bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18078: Hdac4 Degradation Involves Hdac Inhibition-Induced Protective Effects in Hypoxia in Mouse Cardiomyocytes
Authors: Zhao Ting C , Du Jian Feng
Published: April 2024

Background:
Histone deacetylases (HDACs) have been recently demonstrated to play critical roles in modulating myocardial protection and cardiomyocyte survivals in response to stress. However, the molecular mechanism(s) of specific HDACs attributable for the regulation of myocyte survivals are poorly understood. Objective: Our goal was to investigate whether HDAC inhibition elicits a protective effect through specific HDAC4, and whether HDAC4 ubiquitination involves induction of cellular protective effect in mouse cardiomyocytes exposed to hypoxia/re-oxygenation.

Methods:
Neonatal mouse cardiomyocytes (1-3 day old) were isolated and then subjected to 48 hours of hypoxia (1% oxygen) followed 2 hours of reoxygenation. Prior to hypoxia cardiomyocytes were infected with adenoviral HDAC4 and adenoviral GFP. Cardiomyocytes were preconditioned with trichostatin A (TSA, 50nmol/L) to block HDAC activity, whereas MG132 (0.2 μmol/L), a selective proteasome inhibitor, was utilized to inhibit the proteasome pathway. The cytotoxicities were estimated by detection of lactate dehydrogenase (LDH) and myocyte viabilities were measured by MTT assays. Western blot was employed to assess HDAC4 degradation. RT-PCR was performed to analyze HDAC4 mRNA.

Results:
Inhibition of HDACs with TSA enhanced cardiomyocyte viabilities and reduced the LDH leakages of cardiomycytes during hypoxia/reoxygenation. Pretreatment of myocytes with MG132 abolished the protective effects of TSA. Infection of myocytes with adv-HDAC4 mitigated HDAC inhibition-induced protection. Co-immunoprecipitation assay and Western blot indicate the HDAC4 uniquitination following TSA treatments. TSA specifically resulted in the reduction of HDAC4 protein, but not mRNA, which was blocked by MG132.

Conclusion:
HDAC inhibition protects cardiomyocytes against hypoxic stress, which depends on HDAC4 and HDAC4 ubiquitination.
Abstract 18114: Continuous Flow LVAD Technology Has Influenced Wait Times and Impacted Donor Allocation in Cardiac Transplantation
Authors: Taghavi Sharven , Jayarajan Senthil N , Komaroff Eugene , Mangi Abeel
Published: April 2024

Introduction:
Bridge to transplantation (BTT) patients with continuous flow Left Ventricular Assist Devices (cfLVAD) are assigned UNOS Status 1A or 1B priority while awaiting heart transplantation (OHT). The influence of cfLVAD on waitlist times and organ allocation was investigated.

Hypothesis:
We hypothesized that cfLVAD patients on the waitlist live longer, allowing them to wait for more favorable donors.

Methods:
The UNOS database was examined from 2005-2012 for all OHTs. The pulsatile flow (pLVAD) era (2005-2008) was compared to the cfLVAD era (2009-2012). The majority of LVADs placed during these 2 eras were corroborated to be pLVAD and cfLVAD respectively. These 2 cohorts were compared to patients that did not receive LVAD.

Results:
Of 16,476 total OHT, 3,270 (19.8%) were BTT. From 2005-2008, 1,389 (16.3%) of OHT were BTT, while from 2009-2012, 1,881 (23.7%) were BTT, marking broader acceptance of device technology (p<0.001). The cfLVAD recipients were older, more often diabetic, and had higher serum creatinine (table). The cfLVAD cohort spent 44.0 days as status 1A while pLVAD patients spent 9.8 days and non-LVAD patients spent 16.4 days as status 1A (p<0.001). The cfLVAD group spent 117.4 numbers of days as status 1B, while the pLVAD cohort spent 104.8 days and non-LVAD group spent 121.7 days in status 1B (p<0.001). One-year waitlist survival was highest in the cfLVAD era (77.5%), as compared to the pLVAD (54.1%) and non-LVAD cohorts (53.6%) (p<0.001). The cfLVAD cohort received older, more male donors that had higher BMI. Ischemic time was lowest in the cfLVAD group. One year post-transplant survival was highest in non-LVAD (91.4%) as compared to cfLVAD (91.0%) and pLVAD patients (87.2%) (p<0.001).

Conclusion:
Despite being older and less favorable recipients, cfLVAD patients spend more time as status 1A and have higher waitlist survival. This may allow cfLVAD patients to receive preferred donor hearts, which may explain their higher post-transplant survival.
Abstract 18119: Mir-16 Modulates Endothelial Dysfunction After Balloon Injury in a Rat Model of Chronic Peripheral Ischemia
Authors: Sorrentino Sabato , Polimeni Alberto , Iaconetti Claudio , Sabatino Jolanda , Gareri Clarice , Carino Annarita , Passafaro Francesco , Colangelo Maria , Covello Caterina , Carvelli Alessandra , Caria Filomena , Tavernese Andrea , Curcio Antonio , De Rosa Salvatore , Indolfi Ciro
Published: April 2024

Background:
Peripheral ischemia is associated with endothelial dysfunction in the coronary district and represents an important predictor of future cardiovascular events such as myocardial infarction and stroke. MicroRNAs (miRs) play an important regulatory role in cells of the vascular wall. Thus, the aim of the present study was to evaluate the role of miRs in mediating remote endothelial dysfunction in a model of peripheral ischemia.

Methods and Results:
Wistar male rats, were divided into the following groups: no treatment (sham); vascular injury on the carotid artery by balloon catheter (BI); femoral artery ligation (AL); ligation of the femoral artery followed, after 21 days, by balloon injury (AL+BI). At 21-days-evaluation, real time RT-PCR showed a profound up-regulation of miR-16 levels within ECs extracted by injured carotid artery of AL+BI group compared to the BI group.

