bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17979: A Subset of Patients with Isolated Transposition of the Great Arteries and Double Outlet Right Ventricle Fall Within the Spectrum of Heterotaxy Syndrome
Authors: D'Alessandro Lisa C , Latney Brande C , Paluru Prasuna C , Goldmuntz Elizabeth
Published: April 2024

Background:
Heterotaxy is a rare disorder of laterality. ZIC3 was the first gene in which human disease-causing mutations were identified. Mutations typically result in males with situs ambiguus and complex congenital heart disease; however affected females and one male with isolated transposition of the great arteries (TGA) have been reported. We hypothesized that a subset of patients with heart defects common to heterotaxy but without laterality defects would have ZIC3 mutations. We also sought to estimate the prevalence of ZIC3 mutations in sporadic heterotaxy.

Methods and Results:
Patients with TGA (n=169), double outlet right ventricle (DORV) (n=90), complete atrioventricular canal (n= 41) and heterotaxy (n=53) underwent sequencing of the ZIC3 open reading frame. We tested 90 patients with tetralogy of Fallot (TOF) to correlate genotype with phenotype. Three mutations were detected: 1 female with isolated DORV [c.49G>T (Gly17Cys)], 1 male with isolated TGA [c.98C>T (Ala33Val)], and 1 female with sporadic heterotaxy [841C>T (His280Tyr)] that were absent in 100 Caucasian and 100 African American control patients. We also identified a novel insertional mutation (CPFP333ins) in a family with heterotaxy. No mutations were found in cases with TOF. Transcriptional activation studies demonstrated significantly reduced transcription of the ZIC3 His280Tyr mutant construct.

Conclusions:
Isolated TGA and DORV, like heterotaxy, can arise from mutations in ZIC3, confirming a spectrum of disease that includes isolated cardiac malformations. ZIC3 mutations were found in 2% of patients with sporadic heterotaxy, therefore routine testing should be considered in patients with heterotaxy.
Abstract 180: Quality of Chest Compressions Performed During 1 and 2 Minutes by Medical Students
Authors: Oliveira Renan G , Gonzalez Maria M , Girardi Ruana S , Leão Naianne S , Barros Thalita R , Vianna Caio B , Timerman Sergio
Published: April 2024

Background:
In order to perform an efficient CPR, it is very important to pay attention to the frequency of the thrusts and the depth of the movement being made into the chest. Studies have proven that the quality of the maneuver decreases over time as the minutes progress.

Hypothesis:
We hypothesized that chest compressions correctly performed during one minute are more effective than those continued during two minutes.

Methods:
We trained 48 first year medical students through the “Family and Friends CPR Anytime” course. Next, a minute of continuous compressions on the Resusci Anne training mannequin, with a PC reporting system, were performed. After one week, two minutes of continuous chest compressions were performed on the same mannequin.

Results:
The mean age was 20,94 ±3.51 years, the mean body mass index was 25.7 ±4.7 kg/m
2
and 25 students (55%) were of male gender. Comparing the compressions performed during one and two minutes, respectively: the average rate of compressions per minute were (116 vs. 123), the average of incomplete release (5% vs. 19%), the duty cycle (47% vs. 49%), percentage of compressions with no error (54% vs. 38%), with appropriate depth (57% vs. 48%) and the average depth (48mm vs. 45mm) show significant differences (p=0.01, p<0.01, p=0.03, p=0.01, p=0.30, p=0.03, respectively). The only parameter evaluated that showed no significant difference was the percentage of compressions with correct hand position, 93% vs. 86%, respectively (p=0.35).

Conclusion:
The results of the study show significant differences in important parameters of chest compressions and reveal better quality when performed during one minute rather than two minutes. This corroborates that it would be better to change the rescuer even before the two minute mark has elapsed. Furthermore, the main parameter that needs improvement would be the depth of compressions, reinforcing the need of devices which measure the depth of chest compressions during CPR maneuvers.
Abstract 18002: Coronary Collaterals Predict Improved Survival and Allograft Function in Patients with Coronary Allograft Vasculopathy
Authors: Lavine Kory J , Sintek Marc , Novak Eric , Joseph Susan , Ewald Gregory
Published: April 2024

Coronary allograft vasculopathy (CAV) remains the most prevalent cause of allograft failure and cardiac mortality beyond the first year following heart transplantation. To date there are few proven therapies for this important disease. The presence of coronary collaterals has previously been demonstrated to impart a favorable prognosis in patients with ischemic heart disease. To determine whether the development of coronary collaterals is also associated with improved outcomes in patients with CAV, we performed a retrospective cohort study of all patients followed in the heart transplant clinic at Barnes Jewish Hospital between 1994 and 2008. The primary endpoint was the composite of all cause mortality, retransplantation, and inotrope dependence. LV end diastolic pressure and NYHA class served as surrogate measures of allograft function and heart failure symptoms. We screened 493 patients and identified 60 (13%) with moderate to severe CAV as defined by the International Society of Heart and Lung Transplantation. Coronary collaterals were present in 34 (57%) subjects. Patients with collaterals had a significantly lower risk of death, retransplanation, or inotrope dependence compared to patients without collaterals (OR 0.15, 95% CI 0.05-0.48, p= 0.002). In addition, patients with collaterals had lower LV end diastolic pressures and NYHA class. Multivariate analysis confirmed that the presence of collaterals independently predicted each of these outcomes. Immunohistochemical staining of biopsy specimens collected from patients with CAV revealed alterations in microvascular density that correlated with the presence of angiographically visible collaterals. Together these data demonstrate that the development of coronary collaterals predicts a favorable prognosis in patients with CAV and suggests that interventions aimed at promoting collateral growth may serve as effective therapies for this disease.
Abstract 18040: Directed Screen of Drugs Using Human Cardiomyocytes Derived From Induced Pluripotent Stem Cells with Timothy Syndrome, Lethal Arrhythmia
Authors: Yazawa Masayuki , Bernstein Jonathan A , Hallmayer Joachim , Dolmetsch Ricardo E
Published: April 2024

