bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13709: High-Density Lipoprotein is a Novel Activator of Cardiac Glucose Metabolism in both Healthy and Insulin Resistant Myocardium
Authors: Heywood Sarah E , Henstridge Darren C , Richart Adele L , Alt Karen , Carey Andrew L , Kammoun Helene L , Delbridge Lea M , Hagemeyer Christoph E , Febbraio Mark A , Kingwell Bronwyn A , Siebel Andrew L
Published: July 2021

Aims:
High-density lipoprotein (HDL) is known to increase skeletal muscle glucose uptake, but whether this action extends to the myocardium and has relevance in the setting of ischemia is unknown. This study aimed to determine the effect of HDL on cardiac glucose metabolism both in vitro and in vivo, including during ischemia/reperfusion injury.

Methods and Results:
HDL treatment (50μg/mL) increased glucose uptake (147±10%), glycolysis (154±11%) and glucose oxidation (130±6%) in neonatal ventricular cardiomyocytes compared to saline control. HDL rapidly activated the Akt pathway and an Akt inhibitor (Akti 1/2) abolished HDL-mediated glucose uptake, suggesting an Akt-dependent mechanism. To determine the upstream receptor mechanism HDL binding to sphingosine-1-phosphate (S1P) receptors was blocked with either 1uM VPC23019 (S1P1&3 antagonist) or 1uM CAY10444 (S1P3 antagonist). Both similarly inhibited HDL-mediated glucose uptake. S1P is a known activator of the Akt pathway, thus our data suggests the S1P component of HDL increases glucose uptake via S1P3 activation of the Akt pathway.

The effect of a single intravenous bolus of reconstituted HDL (CSL-111; 80mg/kg) in chow diet (CD) and high fat diet (HFD) insulin resistant C57Bl6 mice was investigated during an oral glucose tolerance test (OGTT). CSL-111 treatment increased cardiac muscle glucose clearance in both CD (168±16%) and HFD (138±11%) mice compared to saline infusion during the OGTT.

To assess whether CSL-111 could increase cardiac glucose uptake in an ischemic setting, a single bolus of CSL-111 (80mg/kg) was given at the beginning of reperfusion in mice following left anterior descending artery (LAD) ligation. CSL-111 trended to increase cardiac glucose uptake ([18F]Fluorodeoxyglucose tracer and PET-CT imaging) by 66% (chow) and 81% (HFD) (treatment effect p=0.07) 1 hour post-reperfusion following LAD surgery. Furthermore, CSL-111 improved long term cardiac functional recovery.

Conclusion:
These data show that HDL increases glucose uptake and utilisation in the heart suggesting a role for HDL therapies in preserving functional myocardium subsequent to acute coronary ischemic syndromes.
Abstract 13823: The Cut-off Point and Boundary Values of Waist-to-height Ratio as an Indicator for Cardiovascular Risk Factors in Chinese Adults Population From PURE Study
Authors: Peng Yaguang , Li Wei
Published: July 2021

Objectives:
To explore a scientific boundary of WHtR to evaluate central obesity and CVD risk factors in Chinese adult population.

Methods:
The data from the Prospective Urban Rural Epidemiology (PURE) China study that carried out during 2005-2007. The final study analytical sample consisted of 43 841 participants (18 019 men and 25 822 women) aged 35-70 years. According to the category of CVD risk factors proposed by Joint National Committee 7 version (JNC7) and the clustering of risk factors, some diagnosis parameters, such as sensitivity, specificity, and receiver operating characteristic (ROC) curve least distance were calculated for hypertension, diabetes, high serum triglyceride (TG), high serum low density lipoprotein cholesterol (LDL-C), low serum high density lipoprotein cholesterol (HDL-C) and clustering of risk factors (number≥2) to evaluate the efficacy each value of WHtR cut-off point. The upper boundary value for severity was fixed on the point whose specificity of the point was gathered more than 90%. And the lower boundary value to indicate over low weight was determined by the percentile distribution of WHtR, at which the 5
th
percentile (P
5
) of point, both in male and female population. Then, basis on the principle of convenient and practical for use, determine the optimal boundary values of WHtR for low weight and obvious central obesity.