A bioinformatics approach revealed highly conserved binding sites for miR-16 in the 3’UTR of ARHGDIA (Rho-GDP dissociation inhibitor 1), an inhibitor of Rho signaling. Interestingly up-regulation of miR-16 was associated with a reduction of the ARHGDIA-transcript levels and a higher activation of the RhoA pathway, with consequent reduction of nitric oxide bioavailability. Accordingly, inhibition of miR-16 in ECs resulted in increased mRNA and protein levels of eNOS, with increased NO production, while up-regulation of miR-16 resulted in increased NF-kB activation in ECs.

Conclusions:
The expression levels of miR-16 are increased in the vascular endothelium of injured arteries in rats with a model of chronic peripheral ischemia, over rats without peripheral ischemia. Such modulation of miR-16 levels may play a key role in modulating endothelial dysfunction through modulation of the RhoA signaling pathway and the transcription factor NF-kB.
Abstract 18135: Synthetic Cannabinoids-Induced Thrombotic Microangiopathy Leading to Acute Heart Failure
Authors: Khanagavi Jagadish , Phatak Prajakta , Kolte Dhaval , Aronow Wilbert S , Lanier Gregg
Published: April 2024

Background:
Synthetic cannabinoids (SCs) are psychoactive compounds marketed as bath additives, incense products and smoked as drugs of abuse. Reports of illnesses attributed to it are on the rise and not much is known about their cardiovascular effects. This is the first reported case of SCs-induced thrombotic microangiopathy leading to acute decompensated heart failure.

Case:
A 20-year-old man with no prior medical problems presented with two seizure episodes. His blood pressure was 176/88 mm Hg and heart rate was 104/minute. Physical exam was unremarkable. Laboratory tests showed anemia, thrombocytopenia and elevated serum creatinine. Elevated serum lactate dehydrogenase level, low haptoglobin and presence of schistocytes confirmed intravascular hemolysis. ADAMTS13 levels and complement levels were normal. A diagnosis of atypical hemolytic uremic syndrome was made and patient started on plasmapharesis. Initial echocardiogram showed normal ventricular function. During hospital course patient developed acute pulmonary edema and fluid overload. Repeat echocardiogram demonstrated severely reduced left and right ventricular function. Patient underwent right heart catheterization and endomyocardial biopsy that showed thrombotic microangiopathy. He was started on inotropes and put on venoarterial extracorporeal membrane oxygenation (ECMO). Patient was continued on plasmapharesis and immunoglobulin therapy that resulted in significant improvement of cardiac function in the next six weeks. Further questioning revealed that patient regularly used marijuana and the synthetic cannabinoid SPICE over the prior few months. His urine was positive for tetrahydrocannabinol and serum toxicology showed two synthetic cannabinoids: Hebrew University (HU) - 320 and SPICE (CP 47,497).

Discussion:
Synthetic cannabinoids can trigger thrombotic microangiopathy and cause acute heart failure. Direct drug-induced endothelial damage with concomitant activation of the clotting cascade is the likely inciting factor and is related to the cumulative dose of the drug. Strong clinical suspicion and systematic analysis for such agents is required to promptly diagnose cases of unexplained heart failure in young and otherwise healthy patients.
Abstract 18184: Deficiency in the Novel Small Leucin-Rich Repeat Protein Podocan Promotes Pressure Load-Induced Cardiac Hypertrophy
Authors: Speidl Walter S , Shenje Lincoln , Badimon Juan J , Schneider David J , Klotman Paul , Hutter Randolph
Published: April 2024

Background:
Extracellular matrix (ECM) molecules have been increasingly implicated in cardiac remodeling, and in particular the myocardial response to pressure overload. Podocan is a novel member of the small leucin-rich-repeat protein family of ECM proteins. We recently have characterized podocan as an inhibitor of the migration and proliferation of vascular smooth muscle cells. Now we are testing if podocan deficiency has an effect on pressure load-induced cardiac hypertrophy.

Methods and Results:
We induced pressure overload cardiac hypertrophy using aortic banding (AB) in mice (age 10-12 weeks) with podocan-/- (n=6) and wild-type (WT) (n=7) genotype. Four weeks after AB, cardiac anatomy and function were assessed by echocardiography. In addition, histological analysis was used to assess the myocardial response to AB. Podocan-deficient mice showed significantly greater cardiac hypertrophy compared with WT mice after AB, whereas no significant differences were observed when comparing sham-operated animals. Heart to body weight ratio was 6±1 mg/g in WT-mice versus 10±2 mg/g with podocan-/- genotype (P<0.05). The expression of podocan and non-phospho-beta catenin (NPBC), an indicator of canonical Wnt-pathway activation, were evaluated by immunohistochemistry in serial myocardial cross-sections (n=12 per animal) (data as mean % cells±SEM). Four weeks after AB, myocardium from mice with WT-genotype exhibited abundant podocan expression both extra-cellular as well as intra-cellular. Podocan expression was also seen in areas surrounding micro-vessels. As expected, podocan was absent in myocardium from podocan-/- mice. Of note, the nuclear expression of NPBC was strongly increased in podocan-/- myocardium compared with WT (34±7% vs. 11±2%, P<0.05). Immunofluorescence double labeling showed colocalization of troponin-I and NPBC in hypertrophic myocardium with podocan-/- genotype.

Conclusions:
Deficiency in podocan promotes cardiac hypertrophy in response to pressure overload. Greater hypertrophy seen in the absence of podocan was associated with evidence of increased Wnt-pathway activation. This first report of the role of podocan in pressure overload identifies it as a novel and important regulator of myocardial remodeling.
Abstract 182: Medical Comorbidities and Age Both Predict Neurological Outcomes in Survivors of Cardiac Arrest Treated With Hypothermia
Authors: Terman Samuel W , Hume Benjamin D , Silbergleit Robert
Published: April 2024

Introduction:
Age is a known predictor of outcome in comatose survivors of out of hospital cardiac arrest (OHCA), but it is unknown whether this is inherent or because age is a marker for overall health status. In a cohort treated with hypothermia, we hypothesized that age and pre-arrest comorbidities would both contain unique neurological prognostic information.