L-type voltage gated calcium channels (LTCs) play essential roles in the generation of cardiac rhythms and in the contraction of the atrial and ventricular myocytes. A de novo missence mutation in the LTC, CaV1.2, results in Timothy syndrome (TS), a multisystem disorder characterized by QT prolongation, lethal arrhythmia and congenital heart disease. To explore the effect of the TS mutation on the electrical activity and contraction of human cardiomyocytes (CMs), we have generated induced pluripotent stem cells (iPSCs) from two TS patients, and differentiated these cells into CMs. Electrophysiological recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. To rescue the cardiac phenotypes, we tested calcium channel blockers (roscovitine, nimodipine and verapamil), beta-blocker (metoprolol), calmodulin kinase II inhibitor (KN-93) and late sodium current blocker (ranolazine) using patch clamp recording and calcium imaging in TS CMs. We found that roscovitine restored the electrical and Ca2+ signaling properties of CMs from TS patients while the other drugs didn’t rescue the phenotypes in TS CMs. This approach using iPSC-derived CMs would be a useful platform to provide a robust assay for developing new drugs to treat human cardiac diseases.
Abstract 18059: Papillary Muscle Abnormalities in Apical Hypertrophic Cardiomyopathy and Their Association with Mid-Ventricular Obstruction: Insignt from Cardiac Magnetic Resonance Imaging
Authors: Shim Chi Young , Yang Woo-In , Kim Young Jin , Kang Min-Kyung , Chung Namsik , Cho Seung-Yun , Ha Jong-Won
Published: April 2024

Background
Abnormal papillary muscles(PM) are often found in hypertrophic cardiomyopathy(HCM) and the significance relating left ventricular(LV) outflow obstruction has been identified. Mid-ventricular obstruction(MVO) can be found in apical HCM and accompanied by apical aneurysm and ventricular tachycardia. We sought to investigate PM structures including numbers, thickness, insertion site and their association with MVO in apical HCM.

Methods
In 44 patients(30 men, age 57±8 yrs) with apical HCM, cardiac magnetic resonsnce was performed to characterize PM morphology. PM numbers, maximal PM thickness in diastole, and their insertion site on LV were evaluated. Patients with isolated asymmetric apical hypertrophy were classified as a pure type, and those with coexistent hypertrophy of the interventricular septum as a mixed type. MVO were examined using Doppler echocardiography and diagnosed when the systolic peak flow velocity at the mid-ventricle was≥2.5 m/s. Subjects were divided into 2 groups according to the presence of MVO; Group I(n=28): MVO(-), Group II(n=15): MVO(+).

Results
The mixed type was more prevalent(54 vs 93%, p=0.014) and posterior wall thickness at mid LV was higher(10.2±1.8 vs 12.9±2.1, p<0.001) in group II compared with group I. Apical aneurysm was found in 3 patients in group II. Group II showed higher PM numbers(2.7±0.8 vs 3.3±0.8, p=0.070) and maximal thickness(8.7±0.9 vs 10.8±1.5, p=0.045). PMs were displaced closer to the LV apex(displaced apically: 68 vs 93%, p=0.042) in almost of group II patients. There was no significant difference in heart rate between two groups.

Conclusion
In apical HCM, patients with MVO showed different PM structures and displacement than those without MVO. Increased number of PMs and their apical displacement can be one of contributors of MVO. Combined with the LV morphologic type, the assessement of PM morphology would be important to predict the development of MVO and its subsequent outcomes in apical HCM.
Abstract 18101: EFFICAS I Results - Are Low Contact Force Parameters Predictors for Gap Formation after Pulmonary Vein Isolation by Radiofrequency Catheter Ablation?
Authors: Neuzil Petr , Wichterle Dan , Cihak Robert , Skoda Jan , Wissner Erik , Fremont Olivier , Yulzari aude , Reddy vivek Y , Kautzner Josef , Kuck Karl-Heinz
Published: April 2024

Objectives
Electrical reconnection of pulmonary veins (PVs) results in recurrences of atrial fibrillation (AF) following PV isolation (PVI). Gaps in the isolation lines may occur due to suboptimal catheter tip-to-tissue contact force (CF) during ablation. EFFICAS I, a multi-center prospective study, evaluated the relationship between CF parameters and gap formation during follow-up.

Methods
Pts with paroxysmal AF underwent PVI using an irrigated RF ablation catheter that provides tip-to-tissue CF information (TactiCath®, Endosense, Switzerland). The operator was blinded to the CF, but CF and Force Time Integral (FTI) were recorded for later analysis. PV antra were divided into 8 segments of interest (SEG). Patients underwent a re-mapping procedure at 3 months to evaluate gap occurrence. Incidence of gaps per SEG at 3 months was correlated with CF and FTI during initial PVI.

Results
Forty pts (59 ± 10 yrs, 30 males) were treated by 10 operators at 3 centers with 2519 RF ablations. Average CF at the right PVs was higher compared to the left PVs (26.0 ± 16.6 g vs. 17.9 ± 13.0 g, p<0.0001). Greater CF was applied to the posterior wall than the left anterior wall (21.9 ± 14.5 g vs. 13.3 ± 9.9 g, p<0.0001). At re-mapping, 26 pts (65%), including 6 pts (15%) with AF recurrence, had 52 gaps out of 318 SEGs (gap ratio 16%). CF was lower in the SEGs with gaps compared to no-gap SEGs (19.5 ± 14.4 g vs. 22.4 ± 14.8 g, p=0.04), but the strongest gap predictor was the minimum FTI applied at each SEG with 213 ± 325 gs for gap vs 434 ± 599 gs for no-gap SEGs (p<0.001). Likelihood for gap considerably increased with minimum FTI < 400 gs (21% vs 5%, p<0.001, Odd Ratio = 4.8) with a significant inverse relationship between minimum FTI and incidence of gaps (Figure).