Results:
For the whole study population, the optimal WHtR cut point for CVD risk factors cluster was 0.50.The cut points for severe central obesity were 0.57 in the whole population. The upper boundary values of WHtR to detect risk factors cluster with specificity above 90% were 0.55 and 0.58 for men and women, respectively. Additionally, the cut-off points of WHtR for each of 4 cardiovascular risk factors with specificity above 90% in male ranged from 0.55 to 0.56, while in female ranged from 0.57 to 0.58. The P
5
of WHtR, which the lower boundary values of WHtR to indicate over low weight, was 0.40 in the whole population.

Conclusion:
WHtR 0.50 was an optimal cut point for CVD risks evaluation in Chinese adults population for both genders. The optimal boundaries of WHtR were 0.40 and 0.57 indicating low body weight and severe risk for CVD respectively in Chinese adults.
Abstract 13846: Factor Xa Inhibition Prevents Cardiac Remodeling Induced by Intermittent Hypoxia in Sleep Apnea Model Mice
Authors: Yoshimura Fumi , Tanikawa Shota , Hosako Shogo , Kato Ryuji , Ijiri Yoshio , Izumi Yasukatsu , Yoshiyama Minoru , Hayashi Tetsuya
Published: July 2021

Introduction:
We have reported that intermittent hypoxia (IH) relevant to sleep apnea increases oxidative stress causing vascular remodeling and heart failure. The serine protease factor Xa in the coagulation cascade elicits inflammatory responses in endothelial cells.

Hypothesis:
We hypothesize that rivaroxaban might attenuate cardiac remodeling induced by IH in sleep apnea model mice.

Methods:
Male C57BL/6J mice at 8 weeks of age were exposed to IH (repeated cycles of 1.5 minute of 5% oxygen followed by 5 minutes of 21% oxygen) for 56 days with/without treatment by rivaroxaban (1.2 g riv./kg chow). After echocardiography, heart was examined by light and electron microscopy, immunohistochemistry, and RT-PCR. HPAECs were cultured under hypoxic conditions (37%, 1% O
2
, 5% CO
2
) with/without rivaroxaban (1 μM).

Results:
IH caused cardiac remodeling (Figure), associated with both systolic and diastolic dysfunction compared with those of normoxia (IH vehicle vs. Normoxia; EF: 51.8% vs. 59.4% and E/e’: 29.4 vs. 22.3), which were attenuated by rivaroxaban (EF: 55.8%, E/e’: 24.6). In right atrial myocardium, IH caused endothelial cell degeneration, dissociation of intercalated discs, vacuolar formation and loss of ANP specific granules. Furthermore, 4-hydroxy-2-nonenal protein adducts and the expression of protease-activated receptor-1 (PAR-1) and NF-kB mRNA were increased by IH. Treatment with rivaroxaban significantly suppressed PAR-1 and NF-kB mRNA expression, increased ANP granules and reduced perivascular fibrosis, preventing cardiac remodeling due to IH.

Conclusions:
Rivaroxaban may attenuate atrial and ventricular remodeling induced by IH at least partly through its anti-inflammatory effect in sleep apnea model mice.
Abstract 13861: Deep Terminal Negativity of P wave in V1 is Associated With Twice Higher Mortality in the Hospital Population
Authors: Tereshchenko Larisa G , Hawkins Lauren , Feldman Trevor , Sklenar Jiri , Henrikson Charles
Published: July 2021

Introduction:
Easily recognizable ECG sign deep terminal negativity of P wave in V1 (DTNPV1) represents an epiphenomenon of a fibrotic heart, and predicts sudden cardiac death in the general population.

Hypothesis:
We hypothesized that DTNPV1 is associated with increased mortality in the population comprised from an entire health system ECG database.

Methods:
We conducted retrospective double-cohort study and screened all 12-lead ECGs over 4 years (2010-2014) at a large hospital system and reviewed medical records to collect baseline clinical characteristics. ECGs from 130,284 individual patients were automatically analyzed in the MUSE ECG database. Children < 18 y were excluded. Two cohorts with different exposures (P-prime in V1), matched by age and sex, were comprised. The DTNPV1 cohort included participants with biphasic P wave in V1 with the amplitude of the terminal negative phase >100 μV. The zero P-prime in V1 cohort was comprised of participants with absent negative terminal deflection of P wave in V1. All-cause mortality served as a primary outcome.