Methods:
We conducted a retrospective cohort study, reviewing electronic medical records of all patients treated with mild therapeutic hypothermia (MTH) in the University of Michigan Emergency Department for OHCA. We categorized patients’ past medical history into a Charlson Comorbidity Index (CCI). Age was analyzed by decade. Neurologic outcomes were determined 6-12 months post-discharge by Cerebral Performance Category (CPC). Logistic models were evaluated by c-statistics and likelihood ratio tests. Trends were evaluated using one-sided Cochrane Armitage tests.

Results:
After exclusions, 123 patients received MTH between 7/1/2006 and 9/14/2012. Favorable neurological outcomes in patients with CCI 0, 1-2, 3-4, and ≥5 are shown (figure). Odds ratio (95% confidence intervals) by CCI category were 1 (ref), 0.4 (0.1-1.0), 0.5 (0.2-1.7), and 0.2 (0.03-0.9) (c = 0.65, p for trend=0.04). Combined Charlson-age index had slightly higher predictive ability (c=0.71, p=0.0004). CCI added significant predictive ability when added onto a model containing only age (c-statistic increased from 0.71 to 0.78; likelihood ratios p=0.0073). Similarly, age added significant predictive ability when added onto a model containing CCI alone (c-statistic increased from 0.65 to 0.78; p=0.0001)

Conclusions:
Both age and pre-arrest comorbidities are associated with outcome in comatose survivors of cardiac arrest, but the former appears to be a stronger predictor. This may reflect limitations of the health index used, but more likely that age is an independent predictor of prognosis rather than a marker for comorbidity.
Abstract 18226: Finding the Ideal Biomaterial for Aortic Valve Repair
Authors: Toeg Hadi D , Abessi Ovais , Al-Atassi Talal , de Kerchove Laurent , El-Khoury Gebrine , Labrosse Michel , Boodhwani Munir
Published: April 2024

Objectives:
Cusp replacement in aortic valve repair (AVr) is associated with increased long-term repair failure. We measured hemodynamic and biomaterial properties after porcine AVr with 4 types of clinically relevant biomaterials to ascertain which material(s) would be best suited for repair.

Methods:
Porcine aortic roots with intact aortic valves were placed in a left heart simulator mounted with a high-speed camera for baseline valve assessment. The non-coronary cusp (NCC) was excised and replaced with autologous porcine pericardium (APP), glutaraldehyde-fixed bovine pericardial patch (BPP; Synovis™), extracelluar matrix scaffold (CorMatrix™), or collagen-impregnated Dacron (HEMASHIELD™). Biomaterial properties, along with St. Jude Medical™ Pericardial Patch with EnCapTM Technology (SJM), were determined and finite element modeling of the aortic valve and root complex were constructed to determine hemodynamic characteristics and leaflet stresses.

Results:
Post-repair geometric orifice areas were significantly reduced in the HEMASHIELD™ (5.06 cm2 [4.24-5.73];P<0.05), and CorMatrix™ ( 5.27 cm2 [4.57-5.56]; P=0.0001) groups when compared to unrepaired valves (6.08 cm2 [5.82-6.83]). Finite element modeling of biomaterials displayed differences in percent changes in total Von Mises stress for both repaired (NCC) and non-repaired left and right cusps with SJM (+4%,+24%) and APP (+5,+26%) having lower percent changes than BPP (+12%,+27%), HEMASHIELD™ (+30%,+9%), and CorMatrix™ (+13%,+32%) when compared to unrepaired valve stresses (Table 1).

Conclusions:
Due to increased stresses found in bovine pericardial patch, HEMASHIELD™, and CorMatrix™ groups, these biomaterials may be associated with late repair failure in AVr. Finally, autologous porcine pericardium and St. Jude Medical™ Pericadial Patch have the closest profile to normal aortic valves; therefore, use of either biomaterial may be best suited.
Abstract 18249: Spatially-Integrated Vectorcardiogram: An Enabling Technique for Arrhythmia Cardiac Gating in High-Field MRI
Authors: Gregory Thomas S , Tse Zion T
Published: April 2024

Background:
Accurate QRS complex detection is essential for Cardiac MR (CMR) gating and Heart Rate (HR) monitoring. Magnetohydrodynamic voltage (V
MHD
) ellipses the real ECG QRS complex in high field MRI, and is severally irregular in patients with arrhythmia. This increases the difficulty of performing CMR imaging.

Objectives:
Detect QRS complexes in arrhythmic ECG signals, robust to effects of MHDs in high-field MRI.

Methods:
ECG data was acquired using an MRI-conditional 12-lead system from two patients diagnosed with Atrial Fibrillation (AF) both outside and in a 3T MRI [1]. A spatially-integrated Vectorcardiogram method (siVCG) was applied for cardiac gating.

The siVCG involves synthesizing a VCG from the ECG (Fig A1-A4) using an inverse Dower transform [2-3]. The resulting VCG (Fig B1-B4) from outside the scanner was then used as a reference to estimate the heart’s principal (HPL) axis and to adapt the VCG pattern of the QRS complex. The VCG inside the MRI was projected onto the HPL axis (Fig C1-C2) to maximize the QRS complex amplitude [1]. The HPL axis was chosen also due to its close alignment with the MRI main field (B
0
) for the minimized V
MHD
(V
MHD
is perpendicular to B
0
). The HPL axis of the projected VCG was numerically integrated along the heart’s perpendicular (HPR) axis (Fig C3). This was performed to take advantage of the
large changes of the VCG signal that happen in the HPL and HPR axes simultaneously during the short duration of the QRS complex
. A threshold was then applied to the result for cardiac gating (D1-D2).

Results:
The siVCG maintained an improvement over the conventional VCG for cardiac gating, with each method having a percent error in these trials of 2.3% and 3.5% respectively (Fig C-D).