Conclusions
Low minimum FTI, as an indicator of catheter stability, is a strong predictor of gap occurrence following previous PVI. This endpoint also correlates with low CF. Optimization of minimum FTI threshold will be determined in ongoing EFFICAS II study.
Abstract 18120: Variants of Toll Like Receptor 4 Have Prognostic Value in Patients with Dilated Cardiomyopathy
Authors: Riad Alexander , Meyer zu Schwabedissen Henriette , Weitmann Kerstin , Grube Markus , Dörr Marcus , Herda Lars R , Empen Klaus , Kieback Arne , Hummel Astrid , Kandolf Reinhard , Hoffmann Wolfgang , Kroemer Heyo K , Felix Stephan B
Published: April 2024

Background
- Dilated cardiomyopathy (DCM) may attend with innate immune activation, but its prognostic value is largely unknown. Since the innate immune Toll-like receptor 4 (TLR4) has been shown to be involved in atherosclerosis, we investigated the impact of coding polymorphisms of TLR4 on development and prognosis of DCM in patients.

Methods and results
- Two previously reported genetic variants of TLR4 (rs4986790, TLR4 c.1187A>G, p.299D>G and rs4986791,TLR4 c.1487C>T, p.T399I) were investigated. Coronary artery disease and other reasons for heart failure were excluded by angiography, myocardial biopsy, two dimensional echocardiography and spirometry. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, age, gender and treatment. Presence of the rs4986790 and/or the rs4986791 variant, respectively, was not associated with an increased incidence of DCM. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular (LV) ejection fraction (P=0.006) and LV dilation (P=0.015) at the follow-up evaluation when compared to carriers of the wildtype gene and isolated rs4986790 or rs4986791 variants, respectively (Figure 1). This was associated with significantly reduced levels of nt-pro brain natriuretic peptide (BNP) in patients carrying the TLR4 wildtype gene and isolated TLR4 variants at the follow-up when compared to the first admissions evaluation. Carriers of both variants did not show a significant decrease of nt-pro BNP.

Conclusion
- Among patients with DCM, the common presence of the TLR4 variants rs4986790 and rs4986791 predict worsened LV ejection fraction, LV dilation and nt-pro BNP levels at the course of time.
Abstract 18192: Free Radical Scavenger Edaravone Inhibited Both Aneurysmal Formation and Progression in Rat Abdominal Aortic Aneurysm Model
Authors: Morimoto Keisuke , Hasegawa Tomomi , Tanaka Akiko , Morimoto Naoto , Okita Yutaka , Okada Kenji
Published: April 2024

Objective:
Effective pharmaceutical treatment for abdominal aortic aneurysm (AAA) has not been established. Recent studies have reported that reactive oxygen species (ROS) are excessively expressed in the aneurysm wall. However, whether ROS play a crucial role in the aneurysm formation and its growth still remains unknown. We investigate ROS inhibition with the free radical scavenger edaravone effectively prevents aneurysm formation.

Methods:
Thirty male Sprague-Dawely rats were used to create experimental AAA model. Rats were divided into three groups; group C (control) received an intraperitoneal injection of saline at 30 minutes prior to the aneurysm preparation, group E (edaravone-early-treated) received an intraperitoneal injection of edaravone 5 mg/kg/day at 30 minutes prior to the aneurysm preparation, and the edaravone-late-treated group (group L) received the same dose of edaravone at 7 days after AAA preparation. At day 7, ROS production was semiquantified by dihydroethidium staining, and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining. The dilatation ratio of AAA at day 28 was calculated.

Results:
At day 7, dihydroethidium staining of aneurysm wall showed that ROS expression was significantly suppressed in group E compared with groups C and L (2.1±0.7 in group E, 4.3±1.8 in groups C and L, p=0.02). Positive cell count of 8-OHdG was significantly lower in group E than that in groups C and L. The aortic dilatation ratio (%) at day 28 in groups E was significantly lower than that in group C (36.7±2.0 vs. 104.7±16.0, p< 0.001) and in group L was significantly lower than that in group C (53.1±2.9 vs. 104.7±16.0, p< 0.001).

Conslusion:
ROS play a crucial role in the aneurysm formation. Edaravone treatment starting even at 7 days after aneurysm preparation completely inhibited aneurysmal growth. Edaravone could be effective pharmaceutical agent for AAA in clinical practice.
Abstract 18237: Inhibition of Adenylyl Cyclase Type 5 Protects Against Obesity and Diabetes
Authors: Ho David , Yan Lin , Zhao Xin , Gao Shumin , Iwatsubo Kousaku , Ishikawa Yoshihiro , Vatner Dorothy E , Vatner Stephen F
Published: April 2024

