bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 92: Dispatcher Instruction in Chest Compression-Only CPR Increases Implementation of Bystander CPR: The Utstein Osaka Project
Authors: Sakai Tomohiko , Iwami Taku , Kitamura Tetsuhisa , Hayashi Yasuyuki , Nishiuchi Tatsuya , Kajino Kentaro , Nishiyama Chika , Hiraide Atsushi , Tasaki Osamu , Kuwagata Yasuyuki , Shimazu Takeshi , Kawamura Takashi , Matsushima Asako , Ueyama Masashi
Published: April 2024

Background:
Although it has been reported that dispatcher-assisted bystander CPR contributes to increasing survival from out-of-hospital cardiac arrest (OHCA), the association between actual implementation of CPR by bystanders and the type of dispatcher instruction has not been sufficiently examined.

Objectives:
To investigate the association between the implementation of bystander CPR and type of dispatcher instruction (chest compression-only CPR (CC-only) or conventional CPR with chest compressions plus rescue breathing).

Methods:
We registered all patients aged >=18 years suffering from OHCA of presumed cardiac origin before emergency medical service (EMS) arrival, and for whom resuscitation was attempted resuscitation by EMS personnel in Osaka Prefecture, Japan from January 2005 to December 2009. Data were prospectively collected by EMS personnel using an Utstein-style database. Odds ratios for implementation of CPR of each type of dispatcher instruction were calculated using multiple logistic regression adjusting for confounding variables.

Results:
During the study period, 17,792 OHCAs of cardiac origin before EMS arrival were registered. In 7953 (44.7%) of them, the dispatcher provided CPR instruction to bystanders, and the proportion increased from 39.7% to 48.1% during the study period (P for trend=0.037). The proportion of CC-only instruction increased from 5.1% to 12.9% (P for trend=0.005). The proportion of CPR with chest compressions by bystanders was significantly higher in the CC-only CPR instruction group than in the conventional CPR instruction group (70.2% [1146/1632] vs. 62.0% [3924/6321]; adjusted odd ratio, 1.54 [95% confidence interval, 1.36-1.73]). Even if the dispatcher instructed conventional CPR with rescue breathing, only 33.0% of bystanders performed rescue breathing with chest compressions.

Conclusion:
Dispatcher instruction of chest compression-only CPR is effective to increase actual CPR by bystanders.
Abstract 9266: Heart Failure, Atrial Fibrillation and Neuromuscular Disorders Determine Mortality in Left Ventricular Noncompaction
Authors: Stoellberger Claudia , Blazek Gerhard , Wegner Christian , Finsterer Josef
Published: April 2024

Objectives and Background:
The long-term prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) is assessed controversially. Aim of the study was to assess parameters influencing mortality and to compare the mortality of LVHT-patients with that of the Austrian general population.

Methods:
Included were all patients in whom LVHT was diagnosed in the echocardiographic laboratory of the KA Rudolfstiftung between June 1995 and February 2011. They underwent a baseline cardiologic examination and were invited for a neurological investigation. Between January and February 2011, the patients were contacted by telephone and assessed if the patient was alive or not.

Results:
LVHT was diagnosed in 162 patients (46 female, mean age 53±16 years) with a prevalence of 0.31%/year. Hundred-sixteen patients (72%) underwent a neurological investigation which revealed specific neuromuscular disorders (NMD) in 25, a NMD of unknown etiology in 74, and was normal in 17 patients. During a mean follow-up of 67 months, the mortality was 4.8%/years and the standardized mortality ratio 6.27 compared with the general Austrian population. By multivariate analysis, significant predictors for mortality were heart failure (Hazard-ratios 3.91, 4.48 and 5.37 for NYHA II, III and IV), atrial fibrillation (Hazard-ratios 3.26) and presence of NMD, either specific or of unknown etiology (Hazard-ratio 1.86).

Conclusion:
Prognostic predictors in LVHT are heart failure, atrial fibrillation and NMD, which stresses the need for a neurologic investigation. Heart failure and atrial fibrillation should be treated consequently in LVHT.
Abstract 9270: Left Ventricular Diastolic Dysfunction is Associated with Increased Vascular Resistance and Reduced VO2max in Patients Awaiting Kidney Transplantation
Authors: Ting Stephen M , Koganti Sudheer , Higgins Robert , Imray Christopher , Aldridge Nicolas , Bland Rosemary , Zehnder Daniel , Banerjee Prithwish
Published: April 2024

Hypothesis:
Chronic heart failure (CHF) is a major contributor to high mortality in chronic kidney disease (CKD) patients. We hypothesize that LV diastolic stiffness, in part caused by loss of large artery elasticity in CKD, promotes reduction in cardiovascular reserve.

Methods:
68 CKD patients (age, 46 ± 13 years; male, 61%) waitlisted for kidney transplantation were prospectively recruited in 2010. TD echocardiography, arterial pulse wave velocity (PWV) and symptom-limited cardiopulmonary exercise testing were performed to determine the relationship between LV diastolic function, arterial stiffness and cardiovascular reserve. Patients were evaluated and categorised into quartile groups according to the level of maximal exercise oxygen capacity (VO2max).

Results:
Reduced VO2max was significantly associated with higher E/E∋ (p= 0.002). E/E∋ was calculated using the averaged of septal and lateral mitral annular lengthening velocities. A high E/E∋ was also associated with a worse anaerobic threshold (AT) (p<0.001). These patients (with low VO2max and high E/E∋) also demonstrated a significantly greater aortic stiffness (p= 0.026). VO2max was inversely correlated with both E/E∋ (r= -0.413, p= 0.001) and PWV (r= -0.355, p= 0.003). Distribution of gender and history of coronary artery disease were no different between the groups.