Conclusions:
The siVCG provides a notable improvement to cardiac gating in high-field MRI over conventional VCG.
Ref:
[1] Tse, MRM, 2013 [2] Fischer, MRM, 1999 [3] Dower, CC, 1980

Acknowledgements:
NIH U41-
RR019703
, NIH R03
EB013873
-01A1, SBIR-1 R43
HL110427
-01
Abstract 18279: Contemporary Trends of Optimal Evidence-Based Medical Therapy at Discharge for Patients Surviving Acute Myocardial Infarction From Korea Acute Myocardial Infarction Registry
Authors: Lee Jang Hoon , Kim Jae Hee , Jang Se Yong , Park Sun Hee , Bae Myung Hwan , Yang Dong Heon , Park Hun Sik , Cho Yongkeun , Chae Shung Chull
Published: April 2024

Background:
Most published studies about the contemporary trends in optimal medical therapy (OMT) were conducted more than 5 years ago. Furthermore, In Asia, only limited data are available for the recent trend of OMT at discharge after acute myocardial infarction (AMI). The aims of this study is (1) to describe the contemporary, as well as changing, prescribing of 4 effective cardiac medications in post-MI hospital survivors and (2) to determine whether use of 4 effective cardiac medications at the time of hospital discharge differ on the basis of age or gender.

Methods:
The Korea AMI Registry (November 2005-June 2011) were multicenter observational study. We examined the discharge medications among 22,646 post-MI survivors who did not have any documented contraindications to anti-platelet drugs, beta-blockers (BBs), angiotensin converting enzyme inhibitors (ACE-I)/ angiotensin II receptor blockers (ARBs) or statins in 6 periods by 12-month interval. OMT was defined as the use of all 4 indicated medications.

Results:
Particularly marked relative increase from period 1 to period 6 were observed in the use of BBs (from 70.3% to 84.5%) and statins (from 77.4% to 83.2%), whereas less dramatic increases were noted in the use of ACE-I/ARBs. Among ACE-Is/ARBs users, marked increases in the use of ARBs (from 17.4% to 32.2%) and declines in the use of ACE-Is (65.7% to 49.3%) were observed over time. Consistent with these trends, there were also marked increases in the use of OMT (from 48.9% to 62.3%). The odds ratios of the use of OMT from period 1 to period 6 were as follows: 1, 1.11 (p=0.034), 1.18 (p=0.001), 1.32 (p <0.001), 1.41 (p <0.001), and 1.57 (p <0.001), respectively, in overall. The use of OMT was significantly higher in men than women over time (p <0.05). Among patients aged 65 years or less, the use of OMT was significantly higher in men than women, whereas there was no significant difference between men and women over time among patients aged 65 to 75 years. Among patients aged more than 75 years, the use of OMT was significantly higher in women than men over time.

Conclusions:
National health improvement program implemented from 2007 markedly increased the use of all 4 effective cardiac medications, particularly in elderly women who were no more undertreated in our study.
Abstract 18308: Prognostic Value of Stress Echocardiography Appropriateness Criteria for Evaluation of Coronary Artery Disease
Authors: Bhattacharyya Sanjeev , Kamperidis Vasilis , Chahal Navtej , Shah Benoy , Roussin Isabelle , Li Wei , Khattar Rajdeep , Senior Roxy
Published: April 2024

Background:
Appropriateness criteria for stress echocardiography (SE) have been published to reduce the rate of inappropriate testing. There are limited data validating the prognostic value of these criteria in clinical practice.

Methods:
250 consecutive patients undergoing SE for evaluation of known or suspected coronary artery disease were classified into appropriate, uncertain and inappropriate categories according to appropriateness criteria guidelines. A positive SE was defined as the development of new wall motion abnormalities or a biphasic response. The primary end-point was the composite of myocardial infarction and death.

Results:
Of the 250 SE, 120 (48%) were dobutamine studies and 130 (52%) were exercise studies. Of the 250 patients, 156 (62.4%), 71 (28.4%) and 23 (9.2%) were classified as appropriate, inappropriate and uncertain, respectively. A significantly greater proportion of studies classified as appropriate 71(45.5%) demonstrated inducible ischaemia compared to inappropriate studies 9(12.7%) or uncertain studies 4(17.4%), p<0.0001. During a median follow-up of 12.4 months (inter-quartile range 10.6 - 16.3 months), events occurred in 18 (11.5%), 2 (2.8%) and 0 patients classified as appropriate, inappropriate and uncertain respectively. Event-free survival was significantly reduced in patients with a SE demonstrating ischaemia compared to patients without inducible ischaemia, p <0.0001. Kaplan Meier curves demonstrated reduced event-free survival in patients with whose studies were classified as appropriate compared to inappropriate (p=0.01) or uncertain (p=0.05). There was no difference in event free survival between those classified as uncertain or inappropriate (p=0.48). The only independent predictors of mortality or myocardial infarction were a positive SE (hazard ratio 5.39) and left ventricular ejection fraction (hazard ratio 0.95).

Conclusion:
Appropriateness criteria for evaluation of coronary artery disease have the ability to both determine the need for stress testing and identify patients at high risk of ischaemia, subsequent revascularisation and cardiac events.
Abstract 18384: Hypoxia-Induced FOXC2 Expression in Human Endothelial Cells is Dependent on the MEK and PI3K Pathways
Authors: Koo Hyun-Young , Shim Kyoo S , Liu Ting , Millay Meredith , Dietz William , Schultz Kathryn M , Kamide Christine , Misener Sol , Kume Tsutomu
Published: April 2024