Results:
Each cohort consisted of 3,435 patients (mean age 58.0±16.2y; 44.8% female). In DTNPV1 cohort mean P prime in V1 amplitude was -119.4±19.6 μV. Over a mean follow-up time of 2.5 years, 7.6% patients in the zero P-prime V1 cohort and 14.3% patients in the DTNPV1 cohort had died (Figure). In Cox regression analysis, DTNPV1 was associated with a two-fold increase in risk of mortality after adjustment for age, sex, coronary artery disease, history of myocardial infarction, chronic obstructive lung disease, diabetes, liver disease, ventricular tachycardia, and atrial fibrillation/flutter [HR 1.94 (1.65-2.28); P<0.001].

Conclusions:
DTNPV1 in a population from an entire health system ECG database is independently associated with twice higher risk of all-cause death, as compared to patients without negative deflection of P prime in V1.
Abstract 13895: HOE642 Used During Resuscitation Induced Obviously Adverse Hemodynamic Effects Which May Be Improved by Hypothermia
Authors: Dong Jiaxu , Nie Chaoran , Chen Meng , Hou Lina , Han Fei
Published: July 2021

Introduction:
HOE642, the sodium-hydrogen exchanger inhibitor, can delay the opening of mitochondrial permeability transition pore (mPTP) and reduce mitochondrial-derived superoxide production. It was reported HOE642 improved neurological recovery after prolonged ischemia.

Hypothesis:
We sought to find the effects of HOE642 with or without hypothermia on resuscitation in rats.

Methods:
Thirty male SD rats (240-340g) were included. Cardiac arrest was induced by 8 min asphyxia. Rats were divided into 4 groups: (1) normothermia group (N group, n=9), rectal temperature (Trec) maintained at 37±0.5°C; (2) hypothermia group (H group, n=7), Trec maintained at 37±0.5°C during cardiac arrest and CPR periods, rats were cooled to 33°C in 3 min after ROSC, Trec maintained at 33±0.5°C for 1 h, rewarmed gradually to 37±0.5°C during the following 1 h; (3) HOE642 group (n=7), Trec maintained the same as the N group, HOE642 was given (1mg/kg, iv) when initiating CPR; (4) hypothermia and HOE642 group (H+HOE642 group, n=7), Trec maintained the same as the H group, HOE642 was given the same as the HOE642 group. Epinephrine (0.01mg/kg) was used when initiating CPR. Epinephrine (1μg) was used to maintain MAP ≥ 60mmHg after resuscitation.

Results:
There were no significant difference about the baseline characters, CA time, CPR time, and survival among groups. HOE642 did not influence the rate of ROSC. MAP in the H group (113.4±36.7mmHg) was significantly higher than the HOE642 group (67.4±18.5mmHg) and the H+HOE642 group (69.0±17.6mmHg) when ROSC (Fig. 1). MAP in the H group (77.4±21.1mmHg) was significantly higher than the HOE642 group (55.1±18.4mmHg) after 60 min of ROSC. Epinephrine used after ROSC in the HOE642 group (9.4±5.3μg) was significantly more than the N group (0.9±1.1μg), the H group (1.6±1.8μg), and the H+HOE642 group (2.3±1.6μg).

Conclusions:
HOE642 used during resuscitation induced hypotension. Hypothermia may prevent the adverse hemodynamic effects caused by HOE642.
Abstract 13920: Impact of Diabetes on Acute Kidney Injury After Myocardial Infarction: Possible Involvement of Toll-like Receptor in the Kidney
Authors: Ohno Kohei , Kuno Atsushi , Muratsubaki Shingo , Murase Hiromichi , Kouzu Hidemichi , Tobisawa Toshiyuki , Ogasawara Makoto , Nishizawa Keitaro , Yano Toshiyuki , Tanno Masaya , Miki Takayuki , Miura Tetsuji
Published: July 2021

Background:
Comorbid acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI). Although type 2 diabetes (T2D) is a well-known risk factor of AKI after MI, the mechanism of the increased risk remains unclear. Here we hypothesized that T2D increases AKI after MI via toll-like receptor (TLR)-mediated inflammation.

