bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1103: Integrin-linked Kinase and Laminin alpha 4 Mutations Cause Human Cardiomyopathy
Authors: Knöll Ralph , Postel Ruben , Krätzner Ralph , Hennecke Gerrit , Vacaru Andrei M , Vakeel Padmanabhan , Knöll Gudrun , Schäfer Katrin , Bos Erik , Hertog Jeroen den , Peters Peter J , van Eeden Fredericus , Schaper Jutta , Schaper Wolfgang , Hasenfuss Gerd , Schultheiss Heinz-Peter , Chien Kenneth R , Bakkers Jeroen 
Published: July 2021

Background - Dilated Cardiomyopathy (DCM) is a syndrome characterized by ventricular dilation, contractile dysfunction and symptoms of congestive heart failure. Extracellular matrix proteins such as laminins as well as endothelial cells are known to influence cardiomyocyte performance, however a molecular link between mutations in the ECM and DCM has not been provided.
Methods and Results - Using a forward genetic screen in zebrafish to identify novel genes required for myocardial function we were able to identify the lost-contact (loc) mutant, encoding a nonsense mutation in the integrin-linked kinase (ILK) gene. This loc/ilk mutant is associated with both, a severe defect in cardiomyocytes as well as in endothelial cells leading to severe myocardial dysfunction. Additional experiments revealed the epistatic regulation between the ECM component laminin alpha 4 (LAMA4), integrin and ILK, which led us to screen for mutations in the human ILK and LAMA4 genes in patients with severe dilated cardiomyopathy (DCM). We identified two novel amino acid residue altering mutations (2828C>T (Pro943Leu), 3217C>T (Arg1073X)) in the integrin interacting domain of the LAMA4 gene and one mutation (785C>T (Ala262Val)) in the ILK gene. BIAcore quantitative protein/protein interaction data, which have been used to determine the equilibrium dissociation constants, point to the loss of integrin binding capacity in case of the Pro943Leu (KD=5 +/− 3 uM) and Arg1073X lama 4 (KD=1 +/− 0.2 uM) mutants in comparison to the wildtype lama 4 protein (KD = 440 +/− 20 nM). Cell attachment assays point to a defect in endothelial cell adhesion when LAMA4 mutants have been expressed in vitro and used as a substrate. 785C>T (Ala262Val) ILK did not change its affinity, as measured by GST pull down assays as well as by a yeast 2 hybrid analysis, to a well known interacting protein such as b-parvin but revealed a 63% decrease in kinase activity. Additional functional data point to the loss of endothelial cells in affected patients as a direct consequence of the mutant genes, leading ultimately to heart failure.
Conclusions - We report the first human mutations in the LAMA4, integrin and ILK system and provide a new mechanistic basis for DCM in man, which involves endothelial cells as well as cardiomyocytes.
Abstract 1391: Atherogenic Dyslipidemia Predicts Accelerated Progression of Atherosclerosis in Patients with Coronary Artery Disease
Authors: Galla John M , Tuzcu E. M , Wolski Kathy , Kalidindi Srinivasa , Nissen Steven E , Nicholls Stephen J 
Published: July 2021

Background: Atherogenic dyslipidemia (AD) is characterized by the combination of elevated serum triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and small-dense low-density lipoprotein cholesterol (LDL-C) and has emerged as a powerful risk factor of coronary disease. The effect of AD on the progression of plaque burden remains incompletely defined. This analysis aimed to determine the impact of AD on measures of atherosclerotic progression in patients receiving intensive lipid lowering therapy.
Methods: 910 patients with angiographic coronary artery disease treated with atorvastatin to a goal LDL-C of 100 ± 15mg/dl received torcetrapib or placebo. Atheroma burden was determined by intravascular ultrasound performed at baseline and following 24 months of treatment. Baseline and changes in atheroma burden were investigated in patients stratified according to the presence or absence of an AD phenotype (HDL-C < 45 mg/dL for men and < 50mg/dL for women, triglycerides 150 – 600mg/dL and LDL-C < 160mg/dL)
Results: 20.4% of patients met the criteria for AD. Patients with AD were younger (55.5 v 58 years, p=0.003), had higher body mass index (30.9 v 29.3 kg/m2, p<0.001) and were more likely to fit the definition of the metabolic syndrome (93 v 30.3%, p<0.001). Accelerated progression of percent atheroma volume (PAV, +0.76 v +0.01%, p=0.001) and total atheroma volume (TAV, −4.75 v −7.18 mm3, p=0.022) was observed in patients with AD. Patients with AD were less likely to undergo substantial regression (reduction in PAV >5%, 12.9% v 24.2%, p=0.001) and more likely to undergo substantial progression (increase in PAV >5%, 34.9% v 23.2%, p=0.001) No differences were observed between treatment groups with regard to changes in PAV (0.59 v 0.99%, p=0.727) or TAV (−5.7 v −3.8 mm3, p=0.461) in patients with AD. On multivariate analysis, the presence of atherogenic dyslipidemia was an independent predictor of increase in PAV (p=0.004) and TAV (p=0.045).
Conclusions: Despite aggressive lipid lowering therapy, AD is an independent predictor of accelerated progression of atherosclerosis. With a rise in the prevalence of obesity and its metabolic complications there is an increasing need to intensively modify factors that place these patients at high risk.
Abstract 1410: Clarithromycin Inhibited MMP-9 Activation and Attenuated Acute and Chronic Rejection in Murine Cardiac Allografts
Authors: Suzuki Jun-ichi , Ogawa Masahito , Takayama Kiyoshi , Isobe Mitsuaki 
Published: July 2021

