patients had sustained ROSC. Of those, 23 patients (16.5%) survived at 6 month and 16 patients (11.5%) had favorable neurological outcome (CPC 1,2). Survival rate at 6 months were significantly higher in patients with a higher albumin group and neurological outcomes were also more favorable in higher albumin group.

In a Cox proportional hazard regression analysis for 6-month survival, patients with lower categories of albumin had increased mortality rates before and after multivariable adjustment. (p value for linear trend < 0.05)

Conclusion:

Serum albumin is a robust predictor of long-term mortality and associated with neurological outcome in patients with sustained ROSC from OHCA
Abstract 234: Quantifying the Effect of CPR Quality on Cardiac Arrest Outcome: A Meta-analysis
Authors: Wallace Sarah , Abella Benjamin S , Becker Lance
Published: April 2024

Objective
: While evidence has accrued that CPR quality impacts cardiac arrest outcome, the effect size of variation in CPR quality remains poorly characterized. Furthermore, the relative contributions of chest compression (CC) components (such as rate and depth) to successful resuscitation remain unclear. We sought to measure the effect of CPR quality on cardiac arrest outcome through systematic review and meta-analysis.

Methods:
A comprehensive search was performed for English-language articles using PubMed, MEDLINE, Cochrane Library, and direct author contact. We included any clinical study assessing CPR performance on adult cardiac arrest patients where survival was a reported outcome, either return of spontaneous circulation (ROSC) or survival to admission or discharge. Effect sizes were reported as mean differences. Missing data were resolved by author contact. Estimates were segregated by CPR metric (CC rate, depth, no-flow fraction, and ventilation rate), and a random-effects model was applied to estimate an overall pooled effect. Evidence for statistical heterogeneity between studies was tested via goodness of fit (X
2
).

Results:
Of 603 abstracts evaluated, 8 studies published between 2005 and 2012 met inclusion criteria. These 8 studies included 2113 unique arrest cases (1937 out-of-hospital, 176 in-hospital). Mean age was 68.0 years, 64.1% of the cohort was male, overall ROSC was 31.2%, and survival to discharge was 4.9%. Arrest survivors were significantly more likely to have received deeper CCs than non-survivors (mean difference 2.44 mm, 95% CI 1.19 to 3.69 [p<0.001], n=6 studies, p for heterogeneity=0.9). Survivors were also significantly more likely to have received CC rates closer to 85-100 cpm than non-survivors (absolute mean difference from 100 cpm -5.04 cpm, 95% CI -8.44 to -1.65 cpm [p=0.004], n=6 studies, p for heterogeneity=0.2). Findings for depth and rate did not vary by arrest location, CPR performer, study quality, or outcome type. No significant difference in no-flow fraction (n=5 studies) or ventilation rate (n=3 studies) between survivors and non-survivors was observed.

Conclusions:
Deeper chest compressions and rates closer to 85-100 cpm are significantly associated with improved survival from cardiac arrest.
Abstract 254: Quality of 2-Minute Continuous Chest Compressions by Medical Students and Lay Rescuers
Authors: Gianotto-Oliveira Renan , Gonzalez Maria Margarita , Gianotto-Oliveira Gustavo , Podolsky-Gondim Guilherme , Vianna Caio B , Timerman Sergio , Kalil Filho Roberto
Published: April 2024

Background: The performing of quality chest compressions is highly emphasized in the American Heart’s 2010 Guidelines. Moreover, it addresses the importance of continuous chest compressions (hands-only) as the best approach when faced with a sudden cardiac arrest victim when a ventilation barrier device is not available.

Hypothesis: We hypothesized that first-year medical students perform two-minute continuous chest compressions with lower quality than those performed by lay rescuers who had Heartsaver ® CPR AED training at least every 2 years.

Methods: The volunteers initially attained the Heartsaver® CPR AED course. After approximately 30 minutes they performed 2 minutes continuous chest compressions in the Resusci Anne training mannequin, with a PC reporting system.

Results: When comparing the 76 medical students with the 74 trained lay rescuers, the average age (20 vs. 40 years), the male gender (54% vs. 92%), the mean body mass index (24.9 vs. 27.3 kg/m2) and physical activity (55% vs. 36%) presented significant differences, p<0.01, p<0.01, p<0.01 and p=0.04, respectively. Regarding the quality of chest compressions, the average rate (121 vs. 124 compression/minute), duty cycle (47% vs. 45%), the percentage of compressions with correct hand positioning (87% vs. 90%) and the average depth (45 vs. 49 mm), showed no significant difference, p=0.05, p=0.06, p=0.32 and p=0.10, respectively. However, the percentage of adequate depth compressions (43% vs. 58%) and the percentage of compressions without error (36% vs. 50%) revealed a significant difference, p=0.01 and p<0.01.

Conclusion: In conclusion, the results show that important parameters like the percentage of compressions with adequate depth and compressions without error had a significant difference, demonstrating that although being lay rescuers, the constant cardiac resuscitation training allows performing higher quality chest compressions than those performed by medical students. It’s need ongoing training of medical students, because they must perform good-quality chest compressions too.
Abstract 257: Clinical Decision Tree Model in Patients with Out-of-Hospital Cardiac Arrest for Predicting Neurological Outcome at the Emergency Department
Authors: Goto Yoshikazu , Maeda Tetsuo , Goto Yumiko , Ohta Keisuke
Published: April 2024

Introduction:
The ideal factors for predicting neurological outcomes in patients with out-of-hospital cardiac arrest (OHCA) remain elusive.

Hypothesis:
We hypothesized that a novel decision tree model using 4 pre-hospital variables can predict neurological outcome after OHCA at the emergency department.

Methods:
We analyzed 390226 adults in whom resuscitation was attempted after non-traumatic OHCAs in a prospectively recorded nationwide Utstein-style database in Japan over 5 years (2005-2009). The endpoint was 1-month survival with good neurological outcome (cerebral performance category scale, 1-2). We developed a prediction model using data from 4 years (2005-2008,
n
= 307896), with validation using external data from 2009 (
n
= 82330).

Results:
Overall 1-month survival and good neurological outcome rates were 4.19% and 1.99%, respectively. Multivariate logistic regression analysis indicated the following pre-hospital factors to be significant: shockable initial rhythm (odds ratio [OR] 5.87; 95% confidence interval [CI] 5.23-6.60), emergency medical service (EMS) personnel witnessed (OR 3.40; 95%CI 3.15-3.69), witnessed arrest (OR 3.05; 95%CI 2.83-3.28), and age (OR 3.24; 95%CI 2.97-3.53). Using recursive partitioning analysis with these 4 predictors, we developed a clinical decision tree model: if a witnessed OHCA patient had shockable initial rhythm, the probability of good outcome was 20.0% (age<71) or 10.3% (age>or=71); if an unwitnessed OHCA patient had shockable initial rhythm, the probability of good outcome was 6.8% (age<81) or 1.8% (age>or=81); if a witnessed OHCA patient had unshockable initial rhythm, the probability of good outcome was 3.8% (EMS personnel witnessed arrest) or 1.1% (EMS personnel unwitnessed arrest); if an unwitnessed OHCA patient had unshockable initial rhythm, the probability of good outcome was 0.5% (age<71) or 0.2% (age>or=71). The c-statistics for this model in the groups for development and validation were 0.867 (95%CI 0.861-0.873) and 0.887 (95%CI 0.877-0.896), respectively.

Conclusions:
Stratification of patients using a decision tree model accurately provides the severity of OHCA classification rules and can predict good neurological outcomes after OHCA at the emergency department.