Methods and Results:
OLETF, a rat model of obese T2D, and LETO, non-diabetic controls, at 25-30 weeks of age were randomized into sham and permanent coronary ligation (MI) groups. At baseline, body weight (617±23 vs. 537±13 g), fasting plasma glucose (267±32 vs. 153±15 mg/dl) and urinary protein level (6.4 vs. 0.6 g/gCr), but not serum creatinine, were significantly higher in OLETF than in LETO. Histologically, glomerular size was increased by 17% without mesangial proliferation in OLETF compared to that in LETO, indicating that OLETF developed early-stage nephropathy by this age. At 12 h after MI, mRNA levels of TLR2, TLR4, IL-6 and TNF-α in the kidney were increased by 1.6-, 1.2-, 2.6-, 1.5-fold, respectively, in OLETF but not in LETO. Furthermore, immunoblot analyses showed that phosphorylation levels of p38 MAPK and JNK, downstream mediators of the TLR signal, were significantly elevated by MI in OLETF. Histological abnormalities in the kidney or increase in serum creatinine were not detected in either LETO or OLETF 12 h after MI. However, in immunohistochemical analyses, areas positive for neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were significantly increased by 4.0- and 5.3-fold, respectively, and NGAL mRNA level was increased by 1.8-fold after MI in OLETF but not in LETO. In sham-operated LETO and OLETF, areas positive for NGAL and KIM-1 were barely detected. Infarct sizes were similar and cardiac BNP mRNA levels in the non-infarcted left ventricle were equally elevated at 12 h after MI in LETO and OLETF, suggesting that MI-induced cardiac loads were comparable in the two groups. However, mortality at 48 h after MI was significantly higher in OLETF than in LETO (68% vs. 18%, P<0.05).

Conclusion:
The results suggest that AKI after MI is enhanced in T2D via TLR-mediated inflammation. The cardio-renal interaction may underlie increased post-MI mortality in T2D.
Abstract 13944: J Relationship of Body Mass Index of 22-year Cardiovascular Disease Mortality versus Body Mass Index
Authors: Kostis William J , Cabrera Javier , Wang Fei , Guterl Sara J , Amaratunga Dhammika , Pantazopolous John S , Kostis John B
Published: July 2021

Introduction:
J relationships of body mass index (BMI) with mortality have been described. However, little data are available on long-term follow-up in controlled clinical trials with respect to cardiovascular (CV) and all cause mortality.

Hypothesis:
We tested whether there is a J shape relationship between BMI with CV and all cause mortality at 22 years in the Systolic Hypertension in the Elderly Program (SHEP).

Methods:
SHEP was a placebo controlled, randomized clinical trial of antihypertensive therapy in patients with isolated systolic hypertension aged 60 and older. The relationship between CV and all cause mortality with baseline BMI was examined in 4,211 SHEP participants.

Results:
In unadjusted analyses, a J relationship was observed for all-cause mortality (linear term p=0.0318, quadratic term p=0.3217 and tricubic term p=0.0046) and for CV mortality (linear term p=0.0962, quadratic term p=0.6866 and tricubic term p=0.0908, left figure). The lowest risk was at a BMI of 25.9 for all-cause and 25.5 for CV mortality. The J shaped relationship between BMI and mortality was attenuated after adjustment for age, gender, comorbidities (e.g. diabetes, heart failure) and risk factors for CV disease (e.g. smoking and dyslipidemia, right figure). Age and gender were significant predictors of both all- cause and CV mortality: age p<0.0001, female gender p=0.0063 for all-cause mortality and p<0.0001 for age and p=0.0004 for female gender for CV mortality.

<br/Conclusions:
This study indicates that both very low and very high BMI are markers of high risk. The J relationship between BMI and mortality is mediated by age, female gender, comorbidities and risk factors for CV disease.
Abstract 13956: Cystatin C Based Estimated Glomerular Filtration Rate is a Feasible Parameter for Incident Stroke in Patients With Atrial Fibrillation
Authors: Hashimoto Naoto , Nishiyama Satoshi , Watanabe Tetsu , Wanezaki Masahiro , Yamaura Gensai , Arimoto Takanori , Takahashi Hiroki , Shishido Tetsuro , Miyamoto Takuya , Kubota Isao
Published: July 2021

Introduction:
Chronic kidney disease (CKD) is an important risk factor of stroke in patients with atrial fibrillation (AF). Since AF patients with high CHADS2 score are likely to be old and have history of TIA or stroke, there could be patients who have sarcopenia. Cystatin C based estimated glomerular filtrarion rate (eGFRcys) is less affected by age, gender and muscle mass compared to creatine based eGFR (eGFRcr). We investigated whether eGFRcys is more closely associated with incident stroke in AF patients compared to eGFRcr.

Methods:
We performed transthoracic and transesophageal echocardiography and measured eGFRcys and eGFRcr in 349 patients with paroxysmal AF and chronic AF (256 males, 64.4 ± 11.7 years). We excluded those who had severe valvular heart disease and end stage renal desease. There were 42 patients with stroke history.