Adenylyl cyclase type 5 (AC5) is one of 9 major isoforms of AC. Mice with AC5 gene disruption (knockout, KO) live one third longer than wild type (WT) littermates. Like caloric restriction, the most commonly studied model of longevity, the AC5KO mice weigh 12% less than WT (p<0.05) and have less body fat, i.e., adiposity index, calculated by dividing the sum weights of the three major fat pads (inguinal, retroperitoneal, gonadal) by the body weight, was 50% lower than WT (p<0.05). The first goal of this study was to determine if AC5KO mice are protected, not only against obesity, but also diabetes. Insulin sensitivity, assessed by blood glucose measurement following insulin injection, was improved by 24% compared to WT. Glucose tolerance was also improved, p<0.05. A major limitation of studies in genetically altered mouse models, is that it is difficult to translate these results to the bedside, since it is not possible to knock out a gene in patients. Accordingly, we identified a pharmacological inhibitor of AC5, vidaribine, and examined the extent to which it ameliorated obesity and diabetes. First we demonstrated its selectivity for AC5; the inhibitor reduced inotropic responses to isoproterenol more than WT only in AC5 cardiac transgenic mice, but not in AC6 cardiac transgenic mice. To induce obesity, WT mice were fed a high fat diet feeding for 2 months, increasing body weight by 51% over mice fed a standard diet. WT mice with high fat diet and AC5 inhibitor on board for an additional 3 months, compared with WT mice on vehicle and high fat diet, increased body weight and adiposity index less, p<0.05, by 20% and 28%, respectively, while insulin resistance was reduced by 76% and glucose tolerance was improved by 66% (p<0.05). In AC5KO mice on the high fat diet insulin resistance was also reduced and glucose tolerance was also improved compared to WT on the high fat diet, similar to that observed with the AC5 inhibitor on the high fat diet. Thus, inhibition of AC5 provides a novel target for obesity and diabetes; the effective pharmacological inhibitor of AC5 enhances its clinical relevance.
Abstract 18248: Apolipoprotein E Gene Mutations in Subjects with Mixed Hyperlipoproteinemia and a Clinical Diagnosis of Familial Combined Hyperlipidemia
Authors: Solanas-Barca María , de Castro-Orós Isabel , Bea Ana M. , Cofán Montserrat , Plana Nuria , Ros Emilio , Masana Luis , Puzo José , Pocoví Miguel , Civeira Fernando , Cenarro Ana
Published: April 2024

Introduction
Familial combined hyperlipidemia (FCH) is characterized by elevated levels of total cholesterol (TC) and triglycerides (TG), vertical transmission of a variable hyperlipidemic phenotype, and high risk of premature cardiovascular disease. FCH is the most common cause of primary mixed hyperlipoproteinemia (MHLP). An
APOE
E2/E2 genotype in the presence of MHLP is diagnostic of familial dysbetalipoproteinemia. However, rare dominant mutations in
APOE
, which go undetected with the usual genotyping procedure, may also cause dysbetalipoproteinemia. Uncovering such rare
APOE
variants may change the diagnosis from FCH to dysbetalipoproteinemia.

Objectives
To identify
APOE
mutations associated with dominant MHLP and to establish their frequency in subjects with a clinical diagnosis of FCH.

Methods
We examined 472 unrelated subjects with dominant MHLP and a clinical diagnosis of FCH and 264 unrelated normolipidemic subjects (control group). Clinical and analytical determinations were done in all of them. Screening of
LDLR
and
APOB
gene mutations was performed with Lipochip, version 4 (Progenika, Derio, Spain). Entire
APOE
gene (4 exons and intron-flanking sequences) was sequenced.

Results
In the MHLP group, 10 subjects had the E2/E2 genotype, and then, were diagnosed as dysbetalipoproteinemia. Twenty three subjects were carriers of a functional mutation in the
LDLR
gene. In the left 439 subjects with MHLP, two rare functional
APOE
variants, R136S and DeltaL149, were identified. Nine subjects (2.0%) were carriers of the R136S mutation and 6 subjects (1.4%) were carriers of the DeltaL149 mutation. In the control group, no rare
APOE
mutation was identified. Subjects with R136S mutation had higher VLDL-cholesterol/TG ratio and lower apoB/TC ratio, similar to those of E2/E2 subjects, suggesting a diagnosis of dysbetalipoproteinemia. However, subjects carrying the DeltaL149 mutation did not show this pattern, being their VLDL-cholesterol/TG and apoB/TC ratios similar to those of E3/E3 subjects.

Conclusion
Rare mutations in the
APOE
gene, R136S and DeltaL149, were identified in subjects with mixed hyperlipoproteinemia and a clinical diagnosis of FCH, indicating that the
APOE
gene contributes to this phenotype.
Abstract 18296: A Murine Model of Diet-Induced Insulin Resistance and Cardiomyopathy
Authors: Sta. Teresa Antonio , Kim Jinkyu , Wietecha Tomasz , Hudkins-Loya Kelly , Alpers Charles E , O'Brien Kevin D
Published: April 2024

Background:
Diabetes is associated with a 2- to 3-fold ↑ in risk for congestive heart failure (CHF), due primarily to cardiac hypertrophy and fibrosis. We recently have shown that leptin-deficient, female BTBR mice (BTBR

ob/ob

) develop cardiomyopathy, with a 24-25% ↑ in heart weight and a 5-fold ↑ in fibrosis. We investigated whether the cardiomyopathy phenotype might be replicated with diet-induced obesity in wild-type, BTBR mice.

Methods:
At 4 weeks of age, male and female BTBR mice (n=7-8/group) were placed on one of three diets: 1) standard rodent chow (“Chow”), 2) a “diabetogenic” diet, with 58% of calories from fat and 14% of calories from sucrose (“DD”), or 3) the “diabetogenic” diet with 0.15% cholesterol added (“DDC”). Oral glucose tolerance tests were performed at 8 and 16 weeks on diets. Mice were sacrificed after 16 weeks on diets for determination of heart weights and fibrosis.