Conclusions:
Evidence for diastolic dysfunction with increased LV filling pressure and diastolic stiffness by the measure of E/E∋ was strongly associated with poor functional cardiovascular reserve. The importance of ventriculo-arterial coupling in the complex mechanism of CKD mediated CHF is evidenced by the significant association between high E/E∋ and increased aortic stiffness.
Abstract 9302: Electrocardiographic Criteria for ST-Elevation Myocardial Infarction in Patients with Left Ventricular Hypertrophy
Authors: Armstrong Ehrin J , Bhave Prashant D , Hoffmayer Kurt S , Ganz Peter , McCabe James M
Published: April 2024

Background:
Patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) have ST segment repolarization abnormalities that are difficult to differentiate from an ischemic current of injury. ACC/AHA criteria diagnose ST-elevation myocardial infarction (STEMI) as ≥ 1 mm STE in two contiguous leads, and 2 mm if the STE are isolated to leads V1-V3.Additional criteria are much needed to correctly diagnose STEMI in patients with LVH.

Methods:
We analyzed the ACTIVATE-SF database, a registry of consecutive Emergency Department STEMI diagnoses from 2 medical centers at UC San Francisco. Logistic regression was performed to identify ECG variables that predicted presence of an angiographic culprit lesion.

Results:
We identified 79 patients with electrocardiographic LVH who underwent cardiac catheterization for consideration of primary angioplasty. Just 22 (28%) patients were found to have an angiographic culprit lesion. Patients with a culprit lesion had greater magnitude of ST elevation (3.0 ± 1.8 vs. 1.9 ± 1.0 mm, p = 0.005), more leads with ST elevation (3.1 ± 1.6 vs. 2.0 ± 1.8 leads, p = 0.002), and a greater ratio of ST segment elevation to R wave height (median 25% vs. 9.2%, p = 0.003). Among these univariate factors, adding the median ratio of ST segment to R wave height >25% to the ACC/AHA criteria significantly improved overall diagnostic discrimination: c-statistic 0.65 vs. 0.74, specificity 58 vs. 93%, sensitivity 64 vs. 73%, positive predictive value 40 vs. 78%, and negative predictive value 85 vs. 87%.

Conclusion:
Most patients with chest pain, electrocardiographic LVH and diagnostic ST segment elevation by ACC/AHA criteria have no culprit lesion at angiography. A ratio of the ST segment to R wave magnitude > 25% increases specificity for diagnosis of STEMI without reducing sensitivity. This additional ECG criterion should appreciably improve STEMI diagnosis in LVH and lead to a more appropriate utilization of cardiac catheterization procedures.
Abstract 9316: Serial Changes of Neointimal Coverage Condition and Characteristic are Different between Sirolimus-Eluting Stents, Paclitaxel-Eluting Stents and Zotalolimus-Eluting Stents Implantation: Follow-Up Optical Coherence Tomography Study
Authors: Nakamura Daisuke , Nishino Masami , Lee Yasuharu , Yoshimura Takahiro , Taniike Masayuki , Makino Nobuhiko , Kato Hiroyasu , Egami Yasuyuki , Shutta Ryu , Tanouchi Jun , Yamada Yoshio
Published: April 2024

Background:
The long-term detailed changes of neointima coverage in Sirolimus-eluting stent(SES), Paclitaxel-eluting stent(PES) and Zotalolimus-eluting stent( ZES) remains to be clarified.

Methods:
Of 20 SES (14 patients),13 PES (12 patients) and 9 ZES(7patients)Optical Coherence Tomography( OCT) was used to visualize 2486, 1361 and 1018 stent-struts at 8 months and 2199, 1309 and 1001 stent-struts at 20 months after respectively. The OCT parameters, including incidence of uncovered struts and malapposed struts and averaged neiointimal hyperplasia thickness (NIH) and NIH% = NIH area / stent area, were compared between 8 months and 20 months follow-up. The neointimal charecteristics were classified into 3 groups: homogenous without PLIA(high density neointima without peri-strut low-intensity area(PLIA);homogenous with PLIA (high density neointima with PLIA);heterogenous (low density neointima and layered neointima) .PLIA was defined as a region around stent struts with a homogeneous,lower intensity appearance than the surrounding tissue on OCT images without significant signal attenuation.

Results:
Serial OCT study revealed that the prevalence of uncovered struts decreased in SES, PES and ZES and the prevalence of malapposed struts did not change in SES, PES and ZES. Average NIH and NIH% significantly increased in SES, but average NIH and NIH% significantly decreased in PES and did not change in ZES from 8 months to 20 months. Homogenous without PLIA was most frequent in ZES. It was not different between SES and PES. Homogenous without PLIA increased from 8month to 20month after in PES and ZES,but in SES decreased. Homogenous with PLIA(It suggesting the presence of fibrinoid, proteoglycans, macrophages and lymphocytes pathologically) increased in SES.

Conclusions:
Uncovered struts gradually alleviated in SES,PES and ZES while neointimal hyperplasia condition showed different patters. Neointimal characteristics showed different patterns too.
Abstract 9321: Left Ventricular Dyssynchrony as a Determinant of Torsional Mechanics in Patients with Dilated Cardiomyopathy
Authors: Matsumoto Kensuke , Tanaka Hidekazu , Miyoshi Tatsuya , Hiraishi Mana , Kaneko Akihiro , Tsuji Takayuki , Ryo Keiko , Fukuda Yuko , Tatsumi Kazuhiro , Kawai Hiroya , Hirata Ken-ichi
Published: April 2024

Background:
Although left ventricular (LV) torsion is mainly determined by LV contraction, the impact of dyssynchrony on LV torsional behavior is not fully investigated. Since LV function in reality is a three-dimensional (3-D) phenomenon, 3-D echo methods appear to be advantageous to assess LV torsion. We therefore used 3-D speckle-tracking echocardiography to assess the impact of LV dyssynchrony on LV torsional mechanics in patients with dilated cardiomyopathy (DCM).