Results:
eGFRcys showed better correlation with left atrial volume index, levels of brain natriuretic peptide, von Willebrand factor, and left atrial appendage emptying flow velocity, than eGFRcr. eGFRcys was decreased with increading CHADS2 and CHA2DS2VASc score. Patients with left atrial appendage and/or spontaneous echo contrast had a significantly lower eGFRcys compared to those without. The proportion of patients with stroke was increased with advancing CKD stage in eGFRcys. Although eGFRcys and eGFRcr were associated with stroke in logistic regression analysis, eGFRcys but not eGFRcr was an independent predictor for stroke after adjustment for CHADS2 score.

Conclusion:
eGFRcys is a feasible parameter for incident stroke in AF patients.
Abstract 13963: Evidence of Content-Dependent Functional and Electrical Coupling of Human Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissue With Chronic Infarct Rat Myocardium
Authors: Iseoka Hiroko , Miyagawa Shigeru , Fukushima Satsuki , Yajima Shin , Saito Atsuhiro , Masuda Shigeo , Ito Emiko , Lee Jong-Kook , Sawa Yoshiki
Published: July 2021

Background:
It has been shown that transplantation of engineered cardiac tissue (ECT) derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) into the infarct heart induces electrical communication between the ECT and the native myocardium; however, factors enhancing the electrical integrity and thus the therapeutic effects are not fully understood. We herein hypothesized that content of cardiomyocytes in the ECT may be a key to achieve efficient electrical coupling and functional contribution in chronic rat myocardial infarction (MI) heart.

Methods and Results:
Neonatal rat cardiomyocytes (NRCM), mimicking the host myocardium, were partially covered by the ECT containing iPSC-CMs produced by thermoresponsive culture dishes
in vitro
, to explore electrical communication of the ECT with myocardium. As a result, the NRCM and the ECT showed spontaneous, individual contractions for 2 hours, though they gradually showed electrical and motional synchronization, featuring transmitted electrical pulse from the NRCM to the ECT, as assessed by multi-electrode array. Subsequently, the ECT of different ratios (25, 50, 70, and 90%) of iPSC-CMs were generated by magnetic-activated cell sorting using cardiac specific cell surface marker. As a result, the 70% group exhibited the highest contractile and relaxation properties
in vitro
, as assessed by high-speed video microscopy image-based motion analysis and Ca transient measurement. Finally, the ECTs including 25, 50, 70% CMs were transplanted to immune deficient rat MI model (n=7 each). As a result, ejection fraction was significantly improved in the 50% (52±10%) and 70% (52±12%) groups, but not in the 25% group (35±5%), as compared to the control (35±10%;
P
<0.05). Epicardial optical mapping of Langendorff perfused heart on day 3 showed that the ECTs of 50% and the 70% groups exhibited electrical activity and synchronization with the native myocardium.

Conclusion:
Transplantation of the ECT improved cardiac performance associated with synchronization with the myocardium in rat infarction model, dependent upon content of the cardiomyocytes in the ECT. It was thus suggested that transplanted ECT may behave “working cardiac construct” in the damaged heart.
Abstract 13973: Circulating Eicosapentaenoic Acid to Oleic Acid Ratio and Risk for Cardiovascular Events in Patients With Coronary Artery Disease; Sub-analysis of SHINANO Registry
Authors: Hioki Hirofumi , Miura Takashi , Miyashita Yusuke , Ebisawa Souichirou , Motoki Hirohiko , Izawa Atsushi , Koyama Jun , Ikeda Uichi
Published: July 2021

Background:
Until now, Omega-3/Omega-6 polyunsaturated fatty acid (PUFA) ratio, particularly in ratio of eicosapentaenoic acid (EPA) to arachnidonic acid (AA), has been reported to associate with the incidence of cardiovascular events. However, the clinical impact of monounsaturated fatty acid (MUFA) on cardiovascular events has not been well understood.

Objective:
In this study, we evaluate whether ratio of MUFA to PUFA, especially EPA/Oleic acid (OA), could predict clinical outcome in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI).

Methods:
SHINANO registry was prospective, observational, multicenter cohort study, enrolling 1,923 consecutive patients with CAD. From this registry, we identified 182 patients who measured fatty acid on admission. We stratified according to median of EPA/OA ratio. The primary endpoint was net adverse clinical events (NACE) including cardiac death, nonfatal myocardial infarction, ischemic stroke, PCI for ACS, heart failure, and major bleeding (Bleeding Academic Research Consortium II-IV) for 1-years.