Results:
By 8 weeks on DD or DDC, both female and male BTBR mice had normal fasting glucose, but glucose tolerance (as judged by area under the glucose excursion curve) was significantly impaired vs. Chow-fed controls. Prior to sacrifice at 16 weeks, as compared to Chow, mice on DD or DDC had similar blood pressures and fasting glucose levels. However, necropsy heart weights were 17-18% higher (P<0.01 vs. Chow for both DD and DDC for both genders). In addition, Masson's trichrome stain demonstrated significant increases in fibrosis vs. Chow for BTBR mice fed either DD (P=0.015) or DDC (P=0.029).

Conclusions:
Thus, in both genders, 16 weeks feeding of high-fat, high-sucrose diets to wild-type BTBR mice results in a 2-fold ↑ in fibrosis, and achieves >60% of the cardiac hypertrophy seen in BTBR
ob/ob
females by age 16 weeks. These findings suggest that diabetogenic diet feeding in BTBR mice may represent an efficient model for studying the pathogenic mechanisms underlying cardiomyopathy in insulin resistance and diabetes.
Abstract 18314: Dysfunction of Junctional NCX Following JPH2 Knockdown Alters Spatial Properties of Ca
2+
Sparks and Contributes to Arrhythmogenesis in Mice
Authors: Wang Wei , Dixit Sayali , Wang Qiongling , van Oort Ralph J , Garbino Alejandro , Landstrom Andrew P , Ackerman Michael J , Wehrens Xander H
Published: April 2024

Background.
Na
+
/Ca
2+
exchanger (NCX) is essential in tuning intracellular Ca
2+
and the development of heart failure (HF). We reported that loss of Junctophilin 2 (JPH2) in adult mouse hearts leads to reduced NCX activity in addition to hyperactive RyR2s and more arrhythmogenic Ca
2+
waves. NCX has been found to co-localize with RyR2 recently. However, what is the physiological significance of junctional NCX and whether the reduced junctional NCX activity following JPH2 knockdown contributes to the arrhythmogenesis is still unknown.

Hypothesis.
Dysfunction of Junctional NCX in response to JPH2 knockdown alters spatial properties of Ca
2+
sparks and contributes to arrhythmogenesis.

Methods.
Tamoxifen-treated MCM and MCM-shJPH2 (KD) mice were studied. Contractile function was measured by echocardiography. Open probability of single RyR2 was evaluated by lipid bilayer. Ca
2+
spark were assessed with confocal microscopy. NCX activity was measured by exponential fitting of the declining phase of caffeine-induced Ca
2+
transient.

Results.
JPH2 knockdown increased spark size (MCM: 2.55 ± 0.14; KD: 4.25 ± 0.16, P < 0.001), suggesting an increased occurrence of proarrhythmic macrosparks. Cardiac Contractile function (EF% ) is negatively correlated with Ca
2+
spark size (n = 8, P < 0.05). Increased Open probability of RyR2 (MCM: 0.038 ± 0.018 KD: 0.274 ± 0.142, P < 0.01) is unlikely the reason for the ~70% increase in spark size, since it is not observed in 3 other mouse models with hyperactive RyR2s but normal JPH2 levels (RyR2:S2814D,
mdx
and FKBP12.6
-/-
). Loss of JPH2 also slows Ca
2+
efflux via NCX by ~50% (MCM: 2.70 ± 0.23 vs. KD: 5.11 ± 0.61 s, P < 0.01) without altering NCX expression level. Spark size and NCX activity are negatively correlated (n = 8 mice, P < 0.05), and partial inhibition (~30%) of NCX with 1 mM Cd
2+
significantly increased spark size by 14.0 ± 2.8% (n = 8, P <0.05) in wt mice.

Conclusion.
For the first time we showed that reduced NCX activity increases spatial properties of Ca
2+
sparks and thus arrhythmogenesis. Since reduced JPH2 is associated with HF and NCX plays more important role in human than in murine, reduced junctional NCX activity following loss of JPH2 could be a novel mechanism underlying the development of HF and associated ventricular arrhythmias.
Abstract 18331: Microvascular Thrombosis Increases Pro-inflammatory Gr-1(+) Cd11b(+) Myeloid Cells Activation and Promotes Endothelial Barrier Disruption
Authors: Zemskov Evgeny A , Zemskova Marina A , Gorshkov Boris A , Verin Alexander D , Sazonova Irina Y
Published: April 2024

Vascular thrombosis triggered by accumulation of fibrin results in regional ischemia and blood vessel pathology. Growing evidence demonstrates a strong correlation between thrombogenesis, cardiovascular thrombotic diseases and inflammation. However, the mechanisms that could explain this link are still warranted. Addressing this question, we studied the association between microvascular thrombosis, vascular integrity and pro-inflammatory CD11b+ cells response using plasminogen-deficient mice (Pg
-/-
; B6.129P2-Plg
tm1Jld
/J) whose fibrinolytic system is impaired in the microcirculation.

Methods:
Pg
-/-
mice (25±5 weeks old) were compared to heterozygote (Pg
+/-
) and wild type (Pg
+/+
) littermates. The total blood cell count, flow-cytometry analysis of leukocytes, and cytokine mRNA levels in lung tissue were assessed. The endothelial barrier permeability of lung microvasculature was also analyzed.

Results:
Adult Pg
-/-
mice developed systemic microvascular thrombosis affecting lung tissue as well. Pathological fibrin deposition in microcirculation induced significant increase in platelets (1.4-fold, p<0.001), monocytes (1.7-fold, p<0.01) and granulocytes (3.5-fold, p<0.001) levels in the blood compared to Pg
+/-
and Pg
+/+
controls. Moreover, pro-thrombotic Pg
-/-
mice had microcytic anemia due to low red blood cell volume (36.7 fl versus 41.6 fl, p<0.001) and reduced level of hemoglobin (12.4 g/dl versus 14.6 g/dl, p<0.001). Analysis of leukocytes obtained from the blood and lungs of Pg
-/-
mice showed the significant expansion of activated CD11b+ cell type. Further characterization of these CD11b+ cells by flow cytometry revealed a population with a phenotype of CD11b(+)Gr-1(+). The CD11b+ associated level of VCAM-1 was also significantly elevated (2.0-fold, p<0.05). Moreover, lung micro-thrombosis in Pg
-/-
mice was associated with increased endothelial permeability (1.3-fold, p<0.05) and up-regulation of TNF-α mRNA expression.

