bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18536: Camkii-δ Splice Variants Exert Differential Effects on Heart Failure Development and Myocardial Ischemia / Reperfusion Injury
Authors: Westenbrink B. Daan , Gray Charlie B , Xiang Sunny , Mishra Shika , Shilling Jan , Patel Hemal , Brown Joan H.
Published: April 2024

Background:
Ca2+/calmodulin-dependent kinase II-δ (CaMKII-δ) has been implicated in heart failure development and ischemia / reperfusion injury. It has been suggested that the most abundant cardiac isoforms, CaMKII-δb and CaMKII-δc, serve distinct and opposing roles on cardiomyocyte survival. We therefore evaluated their effects on heart failure development and myocardial ischemia reperfusion injury.

Methods:
Mice with cardiac specific overexpression of the CaMKII-δb or CaMKII-δC, were crossbred with CaMKIIδ knockout (δ-KO) mice to generate mice that exclusively express CaMKII-δb (δb/KO) or CaMKII-δc (δc/KO). Cardiac mRNA profiling, longitudinal cardiac function, survival and the cardiac response to ischemia reperfusion injury were compared.

Results:
Overexpression of CaMKII-δb and CaMKII-δc in the heart resulted in markedly different mRNA expression profile, with less than 10% overlapping genes. Loss of CaMKII-δb resulted in a more severe heart failure phenotype in δc/KO mice, as evidenced by accelerated development of left ventricular dysfunction and a marked reduction in survival compared to conventional CaMKII-δC transgenic mice. In contrast δb/KO mice only developed mild cardiac hypertrophy after 4 months. When challenged by ex vivo ischemia/reperfusion (I/R), δb/KO mice displayed a 75% reduction in infarct size, significantly greater than the reduction observed in KO mice lacking both splice variants. Conversely infarct formation was markedly increased in δc/KO mice (figure). These findings were recapitulated in functional recovery and LDH release. Studies with adult ventricular myocytes indicated that CaMKII-δb and δc have opposing roles in the response to oxidative stress.

Conclusion:
CaMKII-delta splice variants play distinct and opposing roles in heart failure and ischemia / reperfusion injury. These opposing effects may need to be considered when developing CaMKII modulating drugs for clinical application application. .
Abstract 18544: Geometry and Function of Left Ventricle and Mitral Valve After Surgical Repair of Submitral Left Ventricular Aneurysms Assessed with Multi-slice Computed Tomography
Authors: Penkalla Adam J , Solowjowa Natalia , Dandel Michael , Pasic Miralem , Weng Yuguo , Hetzer Roland , Knosalla Christoph
Published: April 2024

Objectives: Surgical repair of submitral aneurysms presents a technical challenge especially if the mitral valve (MV) apparatus is involved. We present our single center surgical experience and the potential of multi-slice computed tomography (MSCT) in the assessment of aneurysm morphology and changes in MV and LV geometry.

Methods: In 05/06-04/12, 21 patients (m:w=17:4, ages 39 to 78, mean 63 yrs; mean NYHA class 2.8) with submitral LV aneurysm were operated upon. Echocardiography and MSCT (Somatom Definition, Siemens) were performed before and after surgery. LV and aneurysm end-diastolic/end-systolic volume were measured and indexed to body surface area (LV-EDVI/LV-ESVI, A-EDVI/A-ESVI). LV ejection fraction (LVEF), cardiac output (CO) and cardiac index (CI) were calculated on the basis of MSCT data. MV geometry was characterized by mid-systolic coaptation distance (CD), tenting area (TA) and MV closure angle (MVCA).

Results: Thirty-day and 5-year survival was 88.9%±7.4% and 82.1%±9.5%. Aneurysms were localized in myocardial segments 4/10/11. Preoperative A-EDVI showed a slight systolic increase, demonstrating adverse volume shift. There was reduction of LV-EDVI (141.4±21.6 to 72.7±12.9 ml/sqm, p=0.006) and LV-ESVI (102.2±24.9 to 42.5±9.9 ml/sqm, p=0.024), LVEF improvement (32% to 45%, p=0.016) and significant increase in CO and CI after surgical repair. Mitral repair/replacement was necessary in three patients. Postoperative reduction of mitral regurgitation (from grade 0.94 to 0.24, p=0.003) corresponded with improvement of MV geometry (CD (reduced from 10.2 to 7.9 mm, p=0.06) and of TA (1.8 to 1.5 sqcm, p=0.04) and MVCA (103° to 116°, p=0.04).

Conclusions: Reconstruction of submitral LV aneurysms can be performed with good mid-term results. MSCT provides valuable information about aneurysm localization, its extent and effect on MV and LV geometry and reverse remodeling, and also functional changes after surgical restoration.
Abstract 18549: Effects of AMR101, a Pure Eicosapentaenoic Omega-3 Fatty Acid, on the Fatty Acid Profile in Plasma and Red Blood Cells in Statin-Treated Patients With Persistent High Triglycerides (Results from the ANCHOR Study)
Authors: Braeckman Rene , Manku Mehar S , Ballantyne Christie M , Stirtan William G , Soni Paresh N
Published: April 2024

