bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1390: Composition Analysis of High Density Lipoproteins in Patients with extreme HDL-C Levels with or without Ischemic Heart Disease
Authors: Sethi Amar A , Maureen Sampson , Warnick Russel , Muniz Nehemias , Nordestgaard Boerge G , Tybjaerg-Hansen Anne , Remaley Alan T
Published: July 2021

Objective:
We hypothesize that patients with high HDL-C levels and Ischemic Heart Disease (IHD) may have dysfunctional HDL or have unrecognized non-conventional risk factors.

Methods:
Individuals with verified IHD with either high HDL-C (n=53; female: ≥73.5mg/dL; male: ≥61.9mg/dL) or low HDL-C (n=42; female:≤38.7mg/dL; male: ≤34.1mg/dL) were compared with subjects without IHD and matched HDL-C levels (n=110). All subjects had normal LDL-C (<160mg/dL) and triglyceride levels (<150mg/dL) and none were treated with LDL-C-lowering medications. After removal of apoB lipoproteins, apoA-I, apoA-II, apoE, triglycerides, free cholesterol, cholesteryl ester, and phospholipids were analyzed (Cobas-Fara). HDL and LDL-subclasses were examined by linear gradient gel electrophoresis (Lipoprint®) and by Segmented Gradient Gel Electrophoresis (S-GGE). Cholesterol (RLP-C) and triglyceride (RLP-TG) content of remnant-like lipoprotein particles were measured by an immunoseparation technique.

Results:
Subjects with high HDL-C levels and IHD had lower apo-AI (p<0.001) and cholesteryl ester (p<0.01) levels compared to controls with high HDL and no IHD. Subjects with low HDL-C and IHD had lower triglyceride (p=0.01) levels compared to controls with matched HDL-C levels and no IHD. The HDL subclass, using S-GGE, with density 1.063–1.100g/ml and diameter 98 –130Å correlated with levels of HDL-C (r
2
=0.66, p<0.0001). LDL subclasses using Lipoprint® exhibited higher fraction of Intermediate Density Lipoproteins (IDL-C) in patients with high HDL-C and IHD when compared with individuals with same HDL-C and no IHD (p=0.006). This was also true in the low HDL-C groups (p=0.01). This was further supported by higher levels of RLP-C and RLP-TG in individuals with high HDL and IHD (p=0.03 and p=0.03, respectively) when compared with respective controls.

Conclusions:
These results suggest that HDL composition rather than HDL-C levels is important in deciphering the protective role of HDL in IHD and that measurement of remnant-like lipoproteins may be useful for identifying patients with high HDL-C that are still at risk for developing IHD.
Abstract 1395: Role of High Mobility Group Box 1 Protein in Post-Infarction Healing Process and Left Ventricular Remodeling
Authors: Kohno Takashi , Anzai Toshihisa , Yoshikawa Tsutomu , Naito Kotaro , Ueno Koji , Miyasho Taku , Okamoto Minoru , Yamada Shingo , Ishizaka Akitoshi , Ogawa Satoshi
Published: July 2021

Background: The appropriate infarct healing process is prerequisite for preventing left ventricular (LV) remodeling after myocardial infarction (MI). High mobility group box1 protein (HMGB1) is derived from necrotic cells and activated macrophages and involved in tissue repair as immunostimulatory signal. However, the role of HMGB1 in post-MI LV remodeling is unknown.

Methods and Results: We examined 35 patients with first ST-elevated acute MI. Peak serum HMGB1 level, determined by serial measurements (q. 6h), did not differ in age, sex, coronary risk factors and infarct site. Its peak level was markedly higher in patients with adverse in-hospital clinical outcomes, including pump failure, cardiac rupture, LV aneurysm and cardiac death, compared with those without (all p<0.05). Then we performed experimental study using rat MI model, induced by permanent left coronary ligation. Anti-HMGB1 antibodies (1 mg/day, MI/antiH, n=20) or control antibodies (MI/C, n=20) were injected subcutaneously every 24 hours for 7 days. Sham-operated rats served as controls (n=10). Quantitative RT-PCR and immunoblotting showed that HMGB1 expression was increased in the infarcted area peaking at day 3 in MI/C compared with sham (p<0.05). Its expression was localized in myocytes and inflammatory cells by immunohistochemistry. The mRNA level of TNF-α (−48%, p=0.03) and IL1-β (−44%, p=0.02) and the number of infiltrated macrophages (p=0.04) in the infarcted area were markedly reduced at day 3 in MI/antiH compared with MI/C. Echocardiographic and hemodynamic studies at day 7 showed increased LV end-diastolic dimension (p=0.03), LVEDP (p=0.03), and decreased LV max dP/dt (p=0.01) in MI/antiH compared with MI/C. Histologically, scar thinning in the infarcted area (0.53±0.23 vs 0.68±0.21 mm, p=0.02) and hypertrophy in the non-infarcted myocardium (2.01±0.23 vs 1.63±0.21 mm, p=0.03) were more prominent in MI/antiH compared with MI/C at day 14.

Conclusions: Elevation of serum HMGB1 level is associated with adverse clinical outcomes in patients with acute MI. However, blockade of HMGB1 in rat MI model aggravated early LV remodeling through impaired infarct healing and advanced scar thinning, suggesting an essential role of HMGB1 in the appropriate repairing process after MI.
Abstract 1404: How Peripheral Cardiac Conduction Cells Adapt to Pressure Overload
Authors: Harris Brett S , Scholz Dimitri , Baicu Catalin F , Jay Patrick Y , Rackley Mary S , O’Brien Terrence X
Published: July 2021

The ventricular peripheral conduction system (PCS) is composed of unique cardiomyocytes responsible in health for the coordinated contraction of every working cardiomyoctye. Although isolated PCS cells have been studied extensively, in vivo study has been limited by difficulties in identifying large numbers of PCS cells, making it unclear how the PCS responds to disease stimuli.