Conclusion:
In a mouse model, microvascular thrombosis promotes the increase of pro-inflammatory GR-1(+)CD11b(+) myeloid cells and endothelial barrier disruption. Our data suggest that Pg
-/-
mice may be an adequate model for further study of therapeutic approaches against vascular leakage.
Abstract 18396: Diffuse Myocardial Fibrosis Quantification by Cardiac MR is Strongly Associated with B-type Natriuretic Peptide (BNP) and Low Ejection Fraction: Implications for Paradigms of Myocardial Dysfunction
Authors: Schelbert Erik B , Ceyrolles William J , Testa Stephen M , Meier Christopher G , Ludwig Daniel R , Blair Alexander J , Kellman Peter , Schwartzman David , Shroff Sanjeev G , Wong Timothy C
Published: April 2024

Background:
While myocardial fibrosis has been proposed as the hallmark of pathologic remodeling, its role in myocardial dysfunction is not always recognized in paradigms of cardiac dysfunction. We hypothesized that myocardial fibrosis: 1) would correlate strongly to BNP, a nonspecific and quantitative metric of cardiac dysfunction and potent predictor of outcomes, even after adjustment for key metrics of cardiac changes; and 2) would be prevalent in the setting of cardiac dysfunction.

Methods and Results:
In 135 patients without myocardial infarction, amyloidosis or hypertrophic cardiomyopathy who were referred for contrast enhanced cardiac magnetic resonance, we quantified the extracellular volume fraction (Ve--a validated and quantitative metric of myocardial fibrosis):Ve = [λ · ρ · (1-hematocrit)] - Vpwhere ρ= specific density of myocardium (1.05), Vp is the myocardial plasma volume fraction (assumed to be a constant 4.5% reflecting capillary density), and λ=[ΔR1
myocardium
] / [ΔR1
bloodpool
] pre and post Gadolinium contrast (where R1=1/T1). T1 was measured with a modified ECG-gated Look-Locker IR-SSFP sequence validated against CuSO4 phantoms. BNP levels were log transformed given their skewed distribution. Elevated Ve was defined as >25%, (above the 99
th
percentile in healthy volunteers). In linear regression models, Ve strongly related to ln BNP (unadjusted t value 8.4, p<0.0001, R2=0.35) even after adjusting for ejection fraction (EF), age, sex, diuretic use, myocardial mass index, and body mass index (adjusted t value 4.4, p<0.0001, R2=0.65). Similar data were obtained when circumferential or meridional wall stress was substituted for EF (not shown). In the 40% of patients with EF<50%, 71% had elevated Ve (chi square 24, p<0.0001). In the 45% of patients with BNP>100 pg/mL, 75% had elevated Ve (chi square 24, p<0.0001).

Conclusions:
Myocardial fibrosis is strongly and independently associated with cardiac dysfunction quantified by BNP levels. Myocardial fibrosis is highly prevalent in those with cardiac dysfunction defined by EF<50% or BNP>100 pg/mL. These data suggest an important role of myocardial fibrosis in human myocardial dysfunction. Paradigms of cardiac dysfunction should include the role of myocardial fibrosis.
Abstract 18440: Hypertension Control in all Age Groups - a VA 10 Year Multicenter Analysis
Authors: Fletcher Ross D , Papademetriou Vasilios , Kheirbek Raya , Amdur Richard , Faselis Charles , Jones Ronald
Published: April 2024

Introduction:
While the benefits of blood pressure (BP) control are well known, BP control is rarely studied in large populations. Elderly patients have been considered difficult to control. We reviewed blood pressure control in a large cohort of VA patients.

Methods:
From September 2000 to August 2010, we assessed BP control in 582,851 hypertensive patients from 15 VA hospitals in various geographic locations around the United States. Patients were divided in 4 groups based on age: G1: <55 (N=176,604), G2: 55 - <70 (N=214,967), G3: 70 - <80 (N=139,103), G4: >80 (N=52,177). Medical interventions to control BP included use of electronic medical records with automated reminders, medical regimen adjustments, and frequent visits to both specialty and nurse run clinics.

Results:
Control rates (BP≤140/90) in FY00 were: 50.0% in G1, 45.5% in G2, 45.5% in G3 and 47.8% in G4. After 10 years of follow up, BP control improved to 73.6% in G1, 74.5% in G2, 75.1% in G3 and 73.2% in G4 (p<0.0001 for all groups compared to baseline). In all age groups, BP levels were lower during summer as compared to winter. Diastolic BP for patients over the age of 55 approached that of those < 55. Systolic and diastolic BP fell more rapidly in the first 6 years than the last 4 years. The stable diastolic BP achieved in the last 4 years permits BP control without deleterious low levels of diastolic BP in elderly patients.

Conclusions:
1) All age groups can be well controlled, with lower rates of control in average systolic and diastolic BP in the last 4 years. 2) Older patients > 70 yo respond well and achieve higher control rates without deleterious lowering of diastolic BP. 3) Seasonal BP variation is seen independent of age.
Abstract 185: Emergency Calls Made Away from the Out-of-Hospital Cardiac Arrest Scene Are Frequently Classified as an Uninformative “Hearsay Call” and Associated with Poor Outcomes
Authors: Tanaka Yoshio , Nishi Daiki , Takei Yutaka , Enami Miki , Ohta Keisuke , Inaba Hideo
Published: April 2024

Backgrounds and Aim
Emergency calls made away from the scene may affect the incidences of telephone-cardiopulmonary resuscitation (CPR) and bystander CPR, and hence may modify the prognosis of out-of -hospital cardiac arrests (OHCAs) recognized or witnessed by citizens. The aims of this study are to investigate the incidence and causes of emergency calls away from the scene and to study their effects on the prognosis of OHCAs.