Results:
Mean age was 72±10 years, 24% female, and 27% was acute coronary syndrome. One-years follow-up was completed in 181 patients (99.5%). Cumulative incidence of NACE was 22 cases. In Kaplan-Meier analysis, incidence of NACE was significantly higher in patients with EPA/OA of 0.03 to 0.12 compared to 0.13 to 0.54 (16.6% vs. 6.6%, Log-rank p=0.025). After adjusting for the calculated propensity score for EPA/OA ≥ 0.13 or not, EPA/OA ≥ 0.13 was remained an independent predictor of NACE (hazard ratio, 0.36; 95% confidence interval [CI], 0.14-0.96; p-value 0.042). The ROC curve of EPA/OA for NACE demonstrated that the area under the ROC curve (ACU) was 0.73 (95% CI; 0.61-0.85).

Conclusions:
This study firstly demonstrated that the patients with high EPA/OA ratio would have low incidence of NACE in patients with CAD who underwent PCI.
Abstract 13993: Soluble CD146 is a Marker of Peripheral Congestion in Global Heart Failure Patients
Authors: Arrigo Mattia , Gayat Etienne , Wong Ka Y , Onat Duygu , Demmer Ryan T , Hayashi Yacki , Sadoune Malha , Tolppanen Heli , Samuel Jane-Lise , Colombo Paolo C , Mebazaa Alexandre
Published: July 2021

Introduction:
CD146 is a component of the endothelial junction. We previously showed that its soluble form (sCD146) is as powerful as plasma natriuretic peptides to detect cardiac origin of acute dyspnea. The source of plasma sCD146 in heart failure (HF) is however unknown.

Hypothesis:
We make the hypothesis that peripheral venous congestion (VC), a typical sign of global ventricular failure, might be the source of increased sCD146.

Methods:
A total of 44 outpatients with heart failure, NYHA functional class II or III, and LVEF <40%, no evidence of VC on physical exam and on stable medical therapy were studied. Patients gave informed consent. To experimentally model VC, venous arm pressure was increased to 30 mmHg above baseline by inflating a pressure cuff around the dominant arm. Blood was sampled from test and control arm (lacking an inflated cuff) before and after 90 minutes of venous congestion. Plasma concentrations of sCD146 were determined by ELISA. Values are expressed as mean ± SEM and groups were compared with paired-samples t-test.

Results:
The age of the study cohort was 54±2 years, 32% were female, 32% had an ischemic etiology and the LVEF was 22±1%. The induction of VC was associated with an increase in circulating levels of sCD146 in the congested arm when compared to baseline (506±33 vs 463±33 ng/ml, p=0.001) and to control arm (476±32 ng/ml, p=0.035). In contrast, no significant increase occurred in the control arm when compared to baseline values (Figure).

Conclusions:
Plasma sCD146 acutely increases in response to experimental peripheral VC. sCD146 could be particularly useful to titrate diuretic treatment in HF patients with global heart failure, possibly preventing end-organ dysfunction and damage from severe and/or long-standing peripheral VC.
Abstract 14005: Myocardium at Risk in Revascularized Non-ST-Elevation Myocardial Infarction Assessed by Cardiac Magnetic Resonance Imaging and Validated by the Invasive Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease Score
Authors: Buckert Dominik , Dyckmanns Nils , Rasche Volker , Rottbauer Wolfgang , Bernhardt Peter
Published: July 2021

Background:
In the setting of acute myocardial ischemia, the hypoperfused portion of the myocardium is in danger of becoming irreversibly injured. This portion of myocardium is often referred to as area at risk (AAR) and is correlated to adverse events and outcome.

Hypothesis:
Aim of the trial at hand was to assess the AAR in patients with acute non-ST-elevation myocardial infarction (NSTEMI) by cardiac magnetic resonance imaging (CMR). Results were validated by the well-established Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease Score (APPROACH-score) that was assessed by invasive coronary x-ray angiography.

Methods:
Sixty-four patients presenting with acute NSTEMI who underwent coronary x-ray angiography including subsequent percutaneous coronary intervention within 72 hours of symptom onset were enrolled. Two blinded readers performed offline angiographic AAR assessment using the modified APPROACH-score. For measurement of AAR by CMR, a 1.5 T whole-body scanner with a 32-channel phased-array surface coil was used. Besides functional and volumetric analyses, a 3D T2-weighted black-blood fat-saturated spin-echo sequence was used for visualization of myocardial edema. Area at risk was calculated as edema volume in relation to left ventricular mass. Using this technique, AAR was quantified semi-automatically by two blinded readers in consensus.