Methods:
To address the hypothesis of whether the PCS undergoes hypertrophy with pressure-overload, we employed a novel EGFP-Connexin40 knock-in transgenic mouse which specifically labels Cx40-expressing cells with enhanced green fluorescent protein (EGFP). The Cx40EGFP heterozygote mouse allows the visualization of the entire PCS at the macro and cellular level and, in previous work, has been shown to have a normal phenotype. We then surgically induced left ventricular hypertrophy (LVH) using transaortic constriction (TAC). Functional echocardiography confirmed LVH averaging a 94 % increase in LV/body weight after 4 weeks with preserved systolic function. Sacrifice confirmed an average 79% increased heart weight (similar to control TAC).

Results:
EGFP positive conduction cells measured in whole heart sections were smaller at baseline by 46% (p<.001) in cross sectional area compared with working cardiomyocytes confirming published data on smaller conduction cell size. Most interestingly, EGFP positive PCS cells also underwent hypertrophy increasing by 30% (p<.001) in response to load. Working cardiomyocytes increased in cell size by 42% (p<.001) after TAC. Immunohistochemistry (IH) was used to confirm the identity of EGFP cells as conduction tissue. Additionally, IH showed a marked increase in expression of the cardiac transcription factor Nkx2–5 in PCS cells relative to working cells.

Conclusions:
We have shown for the first time that peripheral conduction system cardiomyocytes undergo hypertrophy with pressure-overload in a mouse model. In conjunction with our previous finding that Nkx2–5 increases with pressure-overload, this provides an initial characterization of PCS pathophysiology from a cellular perspective.
Abstract 1409: Molecular Imaging of Post-Infarction Cardiac Remodeling and Effects of Anti-Angiotensin Therapy
Authors: Van Den Borne Susanne W , Isobe Satoshi , Verjans Johan , Petrov Artiom , Lovhaug Dagfinn , Li Peng , Blankesteijn Matthijs , Daemen Mat , Pitt Bertram , Hofstra Leonard , Narula Jagat
Published: July 2021

Background.

Collagen deposition and interstitial fibrosis contribute to development of cardiac remodeling and heart failure (HF) after myocardial infarction (MI). We used Tc-99m-labeled Cy5.5-RGD imaging peptide (CRIP), for molecular imaging of the extent of collagen deposition.

Methods.

Of 46 Swiss-Webster mice, (MI) was induced in 41 by left coronary artery occlusion and 5 mice were imaged unmanipulated. Of these, 6, 6, and 5 mice, received intravenous CRIP for micro-SPECT/micro-CT imaging in vivo after 2, 4, and 12 weeks of MI. Eight mice received captopril or captopril with losartan for 4 weeks following MI before CRIP imaging for the assessment of effect of anti-angiotensin therapy on collagen deposition. To evaluate the specificity of the probe, 6 animals received scrambled peptide 4 weeks after MI. The remaining 10/46 mice, received CRIP without a radiolabel after 2 weeks of MI for histological characterization of tracer uptake by two-photon microscopy.

Results.

Distinct myocardial CRIP uptake was observed in the infarct area and border zone. The quantitative uptake in the infarct area, expressed as percent injected dose per gram (%ID/g), was highest in mice at 2 weeks (2.75±0.46%), followed by 4 (2.26±0.09%), and 12 weeks (1.74±0.24%) after MI as compared to uptake in sham-operated mice (0.59±0.19%). In the peri-infarct and remote areas, the uptake was higher at 12 weeks. The histologic characterization revealed specificity of the probe for replacement, interstitial and perivascular fibrosis. Captopril (1.78±0.31%) and combination of captopril and losartan (1.13±0.28%) significantly decreased radiotracer uptake in the infarct. The uptake of scrambled peptide (0.74 ±0.17%) was similar to CRIP uptake in normal myocardium.

Conclusions.

Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling. The CRIP uptake is significantly reduced with captopril and losartan treatment. If proven clinically feasible, such a strategy would help identify and prevent evolution of heart failure in post-MI patients.
Abstract 1423: Pitavastatin Ameliorates Angiotensin II-induced Cardiorenal Insufficiency In eNOS Knockout Mice Through Attenuating Rac-1-mediated Oxidative Stress
Authors: Yagi Shusuke , Aihara Kenichi , Ikeda Yasumasa , Ise Takayuki , Sumitomo Yuka , Iwase Takashi , Akaike Masashi , Matsumoto Toshio
Published: July 2021

Background:
It is well known that angiotensin II (Ang II) generates reactive oxygen species through NADPH oxidase activation, leading to promotion of cardiorenal diseases, especially in a condition with decreased nitric oxide (NO) bioavailability. In previous scientific sessions, we have shown that pitavastatin, an HMGCoA reductase inhibitor, ameliorates Ang II-induced cardiorenal damage in eNOS knockout (KO) mice through inhibition of the TGF-β-Smad2/3 pathway. However, the mechanism underlying eNOS-independent protective actions by pitavastatin has not been fully elucidated.

Methods and Results:
eNOS KO mice at 10 weeks of age were infused with Ang II (2.0 mg/kg/day) by an osmotic mini-pump for 2 weeks and they were divided into 3 treatment groups: pitavastatin (0.2 mg/kg/day), tempol, a free radical scavenger, (1.5 mg/kg/day), or a vehicle. Pitavastatin as well as tempol ameliorated Ang II-induced left ventricular hypertrophy with interstitial and pericoronary artery fibrosis and ameliorated diastolic dysfunction and they attenuated Ang II-induced glomerular damage, such as low glomerular filtration rate, increased albuminuria and PAS-positive glomerular depositions compared to those in vehicle-treated mice. Ang II-induced high mortality rate in eNOS KO mice was restored by pitavastatin as well as tempol treatment. Moreover, in eNOSKO mice, Ang II-induced cardiorenal superoxide production, detected with dihydroethidium staining, and Ang II-induced activity of rac-1-GTPase, a small G-protein involved in the activation of NADPH oxidase, were attenuated by pitavastatin treatment.