Methods:
This study included 65 subjects; 20 DCM with ejection fraction (EF) ≤35% and wide QRS (≥120ms), 20 DCM with EF≤35% and narrow QRS (<120ms), and 25 normal controls. LV torsion was quantified by means of 3-D speckle-tracking echocardiography. LV dyssynchrony was determined as the standard deviation of time-to-peak radial strain from 16 LV segments (dyssynchrony index). Similarly, regional heterogeneity of LV rotation was quantified as the standard deviation of time-to-peak rotation from 16 LV segments (rotational disparity index).

Results:
LV torsion in DCM with wide QRS was significantly smaller than that in DCM with narrow QRS and normals (0.41±0.25*† vs. 0.85±0.39* vs. 2.51±0.70 degrees/cm, *p<0.01 vs. normals, †p<0.01 vs. narrow QRS DCM). LV dyssynchrony and rotational disparity index in DCM with wide QRS were significantly larger than those in DCM with narrow QRS and normals (dyssynchrony index; 127.3±24.0*† vs. 88.8±22.5* vs. 30.9±10.0 ms, rotational disparity index; 115.1±27.5*† vs. 96.0±23.4* vs. 45.0±13.7 ms, *p<0.01 vs. normals, †p<0.01 vs. narrow QRS DCM). Furthermore, multivariable analysis revealed that the EF (β=-0.038, p<0.001) and rotational disparity index (β=-0.007, p<0.01) were independent determinants of LV torsion.

Conclusions:
LV dyssynchrony negatively affects the LV torsional mechanics in DCM patients. This approach may play a clinical role in management of such patients.
Abstract 9358: Time-Course of Left Ventricular Geometry in Arterial Hypertension: The Strong Heart Study
Authors: De Simone Giovanni , De Marco Marina , Roman Mary J , Lee Elisa T , Howard Barbara V , Devereux Richard B
Published: April 2024

Background:
The natural history of hypertensive heart disease is postulated to evolve from concentric LV geometry (LVG) to eccentric and eventually dilated LVG. However, there is no evidence of this evolution, likely due to effect of antihypertensive therapy, and there is no information on whether changes of LVG can be predictable.

Methods:
We examined echocardiograms in 850 hypertensive participants of the 4th phase of the Strong Heart Study (SHS) cohort (50±14 yrs, 486 women), who repeated echo exam after 4 years. LVG was assessed by relative wall thickness.

Results:
LVG remained normal (NN) in 55% of men (M) and 45% of women (W), remained concentric (CC) in 19% M and 30% W, changed from concentric to normal (CN) in 22% M and 19% W, and from normal to concentric (NC) in 4% M and 6% W (p<0.001). Between exams, acute myocardial infarction occurred in 4 participants (0.5%). Participants with concentric LVG at the second exam (NC and CC) were older than the other groups (p<0.001). At the time of initial exam, systolic blood pressure (BP) was slightly higher in participants developing concentric LVG (NC p=0.056), whereas diastolic BP and GFR were lower in those with persistent concentric LVG than in the other groups (both p<0.001). Initial LV mass was higher and ejection fraction (EF) lower in CN and CC than in NN (p<0.0001). Compared to NN, systolic BP increased over time in participants with concentric LVG at the second exam (NC and CC; both p<0.03). On average, EF decreased over time, with the greatest decrease in participants changing LVG from concentric to normal and the minimum decrease in those developing concentric LVG (all p<0.001). No effect of body size, fat distribution and prescription of classes of antihypertensive meds and statins could be detected, but the number of antihypertensive meds used at the time of the initial exam was significantly higher with persistent concentric LVG and lower with evolution from concentric to normal LVG (p<0.001).

Conclusions:
Changes in LV geometry in treated SHS hypertensive participants are not related to type of antihypertensive meds. Persistent concentric LV geometry is related to older age, and increasing systolic BP over time despite greater intensity of anti-hypertensive therapy.
Abstract 9365: Left Ventricular Dysfunction and Cardiac Hypertrophy in Kit Mutant Mice During Aging
Authors: Ye Lei , Zhang Eric Y , Xiong Qiang , Astle Mike , Zhang Pengyuan , Harrison David E , Zhang Jianyi J
Published: April 2024

Aim:
Cardiac progenitor cells marked with c-Kit play an important role in maintaining normal cardiac function. This study aims at comparing effects of Kit mutants, including W/Wv, W41/W41, and W41/W42, on myocardial c-kit + cells profile and their association with left ventricular contractile function , hypertrophy during normal aging.

Methods:
LV function of W/Wv, W41/W41 and W41/W42 mice at age of 4 months and 12 months were determined by echocardiogram using age matched wide type (WT) mice as normal controls. Bone marrow (BM) from normal donor of green fluorescent protein (GFP) marked mice, was transplanted into Kit mutant mice after irradiation to determine whether normal BM repopulation could rescue the LV dysfunction by the regeneration of myocytes from BM cells, or by promote migration of endogenous c-Kit
+
progenitor cells into heart of Kit mutant mice. In addition, cardiac hypertrophy was determined and myocardial c-Kit
+
cells in myocardium were quantified.