AMR101 is an omega-3 fatty acid (FA) investigational new drug containing ≥96% pure icosapent ethyl, the ethyl ester of eicosapentaenoic acid (EPA). This subanalysis of the ANCHOR study evaluated the effects of AMR101 on the FA profiles and relationships between AMR101 and triglyceride (TG) lowering in plasma and RBCs. ANCHOR was a phase 3, double-blind, 12-week clinical study in high-risk statin-treated patients with residually high TG levels (≥200 and <500 mg/dL) despite LDL cholesterol control (≥40 and <100 mg/dL). Patients (N=702) on stable diet were randomized to AMR101 4 g/d, 2 g/d, or placebo. Twenty eight FAs were measured in plasma and RBCs for 153 patients using a gas chromatography/flame ionization detection method. Mean baseline plasma EPA levels were 20, 27, and 24 μg/g for AMR101 4 g/d, 2 g/d, and placebo, respectively; Mean placebo-adjusted EPA levels increased by 650% (P<0.0001) and 268% (P<0.0001) with AMR101 4 g/d and 2 g/d by week 12. Mean baseline plasma EPA expressed as percentage of total FAs (mol%) was 0.4, 0.5, and 0.5% for AMR101 4 g/d, 2 g/d, and placebo, respectively. Mean plasma EPA (mol%) at Week 12 was 3.6, 1.9, and 0.5% for AMR101 4 g/d, 2 g/d, and placebo, respectively. Levels of the EPA metabolite omega-3 docosapentaenoic acid also increased with both doses of AMR101 (P<0.0001). The arachidonic acid (AA)/EPA plasma ratio has been suggested to be useful as a biomarker for arteriosclerotic disease. Mean placebo-adjusted AA/EPA plasma ratio decreased from baseline by 90% (P<0.0001) and 75% (P<0.0001) with AMR101 4 g/d and 2 g/d. Total omega-3 FAs increased and total omega-6 FAs decreased with both doses of AMR101 (P<0.0001). Similar results were observed in RBCs. Increased doses of AMR101 resulted in increased EPA levels and corresponded with reductions in TG. The TG-lowering effect of AMR101 was due to the increase in EPA, as there were no statistically significant changes in plasma docosahexaenoic acid concentrations. Overall, AMR101 significantly increased EPA in plasma and RBCs in a linear, dose-dependent fashion consistent with its TG-lowering effect and caused other shifts in FA concentration and RBC membrane content that may have clinical benefit.
Abstract 18551: The Detection of Diastolic Stunning by Two-Dimensional Speckle Tracking Imaging Improves Initial Diagnosis in Emergency Department Patients with Suspected Acute Coronary Syndromes
Authors: Ishii Katsuhisa , Nagai Takahiro , Komasa Akihiro , Furukawa Atsuko , Tada Eiji , Kataoka Kazuaki , Seino Yutaka
Published: April 2024

Background:
Differential diagnosis of chest pain (CP) in emergency department (ED) is important for the management of acute coronary syndrome (ACS). Regional left ventricular (LV) diastolic dysfunction or diastolic stunning (DS), detected by strain image (SI) derived from two-dimensional speckle tracking technology, may persist after an episode of transient severe myocardial ischemia. We studied the incremental value of the detection of diastolic stunning by SI over the initial diagnosis (InDx) of CP in the ED for identifying patients with ACS.

Methods:
Consecutive 128 patients (75 men, 61 ±13 years) with CP consistent with ACS were enrolled. SI (ARTIDA, Toshiba) was acquired in the apical long-axis, two- and four-chamber views within 6 hrs in ED. Transverse strain curves were obtained and peak values of strain at the closure of aortic valve (A) and at the one third of diastolic duration (B) were measured. The SI-diastolic index (SI-DI) was determined as (A-B)/A×100% and used to identify regional LV DS. In the 40 normal subjects the SI-DIs were 76.5±10.6, 80.7±8.4, 79.4±11.6 % in the territories of the left anterior descending branch (LAD), the left circumflex branch (LCX) and the right coronary artery (RCA), respectively.Clinical evaluation, serial ECGs, and troponin (Tn) were performed in all patients, with coronary angiography (CAG) performed as clinically indicated. The InDx or “definite ACS” (D-ACS) was based on presenting CP, ECG and Tn. Final diagnosis of D-ACS was defined as elevated Tn and significant disease on CAG (>50% stenosis).

Results:
57 patients were diagnosed as having D-ACS. Regional LV DS (SI-DI<40%) had been detected in the perfusion territories of the coronary arteries with culprit lesions in 52 (91%) of D-ACS, whereas it had been noted in 9 (13%) of chest pain syndrome (CPS). SI-DIs were 25.8±15 (n=75), 17.5±14 (n=36), 21.1±11 % (n=14) in the culprit lesions of LAD, LCX and RCA, respectively, and 70±13% (n=217) in the segments corresponding to the non-culprit lesions. For D-ACS, quantitative SI plus InDx increased sensitivity by 28% to 95% (P<0.01), and non-significantly increased NPV by 21% to 97%.

Conclusion:
Adding the detection of regional LV DS by SI to InDx in ED increased sensitivity and NPV for detecting D-ACS.
Abstract 18566: How is the Presence of Obstructive Sleep Apnea Associated with Vasospastic Angina?
Authors: Teragawa Hiroki , Fujii Yuichi , Takemoto Hiroaki , Nomura Shuichi
Published: April 2024

Background:
Vasospastic angina (VSA) is characterized by transient vasoconstriction of the epicardial coronary arteries leading to myocardial ischemia. It characteristically occurs from midnight to early morning. Obstructive sleep apnea (OSA) is caused by obstruction of the upper air passage during sleep, which leads to hypopnea. Although OSA may have an influence on VSA, the association between these two conditions remains unclear. To clarify this relationship, the frequency of OSA (Study 1) and the association between OSA and anginal attacks (Study 2) were investigated.