Background: Matrix metalloproteinases (MMPs) are critical in the development of inflammation and tissue remodeling. MMP-9 is a key member of MMPs and the level is associated with the rejection of heart transplantation. Clarithromysin (CAM), a major macrolide antibiotic, has been many biological functions including MMP regulation. However, little is known about the effect of CAM in heart transplantation via MMP-9.
Methods and Results: To clarify the role of MMPs regulated by CAM in the progression of rejection, we orally administered CAM (100mg/kg) into murine cardiac allograft recipients. CAM improved acute rejection judged by graft survival (control: 7.3+/−0.2 days n=8; CAM: 9.7+/−0.2 days n=8; P<0.05) and by myocardial cell infiltrating area (control: 35.7+/−1.9% n=9; CAM: 19.7+/−3.0% n=9, P<0.05) in a total allomismatch combination. 8 weeks after transplantation, CAM significantly suppressed the development of graft arterial disease (5.1+/−3.0%, n=6) compared to that of non-treatment (25.1+/−6.3%, n=6; P<0.05) in the class II mismatch combination. Immunohistochemically, non-treated allografts showed enhanced expression of T-cells, macrophages, MMP-9 and NF-kappaB while CAM decreased these positive cell numbers. RPA also revealed that CAM-treated allografts significantly attenuated the expression of proinflammatory cytokines such as IFN-gamma, IL-6, IL-10 and IL-15 compared with non-treated grafts. In situ zymography indicated that enhanced MMPs activities were observed in non-treated hearts, while CAM suppressed the levels. In vitro study showed that CAM inhibited the expression of MMP-9 using Western blot and RT-PCR in cytokine stimulated macrophages and SMCs. The effects of inhibited MMP-9 by CAM suppressed SMCs migration (native: 23.5+/−4.5 cells, control: 97.0+/− 5.0, CAM: 53.4+/−4.5, P<0.05) and proliferation (native: 0.44+/−0.01OD, control: 0.56+/−0.03, CAM: 0.44+/−0.004, P<0.05) compared with control.
Conclusion: CAM is useful to suppress allograft remodeling because it is critically involved in the prevention of cardiac rejection through the suppression of MMP-9.
Abstract 1504: Increased Expression of Stem Cell Factor and its Receptor Following LVAD: A Potential Novel Target for Therapeutic Interventions In Heart Failure
Authors: Jahanyar Jama , Youker Keith A , Noon George P , Torre-Amione Guillermo , Koerner Michael M , Loebe Matthias 
Published: July 2021