Results:
Young mice with the Kit mutations showed no defects in LV functional studies in regard of LV ejection fraction (EF) and fractional shortening (FS). However EF and FS were significantly decreased in 12 months aged W41/W42 mice compared with the other three groups. Cardiac hypertrophy, indexed by heart weight/body weight was also significantly increased in W41/W42 mice compared with WT, W/Wv and W41/W41 at 12 months of age. Numbers of myocardial c-Kit
+
cells were significantly reduced in all three Kit mutant mice hearts compared with WT. BM transplantation did not increase c-Kit
+
progenitor cells into Kit mutated mice heart and also did not rescue decreased EF and FS of aged W41/W42 mutated mice.

Conclusions:
The W41/W42 mutants show decreased LV function during normal aging that is accompanied by a significant reduction of myocardial c-Kit+ cell count. Repopulation with normal BM does not increase c-Kit
+
progenitor cells in heart nor prevent reduction of LV function in aged W41/W42 mice. These data demonstrate that heart is not a post mitotic organ, and a normal myocytes turnover rate and normal LV function are supported by a pool of resident KIT+ progenitor during aging.
Abstract 9376: Cardiac-Specific Very Long Chain Acyl-CoA Dehydrogenase Deficiency Induces Dilated Cardiomyopathy and Cold Intolerance in Mice
Authors: Xiong Dingding , Khuchua Zaza , Tokunaga Chonan , Rafferty Kathryn , Martherus Sarkies Ruben Mattheus , Huby Anne-Cecile , Osinska Hanna , Purevjav Enkhsaikhan , James Jeanne , Towbin Jeffrey , Strauss Arnold
Published: April 2024

BACKGROUND:
Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of fatty acids with chain lengths of 14 to 20 carbons. Patients with VLCAD deficiency present with hypoketotic hypoglycemia, cardiomyopathy and sudden death that can be exacerbated by the stresses of fasting and cold. Global VLCAD knockout (KO) mice recapitulate these phenotypes. However, the contribution of cardiac VLCAD in the development of cardiomyopathy and the response to the environmental stressors is unclear. In this study, we assessed the hypothesis that cardiac-specific VLCAD deficiency is sufficient to induce cardiomyopathy and cold intolerance.

METHODS AND RESULTS:
A cardiac-specific homozygous VLCAD KO (csVLCAD KO) mouse was generated by crossing a VLCAD floxed-allele mouse with a transgenic mouse expressing Cre recombinase under the control of the α-myosin heavy chain promoter. Echocardiographic analysis at 6 months of age demonstrated left ventricular dilation and decreased fractional shortening (FS) in csVLCAD KO mice (for FS, 21±1%
vs
29±4% in wild-type mice, p<0.05). Ultrastructural analysis of ventricular myocardium showed widening of the sarcomeric I band, increased sarcomere length and substantial lipid deposits in csVLCAD KO mice. To test if cardiac VLCAD deficiency leads to susceptibility to death caused by cold stress, csVLCAD-KO mice and controls were placed at 4°C. All csVLCAD-KO mice (n=9) became moribund within 4-10 hours, whereas only 1/9 hemizygous and 1/9 wild-type mice died. Unlike global VLCAD KO mice, csVLCAD KO mice did not develop hypoglycemia. To determine if VLCAD deficiency alters mitochondrial fatty acid oxidation in cardiomyocytes, oxygen consumption rates in response to palmitate and glutamate administration were measured. The results indicated that while mitochondrial function was largely preserved, the fatty acid oxidation rate was markedly reduced in csVLCAD-KO mice, measuring 10-15% of WT.

CONCLUSIONS:
Cardiac-specific VLCAD deficiency is sufficient to induce ventricular dilation and cardiac dysfunction as well as cold intolerance, which may be related to reduced fatty acid oxidation and increased lipid deposition in cardiomyocytes.
Abstract 9402: Diffuse Myocardial Fibrosis Negatively Correlates with Exercise Capacity in Children with Subclinical Anthracycline Cardiotoxicity
Authors: Tham Edythe B , Haykowsky Mark J , Chow Kelvin , Kaneko Sachie , Spavor Maria , Khoo Nee S , Pagano Joseph J , Mackie Andrew S , Thompson Richard B
Published: April 2024

Background
The effectiveness of anthracycline chemotherapy in improving survival is limited by late cardiotoxicity. The aim of this study was to examine novel cardiac MRI and echocardiography measures to detect subclinical cardiotoxicity in childhood cancer survivors, and to determine its relationship to exercise capacity.

Methods
Thirty patients (15±3years, 50% male), 8±5 years after anthracycline therapy (cumulative dose 197±84 mg/m
2
), underwent cardiac MRI, echocardiography and cardiopulmonary (cycle ergometer) exercise testing (VO
2peak
). Cardiac MRI assessed volumetric function, mass, and myocardial extra-cellular volume (ECV), a measure of diffuse fibrosis based on changes in blood and myocardial T1 values pre and post gadolinium. Tissue Doppler annular velocities (E’, A’) and peak circumferential and longitudinal strain, strain rate (SR) and torsion, from speckle tracking, were compared to 35 healthy controls (13±4 years). Data (mean ± SD) was analysed using Pearson's product-moment coefficient and unpaired t-tests (p<0.05).

Results
Patients were asymptomatic with normal LVEF (59±7%) but VO
2peak
was 15% lower than age and gender determined healthy predicted values. Myocardial ECV was inversely correlated with mass/volume ratio (r = -0.5, p<0.01), and VO
2peak
(r = -0.5, p<0.01), and lower VO
2peak
correlated with increased cumulative dose (r = 0.4, p<0.05). Echocardiographic measures of systolic function were significantly reduced compared to controls (decreased circumferential and longitudinal strain, longitudinal SR and torsion, p<0.01). Diastolic dysfunction was evident with decreased circumferential and longitudinal diastolic SR and decreased annular velocities (p<0.01) relative to controls. There was no correlation between echocardiographic parameters and ECV or VO
2peak
.