FoxC2, a member of the Forkhead box (Fox) transcription factor family, is critical for vascular formation during embryonic development and tumor progression; however, the role of Foxc2 in pathological neovascularization involving ischemic conditions remains largely unknown. To test the hypothesis that FoxC2 is induced and required for hypoxia-induced angiogenesis, in vitro culture of human umbilical vein endothelial cells (HUVECs) under hypoxia and a myocardial infarction (MI) mouse model were employed. FoxC2 expression in both experimental systems was subsequently assessed. Levels of FOXC2 mRNA were transiently increased in HUVECs after 1 hour of hypoxia. Treatment of a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor (U0126) and a phosphatidylinositide 3-kinases inhibitor (LY 294002) significantly blocked hypoxia-induced FOXC2 expression, whereas culture with a MEK1 inhibitor (PD 98059) did not. Consistent with the in vitro observation, expression of Foxc2 was upregulated in ischemic myocardial tissue of murine hearts in a time-dependent manner from day 1 to day 7 after surgically induced MI. We next examined whether Foxc2 deficiency could influence neovascularization and cardiac repair after MI. Echocardiographic measurements of left ventricular ejection fractions and fractional shortening were reduced in heterozygous Foxc2 null mutant (Foxc2+/-) mice after MI compared to wild-type mice, whereas cardiac fibrosis was increased in Foxc2+/- mice. Most significantly, Foxc2+/- mice had a drastic reduction in capillary vessel formation in the ischemic border zone after MI compared to wild-type mice. Collectively, FoxC2 is transiently induced in vascular endothelial cells in vitro under hypoxia and in ischemic murine hearts after MI, and it is essential for neovascularization during ischemic cardiac repair after MI.
Abstract 18398: Amelioration of Cardiovascular Dysfunction by Nobiletin in Diabetic Rats
Authors: Parkar Nishad , Addepalli Veeranjaneyulu
Published: April 2024

Introduction:
Strategies that interrupt the Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) system have been shown to reduce the ensuing threatening risk factors of cardiovascular complications of diabetes by alteration in Extracellular Matrix

Hypothesis:
We hypothesized that interruption of MMP-2 and 9 can reduce cardiovascular dysfunction of diabetes. Objective of this study was to investigate efficacy of Nobiletin in treatment of cardiovascular dysfunction of diabetes. Nobiletin is a citrus flavonoid with MMP-2 and MMP-9 inhibitory activity.

Methods:
Diabetes was induced by Streptozotocin (55 mg/kg i.p.) in wistar male rats. Four week after the induction of diabetes rats were treated with Nobiletin (25 mg/kg, and 50 mg/kg) for a period of three weeks. At the end of eight week hemodynamic parameters like arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10-5 M) and relaxation responses to acetylcholine (10-9 to 10-4 M) were obtained from aortic rings of diabetic rats. Cardiac hypertrophy was measured and histopathology was done using Masson’s Trichrome stain method. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels.

Results:
Diabetes resulted in significant reduction in heart rate, mean arterial pressure, + dp/dtmax and -dp/dtmax (223 ± 26, 83 ± 9 mmHg, 2673 ± 323 and -2035 ± 216 mmHg/s respectively) when compared with normoglycemic group (285 ± 26, 102 ± 8 mmHg, 3546 ± 324 and -3132 ± 235 mmHg/s respectively). Treatment with 50 mg/kg Nobiletin significantly ameliorated these parameters (254 ± 27, 98 ± 9, 3175 ± 357 and - 2932 ± 243 mmHg/s respectively) compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats (% relaxation 56.3 ± 1.83) and significantly higher in combination treated group (% relaxation 31.3 ± 2.31). When compared with diabetic control group, collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group.

Conclusion:
Results of the present study suggest that Nobiletin attenuate cardiovascular dysfunction in diabetic rats by inhibition of MMP-2 & MMP-9 and can be a potential non glycaemic approach for the treatment.
Abstract 18454: Novel Extracellular Matrix Biomarkers as Predictors of Adverse Outcome in Chronic Heart Failure
Authors: Ueland Thor , Nymo Ståle , Kjekshus John , Mcmurray John J , Wikstrand John , Block Dirk , Zaugg Christian , Aukrust Pål , Gullestad Lars
Published: April 2024

Background:
The extracellular matrix (ECM) plays an important role in left ventricular remodeling and changes in expression patterns of ECM proteins may contribute to the progression of heart failure (HF). Endostatin, biglycan and mimecan are ECM proteins that are abundantly expressed in cardiac tissue but have not been evaluated as prognostic markers in HF. We investigated if they were increased in chronic HF and if levels were associated with adverse outcome.

Materials and methods:
Serum endostatin, biglycan and mimecan were measured in 187 HF patients and 57 matched healthy controls. Associations with adverse outcome were assessed in 1428 patients enrolled in the in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. Outcome included the primary endpoint (cardiovascular (CV) death, nonfatal myocardial infarction, nonfatal stroke; n=408), all-cause mortality (n=422), CV mortality (n=344), coronary endpoint (n=330) and CV mortality/hospitalization for worsening of HF (n=535).

Results:
Serum levels of endostatin, biglycan and mimecan were all increased (31-62% p<0.001) in HF patients vs. controls. In univariate analyses and multivariable analysis (adjusting for LVEF, NYHA class, age, BMI, diabetes, sex, intermittent claudication, heart rate, serum creatinine and apoA1 but not CRP and NT-proBNP), endostatin (continuous variable) was associated with all outcomes. However, the predictive value was markedly attenuated and not significant for any outcome after the addition of CRP and NT-proBNP. Biglycan was moderately but significantly associated with all outcome measures (except coronary endpoint) in univariate analysis but not after multivariable adjustment while no associations were observed for mimecan.

Conclusions:
Serum levels of the ECM proteins endostatin, biglycan and mimecan are all elevated in chronic HF, but add no predictive information beyond NT-proBNP for adverse outcome in older patients with advanced chronic systolic HF of ischemic aetiology.
Abstract 18464: Prognostic Value of Cardiac I-123 Metaiodobenzylguanidine Imaging in Patients With Chronic Heart Failure: A Prospective Comparative Study With Fragmented QRS Complexes
Authors: Takahashi Satoshi , Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Ozu Kentaro , Kondo Takumi , Sengoku Kaoruko , Yamamoto Hironori , Kawai Tsutomu , Ishimi Masashi , Hakui Hideyuki , Fukunami Masatake
Published: April 2024

Backgrounds:
Cardiac I-123 metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with chronic heart failure (CHF). On the other hand, fragmented QRS complexes (fQRS) on the 12-lead ECG, which would be thought to reflect myocardial fibrosis, have been associated with poor outcome in CHF patients. However, there is no information available on the comparison of the prognostic values between MIBG imaging and fQRS in CHF patients.