Conclusions:
Pitavastatin exerts an eNOS-independent protective action against Ang II-induced cardiorenal insufficiency through attenuating rac-1-GTPase-mediated oxidative stress. Our findings suggest that pitavastatin treatment is useful for caridorenal protection in patients with impaired NO bioavailability.
Abstract 1428: Effects of Continuous Positive Airway Pressure Treatment on Endothelial Function and Insulin Resistance in Patients with Obstructive Sleep Apnea and the Metabolic Syndrome
Authors: Watanabe Hideki , Nakagawa Kunio , Kakihana Masaaki
Published: July 2021

Background:
Obstructive sleep apnea (OSA) and the metabolic syndrome are recognized as a risk factor for cardiovascular disease. Cardiovascular events have been reported to have a peak incidence in the early hours after waking in OSA patients. This study was designed to examine the influence of OSA on endothelial function in the early morning in patients with the metabolic syndrome.

Methods:
The severity of sleep-disordered breathing was evaluated by polysomnography in patients with the metabolic syndrome. Ten OSA patients (an apnea-hypopnea index [AHI] >30) with the metabolic syndrome was included in this study, and we also included age-and sex-matched ten non-OSA patients (AHI <5) with the metabolic syndrome in this study. All subjects received pioglitazone for 1 month (1Mo), and then OSA patients received pioglitazone and nasal continuous positive airway pressure (CPAP) treatment for next 1 month (2Mo). Flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID) of brachial artery were measured by using ultrasound system. We also assessed insulin resistance by HOMA-IR. Measurements were performed in the early morning (6:00AM) and the late morning (11:00AM) at baseline, 1Mo, and 2Mo.

Results:
At baseline, there were not differences in FMD, and NID between the early morning and the late morning. After the treatment with pioglitazone (1Mo), FMD in the non-OSA patients was increased in the early and late morning, but FMD in the OSA patients was increased only in the late morning. After the CPAP treatment (2Mo), FMD in the OSA patients was increased in the early and late morning. HOMA-IR was improved at 1Mo in the non-OSA patients, and was improved at 2Mo in the OSA patients.

Conclusion:
OSA is associated with endothelial dysfunction in the early morning and insulin resistance in patients with the metabolic syndrome, and CPAP treatment is effective on the improvement of endothelial dysfunction in the early morning in OSA patients with the metabolic syndrome.
Abstract 1454: Targeted Molecular Imaging Probes For
In Vivo
MR Detection Of Atherosclerotic Lesions Using Antibodies Against Oxidized Low Density Lipoprotein
Authors: Briley-Saebo Karen C , Mulder Willem , Shaw Peter X , Choi Seung-Hyuk , Mani Venkatesh , Tsimikas Sotirios , Fayad Zahi A
Published: July 2021

Background:
Oxidized low-density lipoprotein (OxLDL) plays a key role in the initiation, progression and destabilization of atherosclerotic plaque. Molecular imaging probes that target OxLDL may allow
in vivo
detection of vulnerable plaques. In this study, magnetic resonance imaging (MRI) was used to detect atherosclerotic lesions in apolipoprotein deficient mice (ApoE−/−) using micelles comprised of gadolinium lipids, fluorescent rhodamine, PEG-lipids, and MDA2, a murine monoclonal antibody that binds malondialdehyde (MDA) lysine epitopes present in OxLDL.

Materials and Results:
Untargeted micelles, MDA2-labeled micelles and nonspecific polyclonal IgG micelles were prepared and characterized with respect to OxLDL binding capacity, pharmacokinetics, and biodistribution in wild type (WT) and ApoE−/− mice. MR imaging was performed at 9.4T over a 3-week interval after administration of 0.075 mmol Gd/kg micelles. MDA2 increased the micelle size, blood half-life, and MR efficacy relative to untargeted and IgG-micelles. Maximal plaque enhancement (>125%) was observed 72 hours post MDA2-micelle injection (Figure

). Untargeted and IgG-micelles did not exhibit significant wall enhancement at any of the time points studied. Confocal microscopy revealed that MDA2-micelles accumulate within foam cells associated with atherosclerotic plaque. WT mice showed no significant MR wall enhancement for any of the micelles studied.

Conclusions:
MR imaging using MDA2-micelles demonstrates specific targeting of OxLDL and foam cells and provides excellent MR image quality. This study suggests that it may be feasible to image similar atherosclerotic lesions in humans with MRI.
Abstract 1461: BLADE Is A Novel Membrane Protein That Regulates Endothelial Apoptosis and Consequently Angiogenesis Both In Vitro and In Vivo
Authors: Ikeda Koji , Nakano Ritsuko , Quertermous Thomas , Matsubara Hiroaki
Published: July 2021