Conclusion
Diffuse myocardial fibrosis (increased ECV) is correlated with reduced mass/volume ratios and VO
2peak
in children post anthracyline. While there were abnormalities of systolic and diastolic function, these metrics did not correlate with ECV or VO
2peak
. Myocardial ECV provides a non-invasive early marker of ventricular remodelling that is related to exercise capacity which may be of prognostic value in childhood cancer survivors.
Abstract 9411: Deterioration of Myocardial Infarction in Mice Infected with Periodontal Pathogens, Aggregatibacter Actinomycetemcomitans
Authors: Hanatani Tomoya , Suzuki Jun-Ichi , Ogawa Masahito , Aoyama Norio , Izumi Yuichi , Hirata Yasunobu , Nagai Ryozo , Isobe Mitsuaki
Published: April 2024

Introduction
Chronic inflammation plays a fundamental role in coronary heart disease (CHD). Periodontal disease is a common infectious disease among adults and is a potential source of systemic inflammation. However, the effect of periodontal infection on CHD has not been proven.

Hypothesis
We assessed the hypothesis that periodontopathic bacteria influence myocardial infarction (MI).

Methods
We surgically implanted a chamber into the subcutaneous tissue of each male mouse. Two weeks after the chamber implantation, Aggregatibacter actinomycetemcomitans (A.a., n = 8), which is a major periodontal bacteria, or PBS (n = 6) was injected into the chamber once a week. One week later, MI was induced by permanent ligation of the left anterior descending coronary artery. Seven days after the operation, the ischemic hearts and blood samples were obtained.

Results
The plasma level of anti-A.a. antibody was statistically higher in the A.a.-infected mice than in the vehicle control mice (100.3 ± 20.3-fold vs. control, p < 0.05). Seven days after the experimental ischemia, infarction area of the infected mice by A.a. was significantly larger compared to that in the control mice (p < 0.05). The infarction area/ischemic myocardium ratio was 0.37 ± 0.04 in the A.a.-infected mice, while the infarction area/ischemic myocardium ratio of the control mice was 0.20 ± 0.06.

Conclusions
The experimental infection of periodontal bacteria could deteriorate left ventricular remodeling after MI.
Abstract 9436: Sitagliptin Reduces Plaque Macrophage Content and Stabilizes Arteriosclerotic Lesions in Apoe-Deficient Mice
Authors: Burgmaier Mathias , Liberman Ana , Vasic Dusica , Ostertag Rahel , Esser Melanie , Walcher Daniel , Ludwig Andreas , Marx Nikolaus , Vittone Francesca
Published: April 2024

Objective:
Glucagon-like peptide-1(7-36) (GLP-1) based therapies are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes are at a high risk to develop a severe atherosclerosis, we investigated the effect of GLP-1 on chemokine-induced migration of human monocytes and macrophage MMP-9 expression, both crucial steps in atherogenesis and plaque destabilisation. Furthermore, we explored the translation of these effects to plaque inflammation and plaque stability in ApoE
-/-
mice treated with the DPP-IV inhibitor sitagliptin, which increases plasma levels of active GLP-1.

Methods and Results:
In the modified Boyden-chamber, pretreatment with GLP-1 reduced the MCP-1 induced migration of isolated human monocytes in a concentration dependent manner from a 3.3±0.8 to a 1.4±0.5 fold induction at 10 nM GLP-1 (n = 8, p < 0.05), which was associated with a decreased MLC-phosphorylation in these cells. Similar effects were seen when RANTES was used as a chemokine to induce cell migration. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages as determined by zymography.
In vivo
, treatment of ApoE
-/-
mice with the DPP-IV inhibitor sitagliptin, which increases plasma levels of active GLP-1, resulted in a 75% reduction of macrophage infiltration, a 75% reduction in plaque MMP-9 expression and a more than 3-fold increase in plaque collagen content compared to controls as shown by MAC3, Picrosirus Red and immunohistologic staining, respectively (n=6-8, p < 0.05).

Conclusion:
Thus, GLP-1 reduces plaque inflammation and increases plaque stability potentially by inhibiting chemokine-induced migration of monocytes and by inhibition of macrophage MMP-9 expression. The effects observed may provide a potential mechanism of how GLP-1 based therapies may modulate vascular disease in high-risk patients with type 2 diabetes mellitus.
Abstract 9547: Tissue Doppler and Strain Imaging Can Facilitate Weaning Decisions in Patients with Evidence of Cardiac Recovery Suring Mechanical Ventricular Support
Authors: Dandel Michael , Krabatsch Thomas , Potapov Evgenij , Stepanenko Alexander , Weng Yuguo , Knosalla Christoph , Lehmkuhl Hans B , Hetzer Roland
Published: April 2024

Background:
Echocardiographic monitoring of cardiac size and function during “off-pump” trials is the cornerstone for detection of cardiac recovery during mechanical unloading. Parameters such as left ventricular (LV) diameters and LVEF are helpful to predict the outcome after possible LV assist device (LVAD) removal. However, high inter-observer variability and load dependency of EF measurements are important limitations. Because velocity parameters measurable by tissue Doppler and strain imaging are more reliable for estimation of LV function, we assessed their usefulness for evaluation of recovery.

Methods:
Pulsed-wave tissue Doppler (PW-TD) measurements of systolic wall motion peak velocities (Sm) at the basal posterior wall were performed since 1999 during all “off-pump” trials before LVAD removal and at all follow-up controls of post-weaning cardiac function. Since 2005, 2D strain and strain rate (SR) measurements (radial, circumferential and longitudinal) were also performed before and after LVAD removal. The prospectively collected PW-TD and 2D strain data were evaluated for their usefulness to predict weaning successes.