Methods:
(Study 1) Eighty-seven patients (41 men, mean age 67 years) were included in whom spasm-provocation testing for evaluation of chest symptoms was performed. VSA was defined as >90% narrowing of the epicardial coronary arteries on the angiogram during a spasm-provocation test, accompanied by chest pain and/or ST-segment deviation on ECG. Polysomnography (PSG) was performed in all patients. The presence of OSA was verified using the apnea hypopnea index (AHI) >15/h. The frequency of OSA in VSA patients (VSA group, n = 58) was compared with that in patients in whom negative spasm-provocation testing (non-VSA group, n = 29) was performed. (Study 2) Seventy-seven VSA outpatients were examined in whom PSG was performed (45 OSA, 32 non-OSA), and these patients followed up for at least a year. The number of anginal attacks per month was evaluated. The presence of intractable VSA was defined as uncontrollable angina even after administration of two types of coronary vasodilators.

Results:
(Study 1) No difference was observed in AHI (VSA group: 15.2 ± 1.3/h, non-VSA group: 12.8 ± 1.8/h) and the frequency of OSA (VSA group: 25/58, 43%, non-VSA group: 9/29, 31%) between the two groups. (Study 2) The number of anginal attacks tended to be higher in the OSA group (2.9 ± 0.6/months) than in the non-OSA group (1.3 ± 0.8/months, p = 0.09). The frequency of intractable VSA was higher in the OSA group (47%) than in the non-OSA group (19%, p < 0.05). Logistic regression analysis demonstrated that the presence of OSA was the significant factor responsible for intractable VSA.

Conclusions:
These results suggest that although OSA may not be involved in the pathogenesis of VSA, it may be a deteriorating factor of VSA.
Abstract 18573: Unmasking Phenotypic Micro-heterogeneities in Adult Cardiac Progenitor Cells: Clonal Analysis, Single Cell QRT-PCR, and Fate Mapping
Authors: Noseda Michela , Harada Mutsuo , McSweeney Sara J , Belian Elisa , Leja Thomas , Macaulay Iain , Al-Beidh Farah , Abreu Pavia Marta S , Lumbers Richard T , Koenemann Stephanie , Sampson Robert , Jacobsen Sten E , Schneider Michael D
Published: April 2024

Characterization of adult cardiac progenitor cells (CPC) is incompletely resolved and their potential heterogeneity needs further investigation. Here, we assess the molecular signature, heterogeneity, and origin of adult heart-derived Lin-/Sca-1+ mouse CPCs by clonal analysis, single cell QRT-PCR and fate-mapping. Clonal growth was predicted by the side population (SP) phenotype. Cloned cardiac Lin-/Sca-1+/SP+ CPCs (cSPC) were propagated for >10 months without senescence or loss of the Sca-1/SP phenotype. QRT-PCR of 43 genes in >30 clones showed a consensus signature defined by stem cell-associated markers and key cardiac transcription factors, but lacking markers of pluripotency, primitive or pre-cardiac mesoderm, hematopoiesis, and cardiomyocytes. Clonal analysis revealed mutually exclusive patterns of three core factors (Gata4, Mef2c, Tbx5), masked in the mixed population. Cloned cSPCs showed cardiac (cTnI, MLC2v, sarc MyHC, sarc α-actin), endothelial (vWF) and smooth muscle (SM-MyHC) differentiation after grafting to the heart. Fresh (non-propagated) cSPCs were profiled with microarrays, compared to 3 clones at passage 40, heart, and ESCs: clones largely resembled fresh cSPCs, excepting an increase in proliferation-associated GO categories. Single cell QRT-PCR (Fluidigm) on >40 single fresh cSPCs confirmed both the transcriptional signature of the clones and heterogeneous expression of core cardiac factors. Thus, cSPCs resemble an incomplete but stable form of heart-forming mesoderm. By Cre/lox fate-mapping, we traced cSPCs’ embryological origin. Cardiac SP cells are derived from pre-cardiac mesoderm (98% labelled in Mesp1-Cre/R26R-tdTomato mice) and are not “lapsed” myocytes, neural crest, or hematopoietic in origin (0.2%, 1.2%, 0.2% with Myh6-, Wnt1-, or Vav-Cre). Half are derived from cells formerly expressing Nkx2.5 or Isl1 (52%, 57%), though these are rarely detected in fresh adult single cells (<2%). Thus, our analyses unmask micro-heterogeneities in adult cSPCs, which may represent different states of differentiation or lineage. Expression of key cardiogenic transcription factors in mutually exclusive patterns may represent a mechanism to maintain the stem cell pool and prevent precocious differentiation.
Abstract 18578: Replication of a Risk Prediction Model for Ambulatory Incident Atrial Fibrillation Using Electronic Medical Record
Authors: Parvez Babar , Shah Anushi , Muhammad Raafia , Shoemaker M. Benjamin , Graves Amy J , Heckbert Susan R , Xu Hua , Ellinor Patrick T , Benjamin Emelia J , Alonso Alvaro , Shintani Ayumi K , Roden Dan , Darbar Dawood
Published: April 2024

Introduction:
Atrial fibrillation (AF) contributes to substantial increases in morbidity, mortality and increasing healthcare expenditures. Using data from community-based cohorts, CHARGE-AF investigators developed an AF risk prediction model. We aimed to replicate the CHARGE AF risk model using the Vanderbilt electronic medical records (EMR) repository.

Methods:
We identified a large ambulatory cohort of Caucasians and African Americans of age ≥ 40 years without a prior history of AF, followed by assessment of incident AF over a 5-year period (December 2005 to December 2010) using prospective chart review and validated AF algorithm. Baseline clinical variables (age, ethnicity, sex, height, weight, systolic and diastolic BP, PR interval, current use of antihypertensive medications, DM, MI, CHF, current smoking, and LVH on ECG) were extracted on or within 6 months prior to December 2005. We used multiple imputation for missing values and multivariable Cox proportional hazards analysis to construct our risk prediction model.