Methods
Data from 4861 OHCAs that occurred from April, 2004 to March, 2010 in Ishikawa prefecture were prospectively collected and analyzed. The emergency calls made away from the scene were identified by dispatch records and interviews to callers and/or bystanders.

Results
The incidence of emergency calls made away from the scene was 15.2% (737/4861) for all OHCAs and 10.2% (328/3228) for OHCAs that occurred at home. More than half of emergency call away from the scene was preventable and classified as an uninformative “hearsay” call (52% for all OHCAs and 58% for OHCAs at home). The emergency calls away from the scene were associated with low incidences of telephone-CPR and bystander CPR, and 1-M and 1-Y survivals. Mutiple logistic regression analysis revealed that emergency call made awayfrom the scene is one of independent factors associated with poor outcomes.

Conclusions
Emergency calls made away from the OHCAs scene are frequently classified as an uninformative “hearsay call” and associated with poor outcomes due to low incidences of telephone-CPR and bystander CPR. We should make it known to laypersons in society that they should make an emergency call by themselves as close as to the scene where someone becomes unresponsive.
Abstract 197: The Calcium Sensitizer Levosimendan Improves Long-Term Neurological Outcome After Experimental Cardiac Arrest
Authors: Kelm Robert F , Stebner Sarah , Ullrich Andrea , Schmidtmann Irene , Werner Christian , Engelhard Kristin , Noppens Rüdiger R
Published: April 2024

Introduction:
Neurological disorder after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is common in human survivors. Impaired cerebral blood flow (CBF) and myocardial dysfunction after successful CPR possibly affect neurological outcome. Levosimendan (Orion Corporation, Finland) improves myocardial function and enhances CBF after experimental CA and CPR. The present study investigated the effect of levosimendan on mortality and neurological outcome 7 d after experimental CA and CPR in rats.

Methods:
After governmental animal care committee approval (Koblenz, Germany) 80 male Sprague-Dawley rats (330 - 390 g) were included. In 64 animals asphyxial CA and CPR was achieved, randomized to a group with levosimendan treatment (Levo, n = 32, bolus [12 µg/kg] and infusion for 3 h [0.3 µg/min/kg]), or normal saline treatment (Vehicle, n = 32, bolus and infusion for 3 h [equivalent fluid volume]). For technical control 16 animals received surgical intervention and treatment without CA and CPR (sLevo, n = 8; sVehicle, n = 8). After 9 min of asphyxia and CA, CPR was initiated and experimental treatment was started. Survival, neurological assessment (neuro-deficit-score, NDS) and motor function were evaluated over a 7-d-observation period. Histopathological neuronal injury was assessed using HE-staining (expressed as numbers of viable neurons in cortex and hippocampal formation).

Results:
Survival showed no differences between the CA-groups after 7 d (Levo vs. Vehicle: 25 vs. 28 animals, p = 0.5092). All animals survived in sham-groups. NDS (Group comparison Levo vs. Vehicle: p = 0.003; day 7 of observation period: 13.4 ± 0.6 vs. 14.2 ± 1.4 [mean ± SD]) and cortical neuronal injury (Levo vs. Vehicle: 401 ± 87 vs. 343 ± 57 viable neurons, p = 0.007) were reduced in the Levo-group compared to Vehicle-group. Improved motor function was detected in animals treated with levosimendan (Group comparison Levo vs. Vehicle: p = 0.0091).

Conclusion:
In this model of CA and CPR treatment with levosimendan reduced cortical neuronal injury and ameliorated neurological performance after 7 d of survival. Based on previously demonstrated findings, the improvement of myocardial function and cerebral blood flow during reperfusion by levosimendan may cause this result.
Abstract 199: Miniaturized Chest Compressor Improves Neurological Recovery in a Porcine Cardiac Arrest Model
Authors: Chen Wei , Weng Yinlun , Ye Sen , Wu Xiaobo , Sun Shijie , Weil Max H , Tang Wanchun
Published: April 2024

During cardiopulmonary resuscitation (CPR), blood flow generated by chest compression is the most important factor for successful resuscitation. In the present study, we investigated the effects of a newly developed miniaturized chest compressor (MCC) on carotid blood flow (CBF) and neurological alertness score (NAS) in a porcine model of cardiac arrest. We hypothesized that MCC would yield equal or better CBF and post resuscitation neurological function when compared to a conventional mechanical device (Thumper). Ventricular fibrillation (VF) was induced in domestic pigs weighing between 35 and 36 kg. CPR was initiated after 7 minutes of untreated VF. Animals were randomized to receive mechanical chest compression with either the MCC or Thumper. Both devices provided the same compression rate of 100/min. The initial compression depth was adjusted to achieve a coronary perfusion pressure (CPP) above 12 mm Hg. After 5 minutes of CPR, a single 150J defibrillation (DF) was delivered. If resuscitation was not successful, CPR was continued for 2 minutes before the next DF. The protocol was continued until successful resuscitation or for a total of 15 minutes. After resuscitation, the NAS was measured daily. All animals were resuscitated except 1 from the Thumper group. The CBF during CPR was significantly greater in the MCC group when compared to the Thumper group (Table). A significantly better NAS was observed after resuscitation in the MCC group (Table). MCC significantly increased CBF during CPR which was associated with a significantly improved postresuscitation neurological function.
Abstract 223: Impact of the Number of On-Scene Emergency Lifesaving Technicians and Outcomes from Out-of-Hospital Cardiac Arrests
Authors: Kajino Kentaro , Iwami Taku , Daya Mohamud , Kitamura Tetsuhisa , Nishiuchi Tatsuya , Hayashi Yasuyuki , Sakai Tomohiko , Shimazu Takeshi , Hiraide Atsushi , Kishi Masashi , Yamayoshi Shigeru
Published: April 2024