Introduction: Previous studies have demonstrated the involvement of mast cells (MCs) in cardiac remodeling during heart failure. LVADs cause an influx of MCs into the failing heart, but the underlying mechanism is unknown. We hypothesize that stem cell factor (SCF) induces migration of MCs to the heart. This study investigates the potential role of SCF and its receptor (C-Kit) in promoting the recruitment of stem cell derived MCs during heart failure and following LVAD support.
Methods: Myocardial samples were collected from 10 patients undergoing LVAD implantation (Pre-LVAD) paired with samples taken at the time of heart transplantation (Post-LVAD). Biopsies of 4 normal hearts served as controls. We assessed gene expression of SCF and C-Kit. Additionally, we stained for SCF, C-Kit and tryptase protein and utilized In-situ hybridization to determine the origin of SCF.
Results: Real-time PCR: SCF mRNA is significantly increased (P<0.01) following mechanical circulatory support as compared to paired heart failure tissue. C-Kit mRNA was significantly increased post-LVAD, as compared to normal tissues (p<0.05).
Immunohistochemistry: The C-Kit protein was only expressed on cardiac mast cells. In-Situ hybridization: SCF mRNA was found in endothelial cells, myocytes and interstitial cells. This was confirmed by antibody staining for the SCF protein.
Conclusions: LVADs cause an increase of SCF and C-Kit gene expression during unloading. SCF appears to be an important mechanism for the recruitment and maturation of MCs involved in cardiac remodeling, and we suggest that pharmacologic or biologic modification of SCF may provide a new therapeutic path for heart failure treatment.
Abstract 1641: Attenuation-correction Does Not Improve Quantitative Diagnostic Performance of Myocardial Perfusion SPECT in Women
Authors: Wolak Arik , Slomka Piotr J , Fish Mathews B , Gerlach James , Lorenzo Santiago , Berman Daniel S , Germano Guido 
Published: July 2021

BACKGROUND: Attenuation Correction (AC) for myocardial perfusion single photon emission computed tomography (MPS) had not been evaluated separately in female population despite specific considerations in this group due to breast photon attenuation. We aimed to compare the performance of AC in women using automated quantitative analysis of MPS.
METHODS: Consecutive female pts, 137 low likelihood (LLk) and 115 with coronary angiography performed within < 3 months of MPS, referred for rest/stress ECG gated Tc-99m sestamibi MPS with AC (Vantage Pro, Philips), were considered. Imaging data were evaluated for contour quality control (QC). Additional 50 female LLk studies were used to create equivalent normal limits for studies with AC and with no correction (NC). An experienced technologist (JG) blinded to the angiography and other results performed contour QC. All other processing was performed in a fully automated manner. Quantitative analysis was performed using Cedars Cardiac Suite version 2005, (QPS). All automatic segmental analysis was performed in 17-segment/5 point AHA model. Summed Stress Scores (SSS) ≥ 4 were considered abnormal. Receiver Operator Characteristics (ROC) areas-under- curve (AUC) were obtained by Analyze-It (v 1.171) statistical package.

RESULTS: CAD (≥ 70% stenosis) was present in 70/115 (61%) pts. The normalcy rates were 96% and 98% for studies with and without AC, respectively (P=NS). SSS in studies with or without AC were the same with the exception of normal patients were SSS was higher for studies with AC. The diagnostic performance of MPS with and without AC for detection of CAD is summarized in the table

.

Conclusions: There are no diagnostic differences between quantitative MPS analysis with or without AC in women and no gain in specificity or normalcy rates contrary to previously reported findings in general populations.
Abstract 1642: Head-to-Head Comparison of Myocardial Perfusion SPECT Imaging and Delayed Enhancement Magnetic Resonance Imaging to Detect Myocardial Infarction
Authors: Carlsson Marcus , Arheden Hakan 
Published: July 2021

PURPOSE: Direct visualization of myocardial infarction is possible by delayed enhancement MRI (DE-MRI). The method has been validated in animal studies and patients and is considered to be the reference method for infarct assessment. However, myocardial perfusion SPECT has remained the most common method to depict stress induced ischemia and gives simultaneous information on myocardial infarction. The accuracy of gated SPECT for infarction assessment has been under debate stating that SPECT has limited sensitivity. Therefore, the aim of this study was to determine the sensitivity and specificity of gated SPECT for infarct assessment using MRI as reference method.
METHODS: 96 patients (32 females) referred for myocardial perfusion SPECT imaging were included. A body weight adjusted dose of technetium labelled tetrofosmin was injected at rest and during adenosine infusion and gated SPECT images were aquired in all but 2 patients where SPECT were acquired without ECG-gating. In all patients, DE-MRI were performed the same day. All images were evaluated visually with the observers blinded to all clinical data and to the results of the other imaging study.
RESULTS: In 29 patients infarcts were visualized by MRI. Of these, 25 patients had infarct detected by gated SPECT. Thus, the sensitivity and specificity for infarct detection by gated SPECT on patient basis were 86% and 97%, respectively.
CONCLUSION:. This study has showed high sensitivity and very high specificity for gated SPECT on a patient basis for infarct detection. Thus, gated SPECT can be used for infarct detection with good accuracy in patients with suspected ischemic heart disease.
Abstract 1675: Effect of Rosiglitazone versus Placebo on Rapid Angiographic Progression of Non-Culprit Coronary Lesions in Patients with Type 2 DM
Authors: Finn Aloke , Oh Jae S , Hendricks Michael , Daher Maureen , Nadelson Jeffrey , Crimins Johanna , Kastrati Adnan , Schomig Albert , Bruskina Olga , Palacios Igor , John Michael C , Gold Herman K 
Published: July 2021