Results:
Our study cohort consisted of 63,772 subjects (age 58±11 years, 47% male, 90% Caucasians) with no prior history of AF. Over a mean follow up time of 3.9±0.95 years, 3,383 (5.3%) subjects developed AF in 2.6±1.3 years. In the multivariable model, older age, Caucasian ethnicity, male sex, taller height, greater weight, history of heart failure, LVH on ECG and prolonged PR interval were all significant risk predictors of AF (similar to CHARGE-AF risk model), whereas current use of antihypertensive medication was protective of developing AF (Table). The C-index from our model, 0.768, indicated relatively good discrimination.

Conclusions:
From clinical factors readily accessible in a large de-identified EMR database, we replicated the CHARGE AF risk prediction model to identify individuals at risk for developing AF in an ambulatory setting. This risk model may be used to target high risk-individuals for preventive measures.
Abstract 18601: The Role of ADMA Metabolism in the Regulation of Human Pulmonary Endothelial Cell Function
Authors: Tsang Hilda H , Leiper James , Lao Ka Hou , Barnes Gareth , Wharton John , Howard Luke , Wilkins Martin , Wojciak-Stothard Beata
Published: April 2024

Objective:
Asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication required for the coordinated regulation of pulmonary endothelial permeability and angiogenesis, contributing to the disease.

Methods and Results.
The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells (HPAECs). ADMA inhibited protein expression and cell surface localization of connexin 43 (Cx43) in HPAECs (2-fold decrease, P<0.01), resulting in impaired gap junctional communication, as shown by Fluorescence Recovery After Photobleaching (FRAP). ADMA regulated Cx43 expression and function via the nitric oxide signalling pathway, as effects could be reversed by the nitric oxide donor SNAP, and nitric oxide secondary messengers, cAMP and cGMP. Defective gap junction communication in HPAECs led to endothelial dysfunction, including increased trans-endothelial permeability (1.7-fold increase, P<0.001), and impaired angiogenesis(1.7-fold decrease, P<0.001). The effects of ADMA were prevented by over expressing dimethylarginine dimethylaminohydrolase I (DDAHI), an enzyme that metabolised ADMA, or treatment with the Cx43-gap junction activating drug, rotigaptide.Reduced Cx43 expression was also found in lungs of mice deficient in DDAHI.
In vivo
lung permeability was increased in DDAHI homozygous knockout mice (1.2-fold increase, P<0.05), and was alleviated by application of rotigaptide. Endothelial colony forming cells from IPAH patients showed reduced expression of DDAHI and Cx43 (2-fold decrease, P<0.05), resulting in impaired endothelial barrier function and abnormal angiogenesis.

Conclusions.
ADMA is critical in the regulation of gap junctional communication in pulmonary endothelium. Endothelial cells from IPAH patients show reduced ADMA metabolism resulting in defective gap junctional communication and abnormal angiogenic responses. Enhancing Cx43 function may have endothelium-protective effects in conditions associated with reduced nitric oxide signalling, such as pulmonary hypertension.
Abstract 18607: Prevalence, Outcome, and Predictors of Cardio-Renal Syndrome in Children with Dilated Cardiomyopathy
Authors: Kaddourah Ahmad , Goldstein Stuart , Towbin Jeffrey , Jeffries John
Published: April 2024

Background:
Cardio-renal syndrome (CRS) describes variety of acute or chronic conditions where the primary failing organ can be either the heart or kidney. The prevalence, predictors and outcome of CRS has not been reported in children with dilated cardiomyopathy (DCM).

Methodology:
Data from patients > 1 year of age with DCM enrolled in the Pediatric Cardiomyopathy Registry (PCMR) was assessed. CRS was defined as glomerular filtration rate <90 ml/min/1.73m
2
estimated by modified Schwartz formula (eGFR). Patients with eGFR>150 ml/min/1.73m
2
were excluded. CRS prevalence was determined by cross-sectional design in patients newly diagnosed with DCM using the baseline PCMR data. Survival analysis compared patients with vs. without CRS using annual PCMR data. Regression models were applied on both baseline and annual data to study the interactions between eGFR and different echocardiographic measures.

Results:
The baseline data had 484 children with DCM. Serum Cr data to calculate eGFR were available for 92 patients. Fifty six (62.0%) patients had eGFR < 90 ml/min/1.73m
2
, which is greater than the 48% prevalence published in 3256 healthy historical controls (P<0.001). CRS patients had a mean eGFR of 61 (±22.6) vs. 108 (±14) (P<0.001). Death occurred in 8 (14%) of CRS patients compared to no deaths in patients without CRS (P=0.052) after 7 years follow-up. Univariate regression models showed a significant positive correlation between fractional shortening (FS) and eGFR (P= 0.0013, r
2
= 0.09). No correlation was observed between eGFR and ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD) and LVEDD Z-scores.

Conclusion:
This is the first study to show that CRS is common in children newly diagnosed with DCM and is associated with higher risk of subsequent death. Worsening FS was associated with decreasing eGFR which suggests that patients with poor FS might have significant CRS. We suggest kidney functions should be evaluated systematically in children with DCM to assess for chronic kidney disease and direct potential management.
Abstract 18617: Development of Aortic Root Dilation is Accompanied by Increased Vascular Expression of Proinflammatory Adhesion Molecules VCAM, ICAM and E-Selectin in Patients with Advanced Heart Failure Following Left Ventricular Assist Device Placement
Authors: Lee Michael , Yi Shuiqing , Akashi Hirokazu , Kato Tomoko S , Takayama Hiroo , Wu Christina , Xu Katherine , Collado Elias , Mancini Donna M , Naka Yoshifumi , Schulze Paul Christian
Published: April 2024

Background
Left ventricular assist devices (LVADs) are increasingly used for patients with advanced heart failure. Continuous flow LVADs (cfLVADs) have replaced older pulsatile LVADs (pLVADs); however, effects of attenuated pulse pressure waveforms are largely unknown. We compared vascular histomorphometric and molecular changes in patients on cfLVADs compared to pLVADs.