Endothelial apoptosis is a pivotal process for angiogenesis during embryogenesis as well as postnatal. Here, we identified a novel gene, termed BLADE, that regulates endothelial apoptosis and consequently angiogenesis. BLADE was highly expressed in a variety of human cultured endothelial cells such as endothelial cells from umbilical vein (HUVEC), aorta, coronary artery and microvessels while no expression was observed in non-endothelial cells including HeLa cell, hepatoma cell and vascular smooth muscle cells. Furthermore, BLADE was expressed predominantly in blood vessels during embryogenesis, suggesting its role in angiogenesis. Amino acid sequence analysis revealed that BLADE was a novel membrane protein with no conserved domain reported before. BLADE expression was altered by treatment with VEGF, TNF-alpha and TGF-beta in HUVEC. Knockdown of BLADE in HUVEC using short interference RNA resulted in significant reduction of endothelial apoptosis. In contrast, BLADE knockdown affected neither endothelial cell migration nor proliferation. Among factors associated with apoptosis, Bcl-2 expression was drastically increased in HUVEC by BLADE-knockdown. Further analysis revealed that this increase of Bcl-2 is due to reduced ubiquitination and less subsequent degradation of Bcl-2. Inhibition of Bcl-2 completely abolished the anti-apoptotic effect of BLADE-knockdown. In vitro tube-formation of HUVEC on Matrigel was reduced concomitantly with reduced apoptosis by BLADE-knockdown at early time (12h). Nevertheless, significantly more tubes were preserved at late time (96h) by BLADE-knockdown. Moreover, in vivo angiogenesis assessed by Matrigel-plug was dramatically enhanced by BLADE-knockdown. Taken together, BLADE is a novel factor regulating endothelial apoptosis as well as angiogenesis both in vitro and in vivo. Detailed analysis of BLADE will provide new insights in the regulation of endothelial apoptosis, and in the molecular link between endothelial apoptosis and angiogenesis. Because BLADE is highly preferentially expressed in endothelial cells, inhibition of BLADE might be an ideal approach to enhance endothelial cell survival and angiogenesis without affecting the survival of other type of cells.
Abstract 1483: The Absence of PI3K γ is Beneficial in a Mouse Model of Myocardial Ischemia/Reperfusion
Authors: Haubner Bernhard J , Schwaighofer Julia , Huber Florian , Neely Greg , Kuba Keiji , Conci Elisabetta , Stühlinger Markus C , Alber Hannes , Pachinger Otmar , Penninger Josef , Metzler Bernhard
Published: July 2021

Introduction

-
Phosphoinositide 3-Kinase gamma (PI3Kγ) is a well-known key enzyme in inflammation pathways. Emerging data demonstrate that PI3Kγ plays a distinct role in cardiomyocytes, but its influence in the setting of myocardial ischemia and reperfusion is still an enigma. To clarify these effects we examined the morphology and contractility of PI3Kγ−/−hearts after ischemia and reperfusion.

Methods

-
PI3Kγ knock out (KO) mice and C57 Bl6 wild type (WT) mice were subjected to 30 minutes of ischemia followed by 3 hours, 1 week and 3 weeks of reperfusion. We therefore reversibly ligated the left anterior descending artery (LAD) in an
in vivo
model and harvested the myocardium after the defined time of reperfusion. Histological sections were stained with H&E and Masson Trichrome in order to measure the area of infartion and the amount of interstitial fibrosis. Furthermore, Troponin T serum levels were determined and transthoracic echocardiography was performed for measuring the differences in myocardial contractiliy.

Results

-
Comparing PI3Kγ KO mice with WT mice, we found a significant decrement of Troponin T serum levels in the transgenic group 3 hours after reperfusion (0.77±0.28 vs. 1.28±0.48 ng/ml, p<0.001). In addition, a distinct reduction of myocardial infarction was observed in the KO group compared to the WT mice (3 hours: 1.18±0.31 vs. 1.78±0.45 mm
2
, p=0.001; 1 week: 0.88±0.32 vs. 1.29±0.34 mm
2
, p=0.001; 3 weeks: 0.62±0.18 vs. 1.87±0.59 mm
2
, p<0.001). Furthermore, we showed a matching smaller quantity of myocardial fibrosis in the transgenic cohort (1 week: score 1.23±0.6 vs. 2.13±0.74, p=0.005; 3 weeks: score 1.08±0.79 vs. 2±0.71, p=0.014). Fractional shortening (FS) analysis determined by echocardiography revealed significantly enhanced myocardial contractility in PI3Kγ lacking mice after ischemia and reperfusion (1 week: 37.85±7.71 vs. 23.75±8.78 %FS, p=0.007; 3 weeks: 30.67±4.87 vs. 23.7±7.47 %FS, p=0.043).

Conclusions

-
Our data provide the first evidence for the crucial role of PI3Kγ signalling in myocardial ischemia/reperfusion injury: PI3Kγ deficient mice show a significantly better outcome concerning infarction area, Troponin T elevation, scar size, fibrosis, and contractility at all stages of reperfusion (3 hours to 3 weeks).
Abstract 1514: Effect of Prior Medication on Clinical Characteristics and Hospital Outcome of Acute Coronary Syndromes
Authors: Aguiar Carlos , Ferreira Jorge
Published: July 2021

Background: Patients (Pts) with acute coronary syndrome (ACS) are often on medication at time of admission, because of risk factors and/or prior history of cardiovascular disease. We assessed the influence of prior medication on mode of presentation and prognosis of ACS.

Methods: We studied 18,400 Pts included in a nationwide prospective registry of ACS and determined the influence of prior medication with aspirin (ASA), beta-blockers (BB), angiotensin converting enzyme inhibitors (ACEI), and statins (Stat) on type of ACS and its effect on all-cause hospital mortality.

Results: ACS presentation was more benign in Pts previously medicated with ASA, BB, ACEI or Stat (Table

). Pts on prior medication with these drugs were older, more often female, less often smokers, and more often presented BMI >=25, diabetes, hypertension, hypercholesterolemia, and prior history of cerebrovascular or peripheral arterial disease, MI or myocardial revascularization. Of the 3453 Pts with prior MI, 63.9% were on ASA, 42.0% BB, 47.6% ACEI, and 49.4% Stat. Of the 2946 diabetics, 29.6% were on ASA, 32.5% ACEI, and 25.7% Stat. Of the 1275 Pts with prior stroke/TIA, 36.3% were on ASA and 24.2% Stat. Of the 382 Pts with peripheral arterial disease, 38.8% were on ASA and 33.7% Stat. Overall, 344 (3.4%) of the 9980 non-ST-elevation ACS and 703 (8.3%) of the 8420 ST-elevation MI Pts died. Prior BB was an independent predictor of hospital mortality in non-ST-elevation ACS (adjusted OR = 1.58; 95% CI, 1.09–2.29; p=0.016), but not ST-elevation MI. Prior medication with ASA, an ACEI or a Stat did not influence outcome of either type of ACS.