Background: We examined the effect of 4mg/day rosiglitazone (RSG) versus placebo (PLC) on rapid angiographic progression (RAP) of non-culprit coronary lesions (NCCL) in type 2 diabetes (DM 2).
Methods: Using biomarkers and angiograms from 43 DM 2 enrolled in a randomized controlled double blind trial examining the effects of RSG or PLC on late loss after PCI, we investigated the effects of RSG on RAP of NCCL using logistic regression. All stenoses >=30% of vessel diameter were identified at baseline and quantified by QCA. Patients had 8 month angiography and biomarkers (HOMA (insulin resistance index), insulin, MMP-9, adiponectin (ADI), fibrinogen, hs-CRP, A1C, and LDL and HDL cholesterol) drawn at baseline and 4 months. RAP was defined as >=20% diameter reduction of pre-existing NCCL by QCA, or a new narrowing >=30% arising in a segment angiographically normal at baseline.
Results: There were 52 NCCL in the RSG versus 56 in the PLC. 14.8 % (16/108) of lesions had RAP with 7/52 (13.5%) lesions progressing in RSG versus 9/56 (16.1%) in PLC, p=ns. RSG was not a predictor of RAP. Of the biomarkers and angiographic variables examined, hsCRP was the only predictor of RAP. Patients with a 120 day hsCRP above the 75th percent had an OR of 7.35 [2.35,23] for RAP versus those below. Interestingly, although RSG treatment lowered hsCRP at 4 months (RSG 2.03Â±2.8 mg/dl vs. Placebo 3.37Â±4.25, p=0.06), it did not decrease the likelihood of plaque progression in either the low or high hsCRP groups (see graph). LDL levels at this time were not different (RSG 74Â±23 mg/dl vs. PLC 89Â±32, p=ns).
Conclusion: 120 day hsCRP is a predictor of RAP. Despite lowering 120d hsCRP, RSG did not lower the frequency of RAP.
Abstract 1706: Elevation of Pericardial Fluid Active Matrix Metalloproteinase-9 (MMP-9) Level Is Closely Associated With Left Ventricular Remodeling
Authors: Miyamoto Shoichi , Inoko Moriaki , Nagai Kunihiko , Nakane Eisaku , Abe Tomomi , Sasaki Kenichi , Nakashima Junji , Tanaka Nozomi , Uehara Kyokun , Ueyama Koji , Hosokawa Ryohei , Nohara Ryuji , Fujita Masatoshi 
Published: July 2021

Background: The development of congestive heart failure (CHF) is associated with left ventricular (LV) remodeling. However, fundamental mechanisms that contribute to this remodeling process remain unclear. The matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been demonstrated to play a significant role in tissue remodeling through a number of pathological processes.
Objectives: The purpose of this study was to investigate whether MMPs and TIMPs represent autocrine/paracrine factors and are accumulated in pericardial fluid. We previously reported that active MMP-2 levels in pericardial fluid served as more sensitive and accurate indicators of LV remodeling than did active MMP-2 levels in plasma.
Methods: We measured the concentrations of the enzyme (active MMP-9) in both plasma and pericardial fluid in 20 patients during coronary artery bypass graft surgery.
Results: The active MMP-9 level was significantly higher in pericardial fluid than in plasma (4.68 ± 1.17 vs. 2.58 ± 0.29 ng/ml, p<0.0001). Interestingly, the pericardial fluid levels of active MMP-9 were significantly higher in patients with impaired LV function than in those with normal LV function (5.25 ± 0.57 vs. 2.96 ± 0.65 ng/ml, p<0.0001). Pericardial fluid active MMP-9 levels had closer relations with LVEDVI (r=0.459, p=0.047) and LVESVI (r=0.490, p=0.0321) than did plasma active MMP-9 levels (LVEDVI: r=0.065, p=NS; LVESVI: r=0.254, p=NS). Active MMP-9 levels in pericardial fluid but not in plasma inversely correlated with LV ejection fraction (r=−0.626, p=0.0033).
Conclusions: Active MMP-9 levels in pericardial fluid serve as more sensitive and accurate indicators of LV remodeling than did active MMP-9 levels in plasma. Thus, active form of MMP-9 may be also secreted from the heart into the pericardial space with the progression of CHF, and it may have a pathophysiologic role in LV remodeling process as an autocrine/paracrine factor.
Abstract 1736: Is There An Indication For Transcoronary Ethanol VT Ablation In 2007?
Authors: Sacher Frederic , Sobieszcyk Piotr , Tedrow Usha , Einsenhower Andrew , Seldwyn Andrew , Raymond Jean-Marc , Koplan Bruce , Epstein Laurence , Stevenson William 
Published: July 2021