Introduction:
In Japan, ambulance staffing for cardiac arrest responses consists of a 3-person unit with at least one emergency life saving technician (ELST). ELST's are trained in advanced airway techniques and can administer epinephrine with medial control approval. Recently, the number of ELST's on ambulances has increased since it is believed that this staffing model improves the quality of on-scene care leading to improved patient outcome.

Purpose:
The aim of this study was to evaluate the relationship between the number of ELSTs on scene and outcomes from OHCA.

Materials and methods:
This was a prospective cohort study including all persons aged >=18 years suffering OHCA witnessed by bystanders in Osaka City, Japan from January 2005 through December 2007. All data were collected using an Utstein-style database. Odds ratio of the number of ELSTs on scene for neurologically favorable one-month survival (CPC ≤ 2) were calculated using multiple logistic regression adjusting for the following confounding variables; gender, age, bystander CPR, location, epinephrine, advanced airway, EMS scene time, etiology, and first rhythm.

Results:
Of the 2430 witnessed OHCA patients, one ELST group was present in 644, two ELST group were present in 1370, and three ELST group in 416.The proportion of neurologically favorable one month survival was 4.3% in the one ELST, 5.1% in the two ELST, and 7.7% in the three ELST group. Compared with the one ELST group, the three ELST group had a significantly greater odds ratio for CPC ≤ 2 after adjustment for confounding variables.

Conclusion:
Increasing number of ELSTs on scene was associated with improved outcomes from OHCA in Osaka.
Abstract 224: Effective Chest Compressions Are Related to Gender and Body Mass Index
Authors: Reddy Kruthika , Murray Bosseau , Rudy Sally , Moyer John , Sinz Elizabeth
Published: April 2024

Introduction:
The outcome after cardiopulmonary resuscitation (CPR) depends on effective chest compressions. This prospective, single-center study examined the relationship between a provider's gender and body mass index (BMI) to chest compression depth and rate during CPR.

Method:
After informed consent, 84 medical students were tested for a continuous period of 2 minutes on a simulator (Laerdal Advanced Resusci Annie with PC Skills Reporter) that automatically measured depth and rate of chest compressions. Data collected included average rate and depth and the rate and depth for the first and last 30 seconds of 2 minutes of CPR. Statistical analysis was performed using a Two-Sample T-test, Wilcoxon Mann-Whitney test, Pearson and Spearman correlations. Adequate depth (38-51 mm) and rate (90-110 compressions/minute) were based on 2005 AHA guidelines.

Results:
During the first 30 seconds of CPR, males were more effective than females in administering sufficient compression depth (p=0.0006); a positive correlation was found between compression depth and height (p=0.0203), weight (p=0.0002) and BMI (p value < 0.0001). Similar positive correlations were also found between average adequate depth of chest compressions with BMI (p=0.0039) and weight (p=0.0176). During the last 30 seconds of CPR there was a positive correlation between compression depth and BMI (p=0.0256); however males were 3.58 times more likely than females to continue administering chest compressions for the full 2 minutes and those who completed had a higher median BMI, height and weight. All providers achieved an adequate compression rate.

Conclusion:
BMI and gender have a significant effect on initial chest compression depth and on the duration of continued CPR, but not on compression rate. Smaller people may have a more difficult time achieving adequate depth of compressions during CPR and may require more frequent rotations to maintain good cardiac output. The new AHA Guidelines may exaggerate this difference due to deeper compression recommendations. Further studies are needed to determine the effect on different patient or provider sizes.
Abstract 227: The Effects of Obligatory Training on Attitudes Toward Performing Basic Life Support with Reference to Prior Training Experience
Authors: Enami Miki , Takei Yutaka , Tanaka Yoshio , Nishi Daiki , Takase Keiko , Inaba Hideo
Published: April 2024

Backgrounds and aim
The effects of BLS training on willingness to perform practicable actions in basic life support (BLS) have not been well studied. This study is conducted to determine the effects of an obligatory BLS training on attitude of the participants towards performing basic life support (BLS).

Methods
We gave a questionnaire to attendants of the courses for BLS in authorised driving schools. The questionnaire included questions about participants' backgrounds. The questionnaire explored the participant's willingness to perform BLS in four hypothetical scenarios related to early emergency call, CPR on their own initiative, telephone-assisted chest compressions and use of AED, respectively. The questionnaire survey was conducted in the two terms after revision of Japanese guidelines. The questionnaire was given at the beginning in the first term and at the end of course in the second term.

Results
(see Table) The BLS training augmented the proportions of willingness to use an AED and to perform favorable actions in all scenarios in all attendants with and without prior training, and the proportion to perform the CPR on their own initiative only in attendants without prior training. However, the training failed to increase the proportion of respondents willing to follow telephone-assisted instruction of chest compressions in all respondents with and without prior training. These observations were confirmed by multiple logistic regression analysis including backgrounds of attendants. Analysis of reasons for unwillingness and the actions that negative respondents answered to take suggested that obligatory training increases the confidence of their skill but augments a fear of misjudgment and reliance on other's judgment.

Conclusions
Obligatory BLS trainings and prior training experiences differently affect the attitude towards BLS. The training should be modified for attendants to gain the confidence of judgment in practical situations.