Conclusions: In the real world, Pts at high risk for atherothrombotic disease are insufficiently medicated with ASA, BB, ACEI and/or Stat. Prior medication with these drugs is associated with a more benign clinical presentation of ACS. Further studies are required to clarify the mechanisms conferring increased hospital mortality in Pts with non-ST-elevation ACS admitted on a BB.
Abstract 1606: High Specificity of Prolonged Isovolumic Contraction Time for Reverse Remodeling Associated with Cardiac Resynchronization Therapy
Authors: Miyazaki Chinami , Bruce Charles J , Redfield Margaret M , Espinosa Raul E , Hayes David L , Oh Jae K
Published: July 2021

Background:
Isovolumic contraction time (ICT) and pre-ejection period (PEP) are altered by electrical conduction delay as well as impaired contractility. An abnormal PEP has been used to select patients for cardiac resynchronization therapy (CRT), however, the predictive value of PEP for reverse remodeling (RR) has not been reported. The purpose of this study is to determine the predictive value of ICT and PEP for the RR in a prospective, single center CRT registry.

Methods:
Prospective registry of all heart failure patients undergoing CRT with echo pre-implant and at 3 and 6 months after implant. PEP was measured from the ECG Q wave onset to the aortic valve opening from the left ventricular outflow tract pulsed-wave Doppler tracing. The timing interval from the QRS onset to mitral valve closure was measured (mitral valve closure time). ICT was calculated as PEP-mitral valve closure time. RR was defined as >15% reduction in end-systolic volume (ESV) measured by biplane Simpson’s method. Death due to cardiac cause and heart transplantation during the 6 month period were considered as a non-response in the receiver-operating characteristics (ROC)analysis.

Results:
Echocardiography data was available in 83 patients at 3 and 59 patients at 6 month after CRT. RR occurred in 42 patients (51%) at 3 months and in 32 (54%) patients at 6 months By ROC analysis, the area under the curve (AUC) for predicting RR was 0.74 for ICT (p<0.001) and 0.73 for PEP (p=0.001) (See table

). ICT>123 ms yielded a very high specificity of 90–93% to predict responders at 6 month after CRT either in entire population or after excluding the patients with atrial fibrillation.

Conclusion:
A prolonged ICT is highly specific for predicting reverse remodeling after CRT although it is found in a limited number of patients. A strategy employing a screening ICT measurement may identify patients highly likely to achieve reverse remodeling after CRT, but can not be used to exclude patients for CRT.

ROC analysis
Abstract 1613: Enhanced Expression of Tenascin-C in Granulomas of Patients With Active Cardiac Sarcoidosis
Authors: Terasaki Fumio , Hiroe Michiaki , Imanaka-Yoshida Kyoko , Tsukada Bin , Otsuka Kaoru , Katashima Takashi , Fujita Shuichi , Shimomura Hiroaki , Yoshida Toshimichi , Kitaura Yasushi
Published: July 2021

Introduction: Tenascin-C (TN-C) is a member of the matricellular proteins that do not subserve a primary structural role, but function rather as modulators of cell-matrix interactions, with being evident at sites of inflammation, tissue remodeling or wound healing. Although TN-C is likely involved in the inflammatory process in the granulomatous tissue, their in situ expression in the sarcoid heart has not been clarified.

Hypothesis: We assessed the hypothesis that serum levels of TN-C are increased in patients with sarcoidosis, and the expression of TN-C is upregulated in the myocardium of patients with active cardiac sarcoidosis.

Methods: Serum TN-C levels were measured in 40 patients with sarcoidosis and 23 patients with idiopathic dilated cardiomyopathy (DCM). Sera from 20 normal volunteers served as controls. In addition, we immunohistochemically examined the expression profiles of TN-C in the myocardium from 12 patients with active cardiac sarcoidosis and 10 DCM patients.

Results: Serum TN-C levels were significantly higher in patients with sarcoidosis than in normal controls [79.7±43.3 (SD) ng/ml vs. 30.9±8.8 ng/ml, p=0.001]. In the sarcoidosis group, serum TN-C levels in patients with definite cardiac involvement (n=10) were significantly higher than in those without it (n=30) (119.6±45.0 ng/ml vs. 66.4±34.0 ng/ml, p=0.005) and they were also higher than in DCM patients (vs. 68.2±24.3 ng/ml, p=0.006). Immunohistochemically, expression of TN-C was markedly enhanced in the extracellular matrix surrounding multinucleated giant cells and macrophages in the sarcoid granulomas. TN-C expression was limited to areas with well-formed, active granulomas.

Conclusions: TN-C, produced in extracellular matrix, may be involved in the pathogenesis of sarcoid granulomas. The measurement of serum TN-C levels is useful for the diagnosis of sarcoidosis, and their higher levels may suggest the cardiac involvement.
Abstract 271: Ca
2+
/Calmodulin-Dependent Kinase Kinase β (CaMKKβ) Contributes to AMPK Activation in the Heart during Hypoxia
Authors: Kim Agnes , Li Ji , Hu Jennifer , Edelman Arthur M , Young Lawrence H
Published: July 2021

AMP-activated protein kinase (AMPK) is a stress signaling enzyme that regulates important cellular responses to ischemic stress in the heart. AMPK stimulates glucose uptake and utilization during myocardial ischemia and limits cardiac apoptosis and contractile dysfunction associated with ischemia/reperfusion injury. Activation of AMPK involves allosteric regulation by AMP/ATP ratio as well as phosphorylation by upstream AMPK kinases (AMPKKs) including LKB1 and CaMKKβ. The identity of the AMPKKs involved in the activation of AMPK during myocardial ischemia is not fully defined. The aims of this study were to determine whether