Methods:
We studied 111 CHF outpatients with LVEF <40% in our prospective cohort study. The cardiac MIBG heart-to-mediastinum ratio (H/M) and washout rate (WR) were calculated from the chest anterior view images obtained at 20 and 200 min after isotope injection. Abnormal WR was defined as > 27%. fQRS was defined by the presence of >2 notches on the R wave or the S wave and had to be present in >or=2 contiguous inferior (II, III, aVF), lateral (I, aVL, V(6)) or anterior (V(1) to V(5)) leads.

Results:
During a follow up period of 7.8±4.4 yrs, 39 patients had cardiac death. At multivariate Cox analysis, WR (p=0.0002) and LVEF (p=0.0035) were significantly independently associated with cardiac death, while H/M at the delayed image (p=0.003) and fQRS (p=0.088) showed the association with cardiac death at univariate analysis. Patients with abnormal WR (>27%) had a significantly higher risk of cardiac death than those with normal WR (55% (31/56) vs 15% (8/55), p<0.0001, adjusted hazard ratio 4.1 (95%CI 1.8-9.7)), while there was a tendency of higher risk of cardiac death in patients with fQRS (63%(10/16) vs 31%(29/95), p=0.08, hazard ratio 1.9 (95%CI 0.9-3.9)).

Conclusion:
The cardiac MIBG imaging had more valuable prognostic value than fQRS in CHF patients.
Abstract 18508: Exposure of Adipocytes to High Mobility Group Box 1 Impairs Insulin Signaling via RAGE, While Stimulating Monocyte Recruitment Through TLR2
Authors: Chen Yan , Li Guangping , Liu Yanxia , Williams Kevin Jon , Liu Ming-Lin
Published: April 2024

Background:
Smokers show increased prevalence of insulin resistance for glucose and type 2 diabetes mellitus (T2DM). The underlying mechanisms, however, remain poorly understood. Tobacco smoke exposure increases tissue expression of high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) that activates innate immunity. We recently reported that exposure of human macrophages to tobacco smoke extract (TSE) provokes the release of HMGB1 in two forms: as a soluble molecule and carried on membrane microvesicles (MV). Both soluble recombinant HMGB1 (rHMGB1) and MV-associated HMGB1 on TSE-induced MVs (TSE-MVs) mediate crucial crosstalk with adipocytes by impairing insulin signaling and by recruiting monocytes to the adipocytes -

GOAL- To identify the receptors on adipocytes that mediate the effects of HMGB1 on insulin signaling and monocyte recruitment.

Methods:
Cultured 3T3-L1 adipocytes were incubated for 24h with rHMGB1 or TSE-MVs, in the absence or presence of neutralizing antibodies against different receptors, followed by assays of signaling responses to insulin and chemoattraction of monocytes across a Boyden chamber.

Results:
Exposure of adipocytes to rHMGB1 or TSE-MVs impaired insulin-induced phosphorylations of IRS1 (Tyr612) and AKT (Ser473) and induced MCP1 secretion and hence monocyte transmigration and adherence to the cultured adipocytes. Neutralizing antibodies against RAGE, but not TLR2, improved insulin signaling in adipocytes exposed to rHMGB1 or TSE-MVs. In contrast, neutralizing antibodies against TLR2, but not RAGE, attenuated the induction of MCP1 secretion, and hence inhibited monocyte transmigration and adherence to cultured adipocytes exposed to rHMGB1 or TSE-MV.

Conclusion:
Our results indicate that soluble and MV-associated HMGB1 that is released from macrophages exposed to tobacco smoke mediates harmful macrophage-adipocyte crosstalk through two pathways: via adipocyte RAGE to impair insulin signaling, and via adipocyte TLR2 to induce MCP1 secretion and monocyte recruitment. These pathways may contribute to insulin resistance for glucose and the development of T2DM in individuals exposed to tobacco smoke.
Abstract 18535: Rare Variants Identified With Whole Exome Chip Genotyping Are Associated With Insulin Resistance and Glycemic Control
Authors: Shah Svati H , Kwee Lydia , Stitziel Nathan , Hauser Elizabeth R , Haynes Carol , Kathiresan Sekar , Gregory Simon G , Kraus William E
Published: April 2024

Background:
Insulin resistance (IR) and type 2 diabetes mellitus (DM) are heritable. Application of genome mapping for these traits, primarily with common variants, has incompletely characterized the genetic architecture. We hypothesized that rare coding variants are associated with IR in individuals without DM, and with glycemic control in individuals with DM.

Methods:
Extracted DNA from 611 Caucasian individuals enrolled in the CATHGEN cardiovascular biorepository at Duke University was genotyped on the Illumina Infinium HumanExome BeadChip (241465 single nucleotide variants [SNVs]). Linear regression was used to test each variant for association with glycated albumin (GA) measured in frozen, fasting plasma (a surrogate for hemoglobin A1c and thus a marker of glycemic control in individuals with DM and of IR in individuals without DM), adjusting for age, sex, batch, and principal component-derived ethnicity.

Results:
In individuals without DM, one SNV in an uncharacterized protein (
KIAA1614
, p=3.1x10
-8
) met genomewide significance (p<10
-7
). Other lesser significant SNVs included genes reporting on ribosomal function (
MRPL44
p=5.5x10
-5
,
LACTB
p=1.7x10
-4
), cellular processes (
CENPP
p=2.6x10
-5
;
MEGF6
p=1.6x10
-4
), ion channels (
KCNT1
p=2.0x10
-5
), protein degradation (
ASB10
p=8.1x10
-5
), and in insulin receptor (
INSR
p=9.4x10
-5
) and carbonyl reductase (
CBR1
p=6.6x10
-5
). In individuals with DM, several SNVs met genomewide significance:
WDR27
(p=8.1x10
-12
),
HELQ
(p=2.0x10
-9
), genes involved in cell cycle processes (
NUP214
p=9.8x10
-9
, PTPRJ p=1.6x10
-8
), cell-cell interactions (
CHST9
p=2.6x10-8, multiple protocadherin [
PCDHG
] genes, p=3.3x10
-8
), ion channels (
CACAN1A
, p=4.2x10
-8
),
MMP13
(p=4.7x10
-8
), and
FBLN5
(p=9.1x10
-8
), involved in vascular development and remodeling.