Introduction: TransCoronary Ethanol Ablation (TCEA) was proposed 15 years ago for incessant VTs resistant to any treatment (medications or ablation). However we sought to investigate whether this therapy could still be useful in the area of modern radiofrequency ablation.
Methods: Eight patients (6 males, 55 ±7yo, 2.1 ±0.8 failed VT ablations) out of 586 VT ablation procedures underwent TCEA between 2000 and 2006. After identification of the artery supplying blood to the arrhythmogenic area, an angioplasty balloon was advanced in the artery then VT was induced and cooled saline infusion was performed distal to the balloon. If this did not interrupt VT another artery was targeted. If VT stopped, 1 to 5 ml of pure ethanol (96%) was injected.
Results: All patients had scar related VT (septal:7, left inferior wall:1) with 4 pts having a non ischemic cardiomyopathy. Mean left ventricle ejection fraction prior to the procedure was 23 ±9%. In patients with septal scar, 1st and/or 2nd septal artery were targeted in 5 pts whereas for 2 this was not effective and a distal branch of the circumflex and the conus branch of the right coronary artery were targeted in 2. A branch of the posterior descending artery was targeted in the patient with inferior scar. Acute success was obtained in 5/8 (63%). Two patients experienced complications (transient cardiac stunning after ethanol infusion and delayed AV block). Twenty-four hours after the procedure, mean troponin Ic [0 – 0.1 ng/ml] and CPK-MB [0–5 ng/ml] were respectively 19.75 ±12.79 ng/ml and 121 ±108 ng/ml, mean ejection fraction was 18 ±8%(NS compared to before). With a mean follow-up of 29 ±23 months, 6/8 (75%) patients are still alive with no recurrence in 4 (50%).
Conclusion: TCEA is an option in cases of refractory VT who fail radiofrequency ablation, especially in cases of septal scar.
Abstract 1792: Multiple Biomarker Utilization for Detection of Myocardial Infarction Based on Presentation Sample in Patients with Symptoms Suggestive of Acute Coronary Syndrome
Authors: Apple Fred S , Smith Stephen W , Pearce Lesly A , Murakami MaryAnn M 
Published: July 2021

OBJECTIVES: To determine if multiple biomarkers representative of numerous pathophysiologic pathways increase diagnostic accuracy for early detection of myocardial infarction (MI) in patients presenting with symptoms of acute coronary syndrome (ACS).
BACKGROUND: Cardiac troponin has been accepted as the preferred biomarker for detecting myocardial injury and acute myocardial infarction.

METHODS: Seven biomarkers (myeloperoxidase (MPO), soluble CD40 ligand (CD40L), placental growth factor (PIGF), metalloproteinase-9 (MMP-9), high sensitive C-reactive protein (hsCRP), cardiac troponin I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP)) were measured on admission plasma specimens and estimated glomerular filtration rate (eGFR) calculated in 457 patients presenting with symptoms suggestive of ACS. Median time from symptom onset to presentation was 3.1 hours. Twenty-five (5.4%) patients were diagnosed with acute MI (ICD 410.×1 code). Clinical sensitivities and specificities of each biomarker for AMI were determined based on 99
th
percentile reference values. Forward and backward stepwise logistic regression modeling techniques were used to identify biomarkers independently predictive of AMI.

RESULTS: Clinical sensitivity of the biomarkers ranged from 20% to 96% with specificity ranging from 19% to 89%. Highest clinical sensitivity was MMP-9 but specificity was only 19%. cTnI demonstrated a clinical sensitivity of 72% and specificity of 89% with false negatives occurring in 7 patients and false positives in 49. In multivariate models, cTnI (p < 0.001) and either hsCRP (p = 0.009) or MMP-9 (p = 0.03) and cTnI were independently predictive of AMI. hsCRP or MMP-9 increased specificity to 95% or 94% respectively but reduced sensitivity to 56% and 68% respectively relative to cTnI alone.

CONCLUSION: Our findings support utilization of cTnI alone, rather than a multi-biomarker approach, when using an analytically robust assay based on the 99
th
percentile reference value decision cutoff, as the most clinically accurate biomarker for the early diagnosis of AMI.