CaMKKβ is expressed in the heart and in cardiomyocytes

CaMKKβ is activated during ischemia and

CaMKKβ contributes to AMPK activation during ischemia. CaMKKβ mRNA and protein were found to be expressed in mouse and rat hearts and isolated rat cardiomyocytes. To determine whether myocardial ischemia stimulates CaMKKβ activity
in vivo
, mouse hearts were subjected to regional ischemia by LAD occlusion, and assessed for phosphorylation of CaMKI (Thr
177
), a direct downstream substrate of CaMKKβ. There was a 4-fold increase in CaMKI phosphorylation on its activating Thr
177
site within 2–5 min of ischemia (p<0.05 vs. control). CaMKKβ signaling was transiently activated and correlated with the initial rise in AMPK phosphorylation during the early phase of myocardial ischemia. To further determine whether CaMKKβ participates in ischemia-induced heart AMPK activation and glucose uptake, isolated rat left ventricular papillary muscles were subjected to hypoxia in the presence of a specific CaMKKβ inhibitor, STO-609 (2 μM). CaMKKβ inhibition resulted in a 60% reduction in hypoxia-induced AMPK activation (p<0.01 vs. hypoxia). In addition, inhibition of CaMKKβ yielded an 85% and 30% reduction in hypoxia-induced ACC phosphorylation and glucose uptake, respectively (p<0.05 vs. hypoxia), two well-known downstream consequences of AMPK activation.

CONCLUSION: Myocardial ischemia leads to an early, transient stimulation of the CaMKKβ pathway which correlates with the initial activation of AMPK during ischemic stress. CaMKKβ partially mediates hypoxia-induced activation of AMPK pathway in the heart.
Abstract 1629: Genetic Polymorphism A1675G On Angiotensin Receptor Type 2, Is Implicated In The Expression Of Acute Phase Proteins And The Development Of Coronary Atherosclerosis In Hypertensive Patients
Authors: Tousoulis Dimitris , Koumallos Nikolas , Antoniades Charalambos , Kardara Despina , Antonopoulos Alexis S , Mentzikof D , Vasiliadou Carmen , Vlachopoulos Charalambos , Vavuranakis Emmanouil , Stefanadis Christodoulos
Published: July 2021

Introduction: Renin-angiotensin system affects cardiovascular disease pathogenesis through a balance of angiotensin II effects on proatherogenic constitutive type 1 and antiatherogenic inducible type 2 (AT2R) receptors. The impact of A1675G polymorphism on the development of hypertension and advanced atherosclerosis is controversial. We examined the impact of A1675G polymorphism on AT2R, on the risk for arterial hypertension and coronary atherosclerosis, and its effect on the expression of proatherogenic inflammatory molecules.

Methods. The study population consisted of 310 males: 145 with arterial hypertension and 165 controls, matched for age and risk factors for atherosclerosis. Among hypertensive subjects, 37 had angiographically documented coronary atherosclerosis and 108 had no evidence of atherosclerosis. The presence of A1675G polymorphism on AT2R gene (located in chromosome X) was determined by PCR. Serum levels of C-reactive protein and fibrinogen was measured in all the participants.

Results. The frequency of the A allele was similar between patients with arterial hypertension (64/145, 44.1%) and non-hypertensive subjects (73/165, 44.2%, p=NS), while the risk for arterial hypertension was OR[95%CI]:1.004[0.641–1.574], p=0.985 for the G vs A carriers. However, the risk for coronary atherosclerosis within the group of hypertensive subjects was significantly elevated in the carriers of the A allele (OR[95%CI]:2.128[1.003–4.513], p=0.04 vs carriers of the G allele). Importantly, the presence of the A allele was also associated with significantly higher levels of CRP (4.8±0.8mg/dl) compared to the carriers of the G allele (3.0±0.3mg/dl, p<0.05). Similarly, fibrinogen levels were higher in A-allele carriers (median(25
th
–75th percentile) 395(340 – 455) mg/ml) compared to G-allele carriers (369(320 – 406) mg/ml, p<0.05).

Conclusions: Although genetic polymorphism A1675G on AT2R is not associated with the development of arterial hypertension, it affects the risk for coronary artery disease among hypertensive patients. The presence of the A allele also leads to higher levels of CRP and fibrinogen, implying that this polymorphism may induce atherogenesis by modulating acute phase response in hypertensive individuals.
Abstract 1660: Digital Signal Processing in Implanted Dual Chamber Pacemakers for Improved Atrial Signal Classification and Far-Field-R-Wave Discrimination
Authors: Lewalter Thorsten , Remerie Susann , Tuininga Ype , Ziekenhuis Deventer , Wohlgemuth Peter
Published: July 2021

Background.
Far-Field R-Wave (FFRW) oversensing and P wave blanking are the major causes of inaccurate atrial signal classification in current pacemaker (PM) devices leading to inaccurate stored diagnostic information and to inadequate PM reactions like mode-switching or preventive pacing. The prospective and multi-center MARS (Morphology of Atrial Signals) study therefore investigated during daily life the capabilities of Digital Signal Processing (DSP) in an implanted dual chamber PM to improve P-wave classification accuracy.

Methods
. 55 patients with an implanted dual chamber PM (Vitatron T- or C-series) were included: During 24 hours with daily life activity and a stress test, a Holter ECG collected surface ECG, PM markers and all atrial EGM’s. The DSP algorithm analysed atrial events sensed nearby a ventricular event using the minimum and the maximum amplitude of the digitalized and filtered signal and the maximum and minimum amplitude of the slope signal. After comparing to the characteristics of a normal P wave, each of these atrial signals were then classified as a true atrial signal or FFRW. DSP classification results were then compared to the conventional PM signal classification by three independent reviewers.

Results
. Classification accuracy for the traditional PM functionality after optimizing blanking and sensitivity settings was 97.1% (19.5–100%) as compared to 99.4% (76.9–100%) using the DSP algorithm (p<0.001).