Results:
Heart failure (HF) recurrence after LVAD removal occurred in 10 (31.3%) of 32 patients who underwent PW-TD. Longitudinal and radial Sm was lower in these 10 patients than in those with post-weaning cardiac stability (p < 0.01) Stable patients showed Sm > 8 cm/s. Off-pump Sm ≥ 8cm/s showed predictive values between 87 and 90% for 5 year post-weaning stability. Strain and SR measured in 23 patients revealed higher systolic values in patients with post-weaning stability (p < 0.01). In stable patients global systolic strain and SR values were: ≥ 30% and ≥ 0.9/s for radial thickening, ≥ 15% and ≥ 0.8/s for circumferential shortening, ≥ 12% and ≥ 0.65/s for longitudinal shortening, respectively. Sm, strain and SR instability before and early after LVAD removal appeared predictive for post-weaning recurrence of HF.

Conclusion:
PW-TD and 2D-strain imaging allow distinction between patients with and without the potential to maintain cardiac stability after LVAD removal and can therefore be useful for evaluation of unloading-induced cardiac recovery and also for prognostic assessments before and early after LVAD removal.
Abstract 9559: The Role of Myopalladin in the Interactions of ANKRD1/CARP with the Co-Activator p53 in Hypertrophic Cardiomyopathy
Authors: Cheng Christopher H , Towbin Jeffrey A , Purevjav Enkhsaikhan
Published: April 2024

Background:
Myopalladin (MYPN), a member of the Z-disc that interacts with other Z-disc proteins, including the cardiac ankyrin repeat protein ANKRD1 (CARP). Mutations in MYPN and CARP genes cause human dilated (DCM) and hypertrophic cardiomyopathies (HCM). Both MYPN and CARP have dual distributions in the cytoplasm and nucleus. In the nucleus, CARP is a transcriptional co-activator of p53, repressing expression of the cardiac proteins in an
in vitro
system. A MYPN-dependent cytoplasmic anchoring for CARP is described although the molecular basis of the MYPN modulation of CARP gene transcription is unclear. Previously, our laboratory identified a novel MYPN variant (MYPN
Y20C
) in DCM and HCM patients. A transgenic MYPN
Y20C
cardiac-restricted overexpression mouse model recapitulates the HCM phenotype..

Methods and Results:
In vitro
and
in vivo
studies demonstrated that the MYPN
Y20C
mutation resulted in perinuclear localization in myoblasts while CARP retained its cytoplasmic/nuclear dual distribution; as did wild-type MYPN. Co-immunoprecipitation revealed decreased association between CARP and MYPN
Y20C
suggesting a dissociation of the cellular distributions of CARP and MYPN
Y20C
. In transgenic MYPN
Y20C
hearts, perinuclear MYPN
Y20C
had increased association with p53, a co-activator for negative gene regulation of CARP. Nuclear localization of p53 is a critical element in the activation of its transcription. Its sequestration in the cytoplasm renders the protein non-functional. This resulted in a loss-of-function of CARP gene transcription as demonstrated by increased expression of the CARP-specific sarcomeric protein myosin heavy chain (MHC), and atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP)
in vivo
. CARP was serine phosphorylated and coexpression with MYPN led to suppression of CARP phosphorylation.

Conclusion:
Our study demonstrates a novel role for myopalladin in the development of HCM. The perinuclear/cytoplasmic sequestration of p53 by MYPN
Y20C
resulted in the inactivation of p53, which leads to loss-of-function of CARP gene regulation. Our data also suggests that myopalladin plays a pivotal role in relaying cardiac Z-disc signaling to those proteins involved in CARP phosphorylation/activation.
Abstract 9565: Impact of Hepatic GPAT1 or DGAT2 Deficiency on Plasma Lipids and MTP Inhibitor-Induced Elevation of Liver Triglycerides in Mice
Authors: Houde Caroline , Wong Kenny K , Wang Sheng-Ping , McLaren David G , Mendoza Vivienne , Rosa Ray , Miller Paul L , Stout Steven J , Quan Shuo , Zhang Aiwu , Taggart Andy , Roddy Thomas P , Previs Stephen , Zhou Heather H , Johns Doug , Hubbard Brian K
Published: April 2024

Purpose:
Systemic microsomal triglyceride transfer protein (MTP) inhibitors induce beneficial changes in the serum lipid profile in animals and humans, including reduced total and LDL cholesterol (LDL-C) as well as VLDL triglyceride (TG). However, as a consequence of their mechanism of action, these agents also elevate intestinal and hepatic triglyceride levels. A treatment that ameliorates liver TG accumulation could conceivably prevent hepatotoxicity and provide a path forward for developing these compounds. As a proof of principle, we sought to induce hepatic deficiency of either of two key enzymes in the TG biosynthetic pathway - GPAT1 and DGAT2 - and measure the impact of their loss on liver TG accumulation induced by a MTP inhibitor in mice.

Methods:
A recombinant adeno-associated viral vector (AAV) was used to introduce shRNA directed against either GPAT1 or DGAT2 to the livers of

B6[Tg(CETP)/LDLR
tm1
]

F1 mice - a model with a serum lipid profile similar to humans. Stable isotope tracer techniques were employed to assess the degree to which
de novo
liver TG synthesis was compromised in these animals, thereby indicating
in vivo
target engagement. Once target engagement was confirmed, the animals were challenged with a MTP inhibitor and liver TG levels assessed
ex vivo
one week later. Impacts on the plasma lipid profile were also assessed.