Methods Clinical and echocardiographic data was collected from electronic medical records for 28 LVAD patients (12 pLVAD vs. 16 cfLVAD). Endothelial van Willebrand stores, markers of aortic wall thickness, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at LVAD placement and at explantation during heart transplant. Expression of adhesion molecules was quantified by Western blot.

Results Age (55±13 vs. 62±9 yrs) and duration of LVAD support (279±191 vs. 201±114 days) were similar in both groups. Aortic root dilation was only observed in cfLVAD patients (change in root diameter: +0.32±0.29 in cfLVAD vs. -0.20±0.61 in pLVAD; p<0.05). Decellularization of the aorta (tunica media and adventitia) was observed in cfLVAD patients (media: 22.8±7.1 vs. 48.0±8.0 cells/µm
2
in pLVAD; adventitia: 21.0±9.3 vs. 46.8±11.3 cells/µm
2
in pLVAD; both p<0.01). Decreased media thickness developed only in cfLVAD patients (-0.44±0.01 vs. 0.047±0.006 µm/BMI in pLVAD; p<0.05). Inflammation was higher in cfLVAD patients (T-cells: 5.2±3.2 vs. 8.2±4.2 cells/µm
2
in cfLVAD; macrophages: 5.2±2.6 vs. 6.86±3.3 cells/µm
2
in cfLVAD). Both device types showed an increase in vascular E-selectin, ICAM and VCAM levels following LVAD placement (E-selectin: +39.6% vs. +29.0% in pLVAD, ICAM: +24.42% vs. +19.6% in pLVAD, VCAM: +30.6% vs. +34.0% in pLVAD; all p<0.05). Endothelial vWF stores were preserved in pLVAD patients with near complete depletion in cfLVAD patients.

Conclusion LVAD implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on cfLVADs and associated with aortic media decellularization and endothelial vWF depletion. These findings help to explain the progressive aortic root dilation seen in patients following cfLVAD placement.
Abstract 18695: Role of Autophagy in Amyloidogenic Light Chain Induced Cardiac Toxicity
Authors: Guan Jian , Mishra Shikha , Shi Jianru , Lavatelli Francesca , Rognoni Paola , Las Guy , Merlini Giampaolo , Connors Lawreen H , Seldin David C , MacRae Calum A , Shirihai Orian , Liao Ronglih
Published: April 2024

AL amyloid cardiomyopathy is characterized by the deposition of amyloid fibers from monoclonal immunoglobulin light chain proteins (AL-LC) in the heart. We and others have shown that AL-LC directly results in cardiac toxicity; however, the mechanisms underlying this toxicity remain to be determined. Morphological examinations of hearts from patients with AL amyloid cardiomyopathy reveal increased double membrane autophagosome-like structures and mitochondrial deformation. Using isolated adult rat cardiomyocytes, we therefore examined whether dysregulated autophagy mediates the development of AL-LC induced cardiac toxicity.

Methods and Results:
Autophagy is a dynamic process and autophagic flux is, hence, determined by measurement of LC3-II protein expression in the absence and presence of lysosome inhibitors (E64d and pepstatin A). The autophagic substrate, polyubiquitin-binding protein (p62), was also examined via immunoblotting. We found that LC3-II expression increased in the absence but decreased in the presence of lysosome inhibitors in cardiomyocytes exposed to AL-LC relative to vehicle control. Moreover, p62 expression was increased in AL-LC treated cardiomyocytes, suggesting that AL-LC resulted in impaired clearance of autophagosomes in cardiomyocytes. To define the causal relationship between dysregulated autophagic clearance and AL-LC induced cardiac toxicity, we determined the functional consequences of autophagic inhibition by treatment with 3MA (3-Methyladenine, PI3K inhibitor), or autophagic activation by treatment with rapamycin (mTOR inhibitor). Inhibition of autophagy led to worsen of AL-LC induced cardiac toxicity whereas activation of autophagy protected cardiomyocytes against AL-LC induced cardiac toxicity, as measured by ROS production and cell death.

Conclusion:
Our data demonstrate that AL-LC directly results in impaired autophagic clearance in cardiomyocytes, contributing to the development of amyloid cardiac toxicity and cardiomyopathy. Therapies aimed at modulation of cellular autophagy may provide new treatment approaches for patients with AL amyloid cardiomyopathy.
Abstract 18719: The Morphologic and Topographic Characters of Pulmonary Vein Function in Relation to Velocity of Propagation and Diastology in Heart Failure with Preserved Ejection Fraction: A Dedicated Computed Tomography Study
Authors: Yun Chun-Ho , Hung Shoting , Hung Chung-Lieh
Published: April 2024

The Morphologic and Topographic Characters of Pulmonary Vein Function in Relation to Velocity of Propagation and Diastology in Heart Failure with Preserved Ejection Fraction: A Dedicated Computed Tomography Study Background Diastolic dysfunction (DD), an assumed pathophysiologic intermediate between hypertension and heart failure (HF), has traditional be evaluated by echocardiography. However, data regarding the transition from DD to diastolic HF by assessing pulmonary vein morphological and topographic descriptions utilizing high spatial resolution computed tomography (CT) had been lacking.

Materials and Methods
We studies totally 124 subjects with conventional echo done and 64-slice CT performed. Of all, only 119 had data analyzable for both echo and CT methods. Sequential pulmonary veins orifice diameter and area from all four veins, both max and minimal value, during consecutive 1 R-R heart cycle were analyzed equally into 6 parts. Echo-derived left atrial and ventricular volume, high-frame rate tissue Doppler imaging (TDI), velocity of propagation (VP), estimated LV filling pressure (PCWP by E/E’) and some other diastolic indices were all obtained.