Conclusions:
We have identified several rare variants in biologically plausible genes reporting on diverse cellular processes that are associated with IR in individuals without DM, and with glycemic control in individuals with DM, that would not have been identified using traditional genomewide association (GWAS) screens. These may serve as novel biomarkers and identify novel pathways of IR and DM pathogenesis.
Abstract 18549: Cardiac MR and CT Virtual Angioscopy Demonstrate Normal Coronary Ostial Morphology in Children With Anomalous Left Coronary Artery With Intraseptal Course
Authors: Brothers Julie A , Kevin Whitehead K , Weinberg Paul M , Paridon Stephen M , Fogel Mark A , Harris Matthew A
Published: April 2024

Background:
Anomalous left coronary artery from the right sinus of Valsalva (ALCA) with intraseptal course is generally considered benign but is often confused on imaging studies with the potentially lethal interarterial, intramural ALCA with associated slit-like orifice. The clinical significance differs between the two subtypes and it is important to differentiate them in order to avoid unnecessary surgical exploration. Limited data exist on intraseptal ALCA in the pediatric population.

Methods:
Medical records were retrospectively reviewed on fifteen pediatric patients diagnosed with ALCA between 11/2009 and 3/2013. We also evaluated their coronary artery origins and courses using cardiac magnetic resonance or computed tomography imaging on each patient and virtual angioscopy for three-dimensional assessment of coronary ostial morphology.

Results:
Patients were 5-18 years at diagnosis; seven (67%) were male. The right and left coronary origins arose from the right sinus of Valsalva as a common origin (N=9) or as a single coronary artery (N=6). Thirteen had an anomalous intraseptal left main coronary; two had anomalous left anterior descending with retroaortic circumflex coronary artery. Anomalous coronary ostia were round without evidence of stenosis on all studies (Figure). Echocardiography identified the anomalous vessel but was neither able to describe the intraseptal ALCA course nor directly visualize or confirm a normal ostium in any patient.

Conclusions:
Using cardiac magnetic resonance or computed tomography imaging, we demonstrate the anomalous coronary course and confirm round coronary ostia without ostial stenosis in our pediatric cohort with intraseptal ALCA. These data provide the basis for understanding the benign clinical course of intraseptal ALCA, differentiating it from the potentially lethal interarterial, intramural ALCA, and avoiding unnecessary surgical exploration.
Abstract 18570: Intronic SCARB1 (Scavenger Receptor Class B Type I, SR-BI) rs10846744 Variant Mediates Functional Effect by Enhancer Activity
Authors: Ali Rashid , Kolmakova Antonina , Christenson Lane , Rodriguez Annabelle
Published: April 2024

Objective:
We previously reported the significant association of
SCARB1
intronic rs10846744 in reducing odds ratio for incident coronary heart disease (CHD) in participants of the Multi-Ethnic Study of Atherosclerosis. Using
in vitro
and
ex vivo
approaches, we sought to define the underlining molecular mechanism for this clinical association.

Methods and results:
Using publicly available genome databases, a bioinformatic screen revealed that rs10846744 resided in a region exhibiting DNase I hypersensitivity and H3K4me1 chromatin methylation markers. Gel shift assays revealed significantly lower binding of nuclear proteins to the probe expressing the risk C allele for CHD (
p
<0.001). Yeast-One Hybrid screening revealed NR2F2 as a candidate transcription factor (TF), while bioinformatic screens (HaploReg v2) predicted binding of multiple TFs such as AP2[[Unable to Display Character: 𝛄]], Max, ERα, FOXA1, GATA3 and p300 to this region. Using RNA Seq, we confirmed that lymphocytes isolated from hyperalphalipoproteinemic (HALP) carriers of the risk C allele had significantly higher NR2F2 expression (6.3-fold upregulated,
p
<0.001). Interestingly, under basal conditions rs10846744 did not significantly regulate SR-BI RNA and protein expression in these lymphocytes. Global metabolic profiling from plasma samples of HALP carriers of the risk C allele had significantly higher markers of oxidative stress (42% higher cysteinyl-glycine, oxidized,
p
=0.0136,
q
=0.2437) and lower levels of lysolipids (46% lower,
p
=0.0043,
q
=0.1605).

Conclusion:
The intronic rs10846744 variant resides within a functionally active regulatory region of
SCARB1
, without directly regulating SR-BI expression itself. Our results confirm the importance of dissecting the pathway by which this region influences CHD.
Abstract 18575: Quantitative Assessment of Aortic Valve Calcification by Cardiac CT in the Penn Diabetes Heart Study: Association With Cardiovascular Risk Factors and Coronary Artery Calcium
Authors: Rafeek Hashmi , Churchill Tim , Rasania Suraj , Terembula Karen , Ferrari Victor , Mulvey Claire , Qasim Atif , Reilly Muredach
Published: April 2024

Background:
Aortic valve sclerosis is a common degenerative process defined by irregular calcification and thickening of the aortic valve leaflets without impairment in leaflet excursion. Aortic valve sclerosis (AVS) can progress to aortic valve stenosis. It has also shown to be associated with an increased frequency of myocardial infarction and mortality. Although thought to be increased among those with type 2DM, AVS has not been well characterized in this population. The aim of this study was to quantitatively measure AVS visualized on cardiac CT in a diabetic population and determine the risk factors associated with AVS.