Conclusion
. The DSP algorithm significantly improved the classification accuracy of sensed atrial events as an important prerequisite for a correct diagnostic and therapeutic PM function. The herewith presented approach of analysing atrial signals by form and timing may allow to reduce or even eliminate atrial blanking periods thus leading to larger PM sensing windows to prevent from atrial tachyarrhythmia undersensing without an increase in FFRW sensing.
Abstract 1680: Spatial Distribution of Myocardial Infarction in Patients with Diabetes Mellitus
Authors: Garg Pallav , Candia Susana , Wang John C , Kuntz Richard E , Mauri Laura
Published: July 2021

BACKGROUND: Acute coronary occlusions occur most frequently as a result of rupture of an atherosclerotic plaque. Previous studies have found greater extent of atherosclerotic disease in the coronary arteries of diabetic patients. While the burden of disease is higher in diabetics, less is known about the spatial distribution of myocardial infarction in this population.

METHODS: We sought to compare the spatial distribution of myocardial infarction (STEMI and Non-STEMI) in patients with diabetes mellitus and in those without, based on quantitative coronary and statistical analysis. We analyzed 756 patients with STEMI (n = 556) and NSTEMI (n=200), of which 175 patients comprised the diabetic cohort, and mapped the location of the acute coronary occlusion.

RESULTS: Coronary occlusions were not uniformly distributed throughout each of the major epicardial coronary arteries but tended to cluster within the proximal third of each of the vessels in both cohorts. There was no difference in the distribution of occlusions in diabetics vs. non-diabetics in any of the vessels (left anterior descending artery, P=0.35; left circumflex artery; P=0.33 right coronary artery, P=0.20; Figure).

CONCLUSIONS: Acute coronary occlusions leading to STEMI and NSTEMI in both diabetics and non-diabetics tend to cluster in predictable “hot spots” within the proximal third of the coronary arteries. Identification of these high-risk zones for acute coronary occlusions will lead to future advances in vulnerable plaque detection technology and potentially locally directed preventive strategies.

Spatial distribution of myocardial infarction in diabetics vs. non-diabetics using distance to lesion from the ostium of the coronary artery.
Abstract 1685: Clinical and Angiographic Outcomes following Percutaneous Coronary Intervention with Sirolimus-Eluting Stents vs. Bare Metal Stents in Hemodialysis Patients
Authors: Yachi Sen , Tanabe Kengo , Yamamoto Hirosada , Otsuki Shuji , Yagishita Atsuhiko , Kishi Satoru , Sasaki Shunsuke , Taniwaki Masanori , Nakano Masataka , Nakajima Hiroyoshi , Hara Kazuhiro
Published: July 2021

Background Percutaneous coronary intervention in hemodialysis patients has been hampered by high rate of major adverse cardiac events (MACE). It remains uncertain whether sirolimus-eluting stent (SES) improves clinical outcomes in hemodialysis patients compared to bare metal stent (BMS).

Methods The present study consisted of consecutive 46 hemodialysis patients with 57 lesions treated with SES from August 2004 to April 2006. For comparison, the control group was composed of 67 hemodialysis patients with 70 lesions who were treated with BMS in three years before the introduction of SES. Clinical and angiographic follow-up were performed after 8 months. MACE included all-cause death, myocardial infarction and repeat target vessel revascularization.

Results Baseline characteristics were comparable between the 2 groups except for lesion length. Clinical follow-up was available in all patients. Angiographic follow-up was obtained in 39 patients (84.8%) in the SES group and 49 patients (73.1%) in the BMS group. There was no difference in MACE between the 2 groups (SES;28.3%, BMS;40.3%, p=0.19). As shown in the table

, quantitative angiographic analysis revealed a significant difference in late lumen loss (SES;0.66±0.80mm, BMS;1.07±0.75mm, p=0.01), however, the rate of binary restenosis was identical (SES;31.9%, BMS;40.4%, p=0.38). Of the angiographic restenosis lesions analyzed, focal restenosis pattern was frequently observed in the SES group than the BMS group(SES;93.3%, BMS;23.8%, p<0.0001), whereas diffuse restenosis pattern was dominant in the BMS group.

Conclusion Angiographic parameters favored inhibition of neointimal hyperplasia by SES. However, the inhibitory effect of sirolimus was not translated into clinical superiority over BMS in hemodialysis patients.

Table.

Serial QCA data
Abstract 1693: The Impact of Percutaneous Coronary Intervention on Renal Function in Diabetic Patients With Normal Baseline Serum Creatinine
Authors: Raya Vikram , Roy Probal , Buch Ashesh , Javaid Aamir , Okabe Teruo , Slottow Tina L Pinto , Steinberg Daniel H , Smith Kimberly , Xue Zhenyi , Satler Lowell F , Kent Kenneth M , Suddath William O , Pichard Augusto D , Lindsay Joseph , Waksman Ron
Published: July 2021

Background:
Diabetics are prone to contrast nephropathy. The outcome of diabetics with normal baseline serum creatinine (SCr) undergoing PCI remains under-evaluated. The present study aims to assess the incidence, outcome, and correlates of SCr rise post-PCI in this subset.

Methods:
The study cohort consisted of 570 consecutive diabetic patients with normal SCr (≤1.3mg/dl) who underwent non-emergent PCI. Patients presenting with AMI, shock, and age >75 years were excluded. SCr rise was defined as ≥25% rise from baseline. Study endpoints were post-PCI SCr rise and major adverse cardiac events (MACE) at 6 months. Logistic regression was performed to identify predictors of SCr rise.

Results:
SCr rise occurred in 70 patients (incidence=12.3%). Patients with SCr rise were more likely to be female (55.7% vs. 35.5% p = 0.001) and have a history of congestive heart failure (24.2% vs. 14.7% p=0.048). Patients with SCr rise had greater entry site complications (hematoma, pseudoaneurysm) and need for blood transfusion (16.7% vs.1.7% p<0.001). In-hospital mortality (8.6% vs. 0.2% p<0.001) and length of stay (4.51±5.2 vs. 2.23±2.9 days p<0.001) were significantly higher in patients with SCr rise. No study patient required dialysis. At 6 months, MACE was markedly higher in patients with SCr rise (21.4% vs. 6.0% p<0.001) driven by death and revascularization. Independent predictors of SCr rise were female gender, blood transfusion, and lower body mass index.