ResultsM
Of all 119 subjects (43 non-DD, 44 DD, and 32 DHF) entered for our final study (age: 59.3 ± 11.2, 37% female), we observed a graded enlargement, both max and minimum value, for all 4 pulmonary vein orifices across these three groups (all trend p<0.05). In addition, linear relationship was observed between all 4 PV orifices area and echo-derived PCWP and VP (all p<0.05) value, with both left superior and inferior PV maximum area further related to serum BNP level (both p<0.05). When left superior and inferior PV maximum area were superimposed on LV mass index, PCWP and LA volume, there were significant increase in the DHF prediction model X2 value using likelihood ratio test (both p<0.05).

Conclusion
Topographic PV size estimates using computed tomography rendered detailed assessment of structural and functional characters feasible, which correlated well with diastolic dysfunction. Our data suggested that CT-based PV measure may help identify subjects at risk even in a more early stage heart failure.
Abstract 18728: Plasma Heparin Cofactor II Activity is a Predictor of Diffuse Coronary Artery Narrowing in Patients with Diabetes Mellitus
Authors: Takamori Nobuyuki , Akaike Masashi , Aihara Ken-ichi
Published: April 2024

Background:
Heparin cofactor II (HCII) is a major physiological inhibitor of thrombin action. We previously reported high plasma HCII was protective against in-stent restenosis after coronary stenting and carotid atherosclerosis. Furthermore, we reported that HCII was a predictor of cardiovascular events in patients with coronary heart disease. Kataoka et al reported patients with DM had smaller coronary vessel and longer diseased segment than those with impaired glucose tolerance (IGT) and normal glucose tolerance. HCII and morphologic characteristics of diabetic coronary was unknown.

Methods:
We enrolled 20 diabetic patients examined by coronary angiography, sequentially (13 males and 7 females; age, 67.9+/-10.4yrs, HbA1c>/=7.0%). Coronary cinearteriography was analyzed by quantitative coronary angiography (QCA) with Cardiovascular Measurement System (CCIP-310/W). Segment diameter<1.5mm as diseased lesions were determined. And diseased lesion length and HCII activity were analyzed, statistically.

Results:
The mean plasma level of HCII activities was 101.4+/-18.6%. And the mean of diseased lesion length was 13.7+/-12.0mm. Multivariate analysis showed age, low-HDLemia, smoking habit and disease period of DM were positively correlated with ALL, and HCII activity was negatively correlated. Univariate analysis showed HCII activity was negatively correlated with ALL, and disease period of DM was positively. That is, HCII activity and disease period of DM were correlated with lesion length of coronary artery diffuse-narrowing in diabetic patients. .

Conclusions:
The results suggested that low level of plasma HCII activity was correlated with diffuse coronary artery narrowing in patients with diabetic mellitus.
Abstract 18749: On Pump Beating Maze Procedure For Non-valvular Atrial Fibrillation Via Left Atrial Appendage
Authors: Ishioka Miwa , Katayama Akira , Ozawa Masamichi , Tachibana Hitoshi , Kodama Hiroshi , Dote Keigo
Published: April 2024

BACKGROUND:
The Cox maze procedure is the most effective surgical procedure for atrial fibrillation (AF). In recent years a number of different surgical ablation devices were introduced and new surgical ablation to treat AF are presented.

OBJECTIVE
The purpose of this article was to present a new surgical ablation approach; on pump beating maze procedure via left atrial appendage (LAA) for nonvalvular AF (NVAF).

METHODS:
Between February 2006 and October 2012, 31 patientswith persistent and paroxysmal atrial fibrillation undergoing non valvular heart disease and great vessel surgery using cardiopulmonary bypass (11 with large thrombus of left atrial appendage, 6 with graft replacement for aortic aneurysm, 9 with aortic valve replacement, 1 with ventricular septal defect, and 4 with coronary artery bypass grafting) were underwent the on pump beating maze procedure via left atrial appendage (LAA) using bipolarradiofrequency ablation concomitantly. The average age of patientswas 70 ± 8 years. The mean diameter of left atrium was 48 ± 7 mm. Six patients had paroxysmal atrialfibrillation and the other had permanent. The ablation line of our modification consisted of pulmonary box isolation and isthmus ablation. Pulmonary box isolation was made by right pulmonary epicardial clamp and LA roof and inferior clamp ablation via left atrial appendage. Left isthmus ablation between the line of pulmonary box isolation and mitral annulus was made by bipolar or monopolar pen epicardially. No further atriotomy was performed on the atrial septum or right atrium. After completion of these procedures, the combined surgery was performed. All patients in this series were operated on by the same surgical team. Results: No perioperative morality, cerebrovascular accidents, transient ischemic attacks, or both were documented in this series. One patient required a pacemaker implantation because of sinus node dysfunction. In a mean follow-up of 26±19 months, and 77.8 % of the patients are free from atrial fibrillation.

CONCLUSION:
The LAA maze procedure could be an attractive treatment for atrial fibrillation in non-mitral cardiac surgery without the need for atriotomies.
Abstract 18759: Benefit of TEE in Patients Over 50 with Unexplained Stroke and Normal TTE Study
Authors: Jaiswal Abhishek , Goldbarg Seth H , Kerwin Todd C
Published: April 2024

Objective:
Aside from oral anticoagulation in patients with intracardiac thrombus, current guidelines and scientific evidence do not support specific therapeutic interventions for most other TEE findings. We sought to examine the effect of performing TEE on therapeutic management in patients over age 50 with unexplained stroke. Specific TEE findings sought to explain the cause of stroke generally include cardiac thrombi (particularly LA and LAA) or spontaneous contrast, inter atrial septal anomalies (particularly PFO), and atheromatous disease of the aorta. We hypothesized that there would be minimal incremental value in performing TEE added to a normal TTE study.