Results:
At 42 days post AAV treatment, hepatic GPAT1 and DGAT2 mRNA levels were reduced by over 90% relative to controls by their respective AAV-shRNA vectors. Both treatments were associated with significant and distinct changes in the manner in which intravenously administered
13
C-oleic acid tracer was incorporated into various lipid species by the liver. Of the two treatments, only DGAT2 altered the overall plasma lipid profile, with significantly reduced plasma TG, Apolipoprotein B, and total, VLDL, LDL and HDL cholesterol. Both treatments significantly lowered liver TG levels, both alone and in response to a MTP inhibitor. In the case of DGAT2, the elevated liver TG induced by MTP inhibition was nearly abolished.

Conclusion:
These data provide proof of principle that inhibiting hepatic TG synthesis ameliorates liver TG accumulation in response to MTP inhibition.
Abstract 9594: Risk and Impact of Early and Late Ventricular Arrhythmias in Patients with Continuous-Flow Left Ventricular Assist Devices (CF-LVADs)
Authors: Brisco Meredith A , Sundareswaran Kartik , Milano Carmelo A , Feldman David , Ewald Gregory A , Slaughter Mark S , Farrar David J , Goldberg Lee R ,   for the HeartMate II Clinical Investigators
Published: April 2024

Introduction:
Ventricular arrhythmias (VAs) are common in patients (pts) with LVADs, but most data were obtained from pts with pulsatile LVADs. The incidence, risk factors and impact of VAs in CF-LVAD pts are unknown.

Hypothesis:
VAs in pts with CF-LVADs occur frequently in the first 60 days without decreasing survival or quality of life (QOL).

Methods:
Pts in the HeartMate (HM) II bridge to transplant (BTT n=490) and destination therapy (n=634) trials who received a HM II LVAD were analyzed (n=1125). VAs were defined as those requiring intervention regardless of symptoms. Baseline characteristics, QOL and survival were compared between those with and without VAs. Risk factors were determined using Cox Models with and without 60-day post-implant blanking period.

Results:
A total of 686 VAs in 437 pts (39%) occurred in 1566 patient years (.44 VAs/yr). Most VAs occurred early with 403 events in 29% of pts in first 60 days (2.39 VAs/yr). Survival did not differ in pts with and without VAs (p=.22). Pts with VAs were more likely to be younger than 65 (p<.001), black (p<.001), have lower EF (15.9 vs. 17.4, p<.001), BTT (p=.03), IABP before surgery (p=.009), and history of VAs (p<.001). There were no differences in HF etiology, beta-blocker use, inotropes or pump speed. Significant multivariate risk factors for VAs were age ≥ 65, lower EF, BUN, IABP and VA history. Only EF, IABP, and history of VAs remained significant risk factors for VAs occurring after 60 days. QOL improvements with the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaires were noted in all pts; however, pts with VAs had significantly worse unadjusted QOL on both instruments (p<.001).

Conclusions:
VAs in CF-LVAD pts occur largely in the first 60 days without decreasing survival. Sicker pts (lower EF, presence of IABP) are at greater risk for early and late VAs, with history of prior VAs as the strongest predictor. Presence of VAs may serve as a marker for stunted improvement in QOL post CF-LVAD.
Abstract 9595: Generation of Transgene-Free Induced Pluripotent Stem Cells from Fibroblasts by Small Molecule Chemicals
Authors: Han Ji W , Park Changwon , Lee Min-Young , Kim Hyongbum , Lee JiYoon , Yoon Young-sup
Published: April 2024

Backgrounds:
Reprogramming of somatic cells using viral- and non-viral vectors encoding defined transcription factors to generate induced pluripotent stem (iPS) cells has successfully been achieved over the past few years. However, the current established methods to create iPS cells require viral vectors or plasmids to deliver transgenes into the cells.

Methods and Results:
To obviate the putative problems of genetic contamination in the cells for future clinical application, it is highly demanded to develop new methods to create “safer” iPS cells without any genetic modifications. Here, we for the first time demonstrate successful generation of iPS cell line from mouse fibroblasts with only combinations of small-molecule chemicals such as GSK-3 beta inhibitor, histone deacetylase inhibitor, and G9a histone methyltransferase inhibitor, which act as epigenetic modulators and self-renewal activators. These chemical induced pluripotent stem (ChemiPS) cells have almost the same properties of embryonic stem cells in the expression patterns of pluripotency-related markers, epigenetic status in promoter regions of Oct4 and Nanog, spontaneous differentiation into three germ layers by in vitro embryoid body formation, and formation of teratoma in vivo after injection into mice.

Conclusion:
This study provides the first evidence that sole chemical combinations can reprogram somatic cells, resulting in transgene-free iPS cells. This method will advance the use of iPS cells in clinical application and disease investigation.
Abstract 9602: Serum Proteomic Profiles Predict Coronary Artery Disease in Symptomatic Patients Referred for Coronary Angiography
Authors: LaFramboise William A , Dhir Rajiv , Masterson Robert , Marroquin Oscar C , Mulukutla Suresh R , McNamara Dennis M
Published: April 2024

Coronary angiography is a definitive assay for coronary artery disease (CAD). However, high rates of normals and exposure to ionizing radiation warrant development of tests to identify patients lacking significant CAD without cardiac catheterization. We hypothesized that combinatorial proteomic changes in patient sera correlated with coronary artery disease status.

Methods:
We performed targeted immunoassay profiling of serum from 359 symptomatic patients undergoing coronary angiography. A cohort of 208 patients required stent, angioplasty or bypass graft for hemodynamically significant CAD based on angiography while 151 had no significant disease (No CAD). Both cohorts were comparable in gender, BSA, cholesterol, LDL, creatinine, hypertension and clinical symptoms with a slight difference in age (No CAD: 58+/-10; CAD: 63 +/-11 years, p<0.001). Forty one target proteins implicated in atherogenesis were tested across the 2 groups. Thirty-three proteins were screened among 56 samples, 24 analytes were tested across a 239 sample training set and 12 analytes were validated in 120 additional serum samples.