Methods:
The Penn Diabetes Heart Study is a cross sectional study of T2DM subjects without coronary or renal disease. In all participants free of clinical aortic valve disease and with baseline electron beam cardiac CT, (N=1747, 63.5% male, 61% Caucasian) we quantified aortic valve calcium using the Agatston scoring method. Both logistic and tobit regression, with stepwise backward elimination, were used to examine association of AVS with CHD risk factors.

Results:
AVS was seen in 16.0% of participants. In multivariable logistic regression, AVS was independently associated with older age [OR 3.2, 95% CI (2.6-3.9), p<0.001], male gender [OR 2.1 (1.5-3.0), p <0.001], Caucasian race, and hypertension, [OR 2.45, (1.41-4.26), p<0.001]. Associations were similar across increasing AVS Agatston scores in multivariable tobit regression. AVS was not associated with dyslipidemia, smoking, severity of diabetes, or CRP, but was associated with Lp(a) levels [OR 1.3 (1.12-1.50), p<0.001]. The odds of AVS also increased across increasing levels of coronary artery calcium (CAC) [OR for CAC of 2.2 (1.3-3.8), p = 0.002 for AVS Agatston scores of >0 to 100 and OR of 2.4 (1.1-5.3), p = 0.03 for AVS scores >100) in fully adjusted logistic regression models.

Conclusions:
In diabetics, male gender, Caucasian race, older age, subclinical atherosclerosis and hypertension were independently associated with presence and extent of AVS, but many traditional CHD risk factors were not. This suggests that type 2 DM itself likely may contribute to the development of AVS. Whether AVS is part of the same process as CAC or forms via distinct mechanisms remains to be determined.
Abstract 18583: Posttranslational Modification of Sirt6 Activity by Reactive Nitrogen Species
Authors: Hu Shuqun , Liu Hua , Ha Yonju , Ameril Hossein , Motamedi Massoud , Zhang Wenbo
Published: April 2024

The mammalian sirtuin 6 (SIRT6) is a site-specific histone deacetylase that regulates chromatin structure and fundamental biological processes. It inhibits endothelial cell senescence and inflammation, prevents development of cardiac hypertrophy and heart failure, modulates glucose metabolism and represses tumor growth. The basic molecular mechanisms underlying regulation of Sirt6 enzymatic function remains unknown. Here we hypothesized that Sirt6 function can be regulated via posttranslational modification, focusing on the role of peroxynitrite. Peroxynitrite is one of the major reactive nitrogen species formed by excessive nitric oxide and superoxide generated during cardiovascular diseases. It induces nitration of protein tyrosine residue and alters the structure and function of protein.We found that incubation of purified recombinant Sirt6 protein with various doses (0.5, 1.0, 2.0, 5.0 mM ) of 3-morpholinosydnonimine (SIN-I, a peroxynitrite donor which generates NO and superoxide donor simultaneously) for 30 min at room temperature resulted in increase in Sirt6 tyrosine nitration by 6.6, 8.4, 11.1 and 14.3 fold, respectively. Correlated with the increase in Sirt6 nitration, the intrinsic catalytic activity of Sirt6 was reduced by 43.4%, 47.2%, 53.5% and 70.1% as determined with a Sirt6 deacetylase fluorometric assay kit. Nitration of endogenous Sirt6 were also observed in human umbilical vein endothelial cells and human retinal microvascular cells treated with SIN-1 (5 mM). To further test whether Sirt6 nitration occurs under pathological conditions, we monitored Sirt6 nitration using a model of endotoxin-induced retinal vascular inflammation. Measurement of 3-nitrotyrosine in immunoprecipitated Sirt6 showed that Sirt6 nitration was significantly increased in mice of inflammation. There are four tyrosine residues in Sirt6 which are conserved among human, mouse and rat. Analysis of protein nitration sites by mass spectrometry revealed that tyrosine 257 in Sirt6 was nitrated after SIN-1 treatment. These results demonstrate a novel regulatory mechanism of Sirt6 activity through reactive nitrogen species-mediated nitration under oxidative and nitrative stress.
Abstract 18585: Differential Outcomes in Cardiac Resynchronization Therapy via Surgically Implanted Epicardial LV Leads in Patients With Ischemic and Dilated Cardiomyopathy
Authors: Fu Haixia , CHEN Lu , Wiste Heather , Pretorius Victor , Birgersdotter-Green Ulrika , Cha Yong-Mei
Published: April 2024

Introduction:
Surgically implanted epicardial left ventricular (eLV) lead has been used as an alternative approach when implantation of transvenous LV (tLV) lead in patients requiring cardiac resynchronization therapy (CRT) has failed. Recent literatures noted similarities in clinical response between tLV and eLV-CRT patients. However, comparison between CRT patients with ischemic (ICM) and dilated cardiomyopathy (DCM) is currently lacking in eLV-CRT patients.

Hypothesis:
We hypothesize that DCM patients respond better to eLV-CRT than ICM patients.

Methods:
Of 1038 patients who underwent tLV-CRT implantation at UCSD and Mayo Clinics between 2002 and 2013, 44 (Age 63±15, 28M) had failed tLV lead placement and received eLV-CRT. Electronic Medical Records of these patients were reviewed. NYHA class and echocardiograph were assessed before and after successful CRT implantation.

Results:
Following eLV-CRT implantation, improvements were noted in LVEF (26% vs. 31%, p < 0.01), NYHA class (2.9 vs. 2.3, p < 0.01) and LVESD (57mm vs. 52mm, p = 0.03) in the study cohort. In patients with DCM (n=19), the NYHA class (3.0 vs. 2.3, p = 0.01), LVEF (24% vs. 30%, p = 0.02) and LVESD (57mm vs. 52mm, p = 0.04) had significantly improved following CRT implantation compared to baseline (figures). No statistically significant changes in NYHA class, LVEF and LVESD were observed in patients with ICM (all p > 0.05).

Conclusion:
In this two-center study, eLV-CRT patients with DCM benefited significantly after CRT, as compared to ICM patients. Although larger scaled studies are needed, eLV-CRT may be considered a viable alternative to tLV-CRT, especially in patients with DCM.