Conclusions:
Post-PCI rise in SCr in diabetics with normal baseline values is common and is a marker of late adverse cardiac events. Greater emphasis needs to be placed on prevention and monitoring of rises in SCr in the diabetic population.
Abstract 1702: Blockade of B
1
in Kinin B
2
Receptor knockout mice Deteriorates Cardiac Function and Remodeling post-Myocardial Infarction
Authors: Xu Jiang , Carretero Oscar A , Shesely Edward G , Rhaleb Nour-Eddine , Yang Xiao-Ping
Published: July 2021

We previously showed that the therapeutic effects of ACEi were diminished in B
2
knockout mice (B
2
−/−). However, lack of B
2
per se
did not affect cardiac remodeling and dysfunction post myocardial infarction (MI), which may be partially due to upregulation of B
1
that may play a compensatory role for lack of the B
2.
Here we hypothesize that blockade of B
1
in B
2
−/− mice accelerates and deteriorates cardiac remodeling and dysfunction post-MI. Male B
2
−/− and wild-type controls (C57BL/6J, B
2
+/+) were subjected to sham MI or MI (by ligating the left anterior descending coronary artery) and treated with either vehicle or B
1
antagonist (B
1
-ant, Ac-Lys[(αMe)phe
5
,D-βNal
7
,Ile
8
]desArg
9
BK; 300 μg/kg/day
via
osmotic minipump, i.p.) for 8 weeks. Systolic blood pressure (SBP) was measured weekly by tail cuff, and LV diastolic chamber dimension (LVDd), mass and ejection fraction (EF) were evaluated by echocardiography. We found that SBP, cardiac morphology and function did not differ between strains in sham-MI mice. MI caused a similar increase in LV chamber dilatation and mass and decrease in EF between B
2
+/+ and B
2
−/− (Table

). However, in the presence of B
1
-ant, cardiac remodeling and dysfunction post-MI became more severe in B
2
−/− mice compared to B
2
+/+. SBP and infarct size were similar in all groups. These results suggest that the B
1
receptor may play an important role in preventing deterioration of cardiac function and remodeling post-MI when B
2
receptors are absent.
Abstract 1745: Mitral Leaflet Adaptation to Ventricular Remodeling: Occurrence and Adequacy in 80 Patients With Functional Mitral Regurgitation
Authors: Chaput Miguel , Handschumacher Mark D , Tournoux Francois , Hua Lanqi , Vlahakes Gus J , Guerrero J. L , Levine Robert A
Published: July 2021

Functional mitral regurgitation (FMR) is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about how chronic tethering affects leaflet area, in part because of inability to reconstruct leaflet area in situ. Our aim was to do so in order to explore whether adaptive increases occur that meet the needs of tethered geometry in FMR, and to test the hypothesis that leaflet area influences MR.

Methods and Results. A new method for 3D echo measurement of mitral leaflet area was developed and validated in vivo against sheep valves, later excised. This method was used to study 80 consecutive patients in 3 groups: patients with normal hearts (n=20); with FMR (n=29) from inferior wall motion abnormality (IWMA) or dilated cardiomyopathy (DCM); and with IWMA or DCM but no MR (n=31). Patients with FMR had 23±5% increased leaflet area compared with normal subjects. The ratio of leaflet to annular area was 1.95±0.40, not different among groups (figure

), indicating a surplus leaflet area that adapts to left heart changes. In contrast, the ratio of total leaflet area to that required to close the orifice in mid-systole was decreased in patients with FMR versus normal (1.29±0.15 vs 1.78±0.39, p=0.001) and versus patients with IWMA or DCM but no MR (1.81±0.38, p=0.001). After adjusting for measures of LV remodeling and tethering, a leaflet-to-closure area ratio <1.7 was associated with significant MR (OR=23.2, p=0.02).

Conclusion. Mitral leaflet area increases in response to chronic tethering in patients with IWMA and DCM. However, the adequacy of leaflet adaptation to tethering geometry varies, and may partly explain the heterogeneity of FMR among patients.
Abstract 1756: Determination of the Mechanism of Elevated Left Ventricular Filling Pressures with Exercise: A Simultaneous Echocardiographic-Catheterization Study
Authors: Jaber Wissam A , Borlaug Barry A , Redfield Margaret M , Lee Pui W , Ommen Steve R , Sorajja Paul , Lam Carolyn S , Nishimura Rick A
Published: July 2021

Background:
Exercise normally enhances LV relaxation with minimal change in filling pressure (P). We hypothesize that exercise in hypertensive (HTN) patients increases LV diastolic P through a direct effect on relaxation and ventricular-vascular coupling.

Methods:
Patients (n=21) with HTN, normal EF, and no coronary disease underwent simultaneous micromanometer LV P and echo-Doppler measurements at rest and with low level supine exercise (12 bicycle; 9 arm weight). Continuous volume (V) was obtained from mitral Doppler inflow and end-diastolic (ED) and end-systolic (ES) V from 2-D echo. Relaxation-corrected LV diastolic P was used for PV relationship P = α.e
β*V
; to account for covariance in α and β, LV capacitance (EDV
20
= Ln[20mmHg/α]/β) was reported. Single beat method was used for LV ES elastance (Ees). Group 1 did not increase mean LV diastolic P (mDP) with exercise, Group 2 increased mDP >6mmHg.

Results:
LV diastolic P and arterial and LV ES elastance increased with exercise; EDV was stable; EDV
20
decreased. Compared to Group 1, Group 2 had a greater exercise-induced increase in afterload, associated with increase in LV minimal P and impaired augmentation of relaxation rate (Table

& Figure

).

Conclusions:
In patients with HTN, impairment of ventricular relaxation plays a major role in causing LV filling P increase with exercise, which is related to ventricular-vascular coupling.