Methods:
We retrospectively analyzed consecutive patients over 50 yrs who underwent TEE for unexplained stroke. Patients in sinus rhythm were included if TTE results were normal. Normal TTE was defined as normal LVEF, no intracardiac masses or shunts, absence of severe valvular heart disease.

Results:
TEE images and clinical data of 263 patients were analyzed. Baseline characteristics included mean age of 66.7 yrs, (range 50-91 yrs), 42.5% were female. TEE findings demonstrated complex plaque of the ascending aorta or arch in 44/263 (16.7%). PFO was found in 18/263(%), 25/263(%) had atrial spetal aneurysm (ASA), and 11/263(%) had both ASA and PFO. Spontaneous contrast was seen in 13/263 (4.9%). 1 patient had LA thrombus. Overall 38% had a TEE finding which could explain the etiology of stroke but 1/263 (0.4%) had a finding which changed therapy based on current guidelines or substantial scientific evidence. 6 months follow up was available on 85 patients, and 13(15%) of these patients developed new PAF.

Conclusions:
Our study demonstrates no incremental value of TEE to a normal TTE study in patients over 50 with unexplained stroke in sinus rhythm. As reported in prior studies, it is not uncommon for TEE to disclose findings such as aortic atheroma or interatrial septal anomalies, however these findings generally do not alter therapeutic management and therefore routine performance of TEE in these patients may not be justified. It needs to be determined whether subsequent PAF episodes were etiology or result of stroke.
Abstract 18760: Resident c-kit-positive Cardiac Stem Cells Replenish Cardiomyocytes During Physiological Cardiac Growth
Authors: Torella Daniele , Aquila Iolanda , Vicinanza Carla , Leone Angelo , Bochicchio Angela , Correale Christelle , Waring Cheryl D , Indolfi Ciro , Nadal-Ginard Bernardo , Ellison Georgina M
Published: April 2024

How cell diversity is maintained within the adult heart through normal wear and tear and physio-pathologic remodeling remains an unanswered question. Intriguingly, exercise training produces physiological growth of the myocardium encompassing both myocyte hypertrophy and new myocyte formation. We assessed whether new myocyte formation during exercise training is the direct progeny of resident c-kit-positive (c-kit-pos) cardiac stem/progenitor cells (CSCs). Mice underwent a program of controlled swimming for 28 days. Untrained mice acted as sedentary controls. To distinguish new myocyte formation (detected by BrdU in vivo labeling) due to unexpected myocyte division or to stem cell differentiation, we used double-transgenic mice by crossbreeding the myocyte-specific Myh6-MerCreMer mice with p-lox-LacZ-Stop-lox/eYFP (ZYP) mice. To ascertain a direct relationship between c-kit-pos CSCs and new myocyte generation, we released into the myocardium of ZYP mice a lentiviral vector carrying Cre-Recombinase under the control of the c-kit promoter (Lenti-c-kit/Cre). This strategy permanently labels with YFP only resident c-kit-pos CSCs and allows to track their cell fate. Physical exercise produced rapid myogenic differentiation in c-kit-pos CSCs during the 28 days swimming program, which was followed by an increased number of new myocytes. The inducible myocyte-specific genetic fate-mapping strategy shows that new myocytes are not generated through the division of pre-existing myocytes but rather are replenished by stem/progenitor cells. Importantly, when chimeric GFP bone marrow-transplanted mice were enrolled in the training program, all new myocytes were GFP-negative, thus confirming they were not derived from cardiac homed bone marrow stem cells. Finally, through the Cre/YFP c-kit-pos CSC specific genetic recombination in vivo, we demonstrated that new myocyte formation during exercise training is the direct progeny of c-kit-pos CSC differentiation. These data based on genetic cell fate mapping provide the convincing direct evidence that cardiac workload triggers the in situ cardiac regenerative capacity of c-kit-pos CSCs. This property of the myocardium could be meaningfully exploited for cardiac regenerative therapies.
Abstract 18767: Preoperative Echocardiographic Predictors of Left Ventricular Remodeling After Surgical Correction of Mitral Regurgitation Caused by Leaflet Prolapse
Authors: MacHaalany Jimmy , Parenteau Julie , Dubois-Sénéchal Isaïe-Nicolas , Bernier Mathieu , Costerousse Olivier , Bertrand Olivier F , O'Connor Kim , Dubois Michelle , Voisine Pierre , Sénéchal Mario
Published: April 2024

Background: This study sought to determine whether preoperative echocardiography analysis before mitral valve surgery is predictive of postoperative left ventricular dysfunction in patients undergoing valve surgery for severe mitral regurgitation caused by leaflet prolapse.

Methods: In 72 consecutive patients without coronary artery disease undergoing valve repair (n=29, 40%) or replacement (n=43, 60%), preoperative, early postoperative (1-2 days) and late postoperative (4.5 ± 2.5 months and 18 ± 8.0 months) echocardiographic parameters, including left ventricular (LV) dimensions, volumes and ejection fractions (EF) were measured. Patients were stratified and analysed in 3 different groups according to their respective baseline LVEF (group 1: EF ≥ 60, group 2: EF = 45-59%, group 3: EF < 45%).