Results:
Highly significant increases were detected (false detection level=0.018) in patients with CAD for Apo-B100, fibrinogen, VCAM-1, myeloperoxidase, CRP, resistin, osteopontin, IL-6, IL-1b, IL-10 and NT-pBNP. Apo-A1 fell significantly in this group. A scoring algorithm was derived for patient classification (CAD vs. No CAD) using signatures of 2 to 5 analytes from the 239 patient study. Discrimination of patients without CAD was achieved (86% Negative Predictive Value: NPV) while correctly classifying 95% (PPV) of patients with CAD. Osteopontin, resistin, MMP7 and interferon-g were the most frequent classification biomarkers among diagnostic signatures. Validation studies (120 samples) confirmed this signature plus ACRP30 as the strongest multiplex classifier.

Conclusions:
A non-invasive serum biomarker test has been developed to discriminate between patients with angiographically-confirmed, significant CAD and those without it. The ability to exempt even a small percentage of patients from cardiac catheterization provides significant medical and economic benefits given the growing epidemic of coronary artery disease.
Abstract 9644: Deformation Dynamics and Mechanical Properties of the Aortic Annulus by Four-Dimensional Computed Tomography Insights Into the Functional Anatomy of the Aortic Valve Complex and Implications for Transcatheter Aortic Valve Therapy
Authors: Hamdan Ashraf , Guetta Victor , Konen Eli , Goitein Orly , Segev Amit , Raanani Ehud , Spiegelstein Dan , Hay Ilan , Di Segni Elio , Eldar Michael , Schwammenthal Ehud
Published: April 2024

Objectives:
To assess deformation dynamics and mechanical properties of the aortic annulus.

Background:
Understanding dynamic aspects of functional aortic valve anatomy is important for beating-heart transcatheter aortic valve implantation (TAVI).

Methods:
Thirty five patients with aortic stenosis and eleven normal subjects underwent 256-slice computed tomography (CT). The aortic annulus plane was reconstructed in 10% increments of the RR-interval. For each phase minimum diameter (Min), ellipticity index (EI), cross-sectional area (CSA), and perimeter (Perim) were measured (Figure 1). In a subset of 10 patients Young's elastic module was calculated from the stress-strain relationship of the annulus.

Results:
In both subjects with normal and with calcified aortic valves Min increased in systole (12.3 ± 7.3% and 9.8 ± 3.4%, respectively; P < 0.001) and EI decreased (12.7 ± 8.8% and 10.3 ± 2.7%; P < 0.001, respectively). CSA increased by 11.2 ± 5.4% and 6.2 ± 4.8, respectively (P < 0.001). Perim increase was negligible in patients with calcified valves (0.56 ± 0.85%; P < 0.001) and small even in normal subjects (2.2 ± 2.2%; P = 0.01). Young's modulus was calculated as 13.2 MPa in patients. Kolmogorov-Smirnov analysis, showed significant differences between maximum and minimum values for all parameters except perimeter.

Conclusion:
The aortic annulus, generally elliptic, assumes a more round shape in systole, thus increasing CSA without substantial change in perimeter. Perimeter changes are negligible in patients with calcified valve, because tissue properties allow very little expansion. Figure 1: Reconstruction of the aortic annulus from the sagittal (A) and the coronal planes (B). The aortic annulus is defined as the circumferential connection of the aortic leaflets' most basal attachments in the reconstructed axial plane (C). Measurements of the minimum and maximum diameter (D), the perimeter (E), and the area (F) were performed in this plane.
Abstract 9652: Layer-specific Analysis of Myocardial Ischemic Memory Using Speckle Tracking Echocardiography
Authors: Sakurai Daisuke , Asanuma Toshihiko , Masuda Kasumi , Hioki Ayana , Nakatani Satoshi
Published: April 2024

Background:
Recently, speckle tracking echocardiography has allowed us to easily quantify not only regional myocardial but multilayer deformation. Post-systolic shortening (PSS) is a sensitive marker of myocardial ischemia and remains even after relief from brief ischemia (ischemic memory). However, differences of ischemic memory among the layers are unclear. The aim of this study was to evaluate ischemic memory of PSS-related parameters with multilayer analysis using speckle tracking echocardiography.

Methods:
In 9 open-chest dogs, left ventricular short-axis images were acquired at baseline, during occlusion of the left anterior descending coronary artery (2 min), and after reperfusion (10, 20, and 30 min). Circumferential strain profiles were analyzed in three layers (endocardial, mid-wall, and epicardial). Peak systolic strain (ε
S
) and strain at aortic valve closure (ε
AVC
) were measured. Post-systolic index (PSI) and time to peak strain (T
P
) were calculated as parameters of PSS.

Results:
In all three myocardial layers, ε
S
and ε
AVC
decreased during occlusion compared with baseline, but these parameters returned to the baseline levels immediately after reperfusion. In the endocardial and mid-wall layers, PSI significantly increased during occlusion, and the increase remained until 20 min after reperfusion (Figure). T
P
also significantly increased until 20 min after reperfusion in both layers. On the other hand, in the epicardial layer, PSI and T
P
did not significantly change after reperfusion because PSS did not persist.

Conclusion:
With multilayer analysis using speckle tracking echocardiography, ischemic memory of PSS-related parameters remained longer in the endocardial and mid-wall layers than the epicardial layer. Layer-specific analysis may be useful for assessing ischemic memory.