Results: Over a mean follow-up period of 546 ± 244 days, our cohort’s echocardiographic parameters showed the following reductions from baseline: LVEF: 56% ± 8 to 53% ± 9 (p<0.0001), LV end-diastolic dimension: 58.0mm ± 8.0 to 47.0mm ± 5.0 (p<0.0001) and LV end-systolic dimension: 41.0mm ± 8.0 to 33.0mm ± 6.0 (p<0.0001) respectively. Subgroup analysis revealed that only those with LVEF ≥ 60% recovered to a completely normal EF. Additionally, two-third of the observed changes in LV diameters and volumes occurred in the first 6 months. No difference in remodelling parameters was seen during the follow-up period between patients who underwent mitral valve replacement versus mitral valve repair. Finally, multivariate analysis demonstrated that pre-operative LVEF is an independent predictor of a poor post-operative LVEF (OR = 1.504 [1.249 - 1.966; p<0.0001]).

Conclusions: In patients with pure severe mitral regurgitation due to leaflet prolapse, significant positive LV remodelling can be expected irrespective of patient’s baseline EF. Remodelling is more important in the first 6 months after surgery but is usually progressive and occurs over a long follow-up period (≥ 12 months); however, only those with baseline EF ≥ 60% will usually recover to a normal EF. This reinforces our understanding that contemplation of early surgical intervention for severe mitral regurgitation secondary to leaflet prolapse will most likely yield a favourable effect on LV remodelling.
Abstract 18787: Population-Based Data from Western Alaska Native People Show High Rates of CHD and Stroke Mortality: The WATCH Study
Authors: Metzger Jesse S , Koller Kathleen R , Hopkins Scarlett , Asay E D , Wolfe Abigail W , Kaufmann Cristiane , Austin Melissa A , Umans Jason G , Howard Barbara V , Boyer Bert B
Published: April 2024

Background:
Early low rates of CVD among Western Alaska native people were attributed to consumption of omega-3 rich foods. Mortality data suggest that rates are rising, but no population-based data have been reported.

Methods:
The Western Alaska Tribal Collaborative for Health (WATCH) combines three ongoing population-based studies - EARTH, CANHR, and GOCADAN, as well as data from the ASP. The consolidated cohort, the largest study of Western Alaska Native people, consists of 4,569 men and women >18 yrs of age who underwent baseline exams between 2000 and 2010 and were followed an average of 6.7 years (<1% lost to follow-up). CHD, stroke, and all CVD mortality were reviewed and adjudicated using standardized criteria. CHD deaths included MI, definite sudden death due to CHD, and definite fatal CHD. Stroke included those with evidence of rapid fatal onset of localized neurologic deficit or imaging consistent with stroke. CVD included CHD, stroke, and other fatal CVD. Age-adjusted rates (to the 2000 US census) were compared with those of US Whites and Blacks.

Results:
The baseline cohort was 54% female (mean age 40y for men and 42y for women) (Table). After an average 6.7 years, there were a total of 48 CVD deaths, 30 from CHD, and 17 from stroke. In Western Alaska native people, CHD mortality was similar to that of US Whites, with mortality in men exceeding that in women, but somewhat lower than rates for US Blacks; stroke mortality was similar in men and women, exceeding rates in both US Whites and Blacks.

Conclusions:
These results demonstrate high rates of CVD mortality, especially for stroke, compared with US Whites and Blacks, suggesting increasing rates in Western Alaska native people. Longer follow up to increase sample sizes is needed to confirm this trend, and the role of risk factors in these changes needs investigation. However, even these limited data suggest that community-based CVD prevention is needed in these populations.
Abstract 18804: Relationship of Left Ventricular Circumferential Strain with Preload and Afterload Using Feature-Tracking MRI
Authors: Holtzman Dvorah G , McLaughlin Jeannette , Rhee Peter , Kadiyala Madhavi , Cao Jie J
Published: April 2024

Background:
Myocardial Strain is a sensitive measure of left ventricular (LV) global and regional myocardial deformation. Its association with preload and afterload is yet to be elucidated. We assessed circumferential strain using Feature-tracking (FT) MRI and investigated the relationship of strain with preload and afterload using hemodynamics assessed during left heart catheterization.

Methods:
Forty nine patients undergoing clinical cardiac catheterization were prospectively recruited for same day research cardiac MRI. Circumferential strain was assessed by analyzing endocardial deformation of the cine images in mid LV short axis planes using FT-MRI (Diogenes TomTec Imaging Systems). LV end diastolic pressure (LVEDP) and LV end systolic pressure (LVESP) were assessed during cardiac catheterization. Meridional wall stress was calculated using the formula: σ
m
=PR/2h (l+h/2R) where p was the pressure, R the radius and h the average myocardial wall thickness. LV preload and afterload were defined as the meridional wall stress at end diastole and systole.

Results:
The cohort mean age was 60 ± 13 years, 32 (65%) male. The average circumferential strain was -22.5±7.9%, LV ejection fraction (LVEF) 50 ± 14%, LVEDP 16±7 mmHg and LVESP 135±28 mmHg. In a univariate analysis, circumferential strain was most strongly associated with LVEF (r=-0.91, p < 0.001) followed by LV end systolic volume (r= 0.864, p< 0.001), LV end diastolic volume (r= 0.790, p < 0.001) and LV mass (r=0.572, p<0.001). Of LV hemodynamic properties, strain was associated with LVEDP (r=0.517, p< 0.001) but not with LVESP (r=-0.110, p = 0.450). However, the association became much stronger when hemodynamics were expressed as preload (r=0.681, p<0.001) and afterload (r= 0.820, p< 0.001). In a multivariate linear regression model adjusting for LVEF, LV mass, LVESP, LVEDP, preload and afterload , circumferential strain was only associated with LVEF (p <0.001) and afterload (p=0.009).

Conclusion:
Circumferential strain assessed by FT- MRI is a sensitive measure of left ventricular systolic function. Preload and afterload are more important than intraventricular pressure alone in the relationship of strain to hemodynamics. However, afterload is likely the most important hemodynanic variable.