Results:
Mean age of study cohort was 62.9 years. Forty-four subjects were male (73.3%), mean symptom-to-balloon time was 1212 ± 976 min. The resulting mean AAR determined by the modified APPROACH-score was 28.6 ± 10.0%. The mean CMR derived AAR was 27.9 ± 13.7%. CMR assessment tended to slightly underestimate the AAR in comparison to angiographic scoring (difference -0.21 ± 8.1 %, p=NS). A good correlation between the AAR assessed by CMR and by angiography (r=0.84, p<0.0001) was observed.

Conclusion:
T2-weigthed CMR is able to quantify the AAR with very good correlation to the angiographic APPROACH-score in NSTEMI patients. Therefore, CMR might serve as an excellent surrogate in clinical reperfusion trials.
Abstract 14070: Combination of Clinical, Electrocardiographic and Echocardiographic Parameters Predict the Onset of Atrial Fibrillation
Authors: Soeki Takeshi , Bando Sachiko , Matsuura Tomomi , Tobiume Takeshi , Uematsu Etsuko , Kusunose Kenya , Ise Takayuki , Yamaguchi Koji , Yagi Shusuke , Fukuda Daiju , Yamada Hirotsugu , Wakatsuki Tetsuzo , Shimabukuro Michio , Sata Masataka
Published: July 2021

Bacground:
The ability to identify risk markers for first atrial fibrillation (AF) is critical to the development of preventive strategies. Prior studies have demonstrated that advanced age, diabetes, hypertension, and cardiovascular disease increase the risk of developing AF. Echocardiographic left atrial (LA) size and diastolic dysfunction are also shown to predict the onset of AF. Furthermore, a recent study has revealed that the addition of premature atrial contraction (PAC) count to a validated AF risk algorithm provides superior AF risk discrimination. However, it remains unknown whether a combination of clinical, electrocardiographic, and echocardiographic parameters predict the onset of AF. In the present study, we evaluated the predictive value of the combined score including these parameters.

Methods:
We retrospectively studied 1,040 patients without AF in whom both echocardiography and 24-hour Holter electrocardiography were performed from May 2005 to December 2010 and could be followed thereafter. During the follow-up period of 70.0±29.1 months, we investigated the new onset of AF.

Results:
Of the 1,040 patients, 103 developed AF. Patients who developed AF were older than patients who did not. Total heart rate, PAC count, max RR interval, and frequency of sinus arrest quantified by 24-hour electrocardiography were associated with the new onset of AF. Left atrial diameter (LAD) determined by echocardiography was also associated with the development of AF. In multivariate Cox analyses, age, PAC count, max RR interval, and LAD were independently associated with the development of AF (multivariable-adjusted hazard ratios per SD: age 1.49, PAC count 1.16, max RR interval 1.21, and LAD 1.34). Furthermore, the predictive value of the combined score using these 4 parameters (hazard ratios per SD: 1.80) was higher than that of each parameter.

Conclusion:
The combined score using age, PAC count, max RR interval, and LAD could help to identify risk of the new onset of AF.
Abstract 14071:
In-vivo
Assessment of the Peri-infarcted Region by a Novel Micro-electrode Array System in a Large Animal Model of Myocardial Infarction
Authors: Plenge Tobias , Guschlbauer Maria , Maul Alexandra , Halbach Marcel , Krausgrill Benjamin , Sterner-Kock Anja , Stevens Daniel , Baldus Stephan , Ladage Dennis
Published: July 2021

Introduction:
Ventricular arrhythmias are life threatening complications in ischemic cardiomyopathy associated with significant mortality. Inhomogeneity in conduction and dispersion of refractoriness are substrates for reentry tachycardias. Micro-electrode array (MEA) systems are currently used to study extracellular field potentials of myocytes in vitro.

Hypothesis:
Aim of this study was to validate and apply for the first time a novel epicardial MEA 128-channel electrode in a large animal model of myocardial infarction (MI).

Methods:
We induced MI by percutaneous coil occlusion of the proximal LAD in swine (body weight: 20±1.5 kg, n=6). Epicardial mapping
in-vivo
was performed by a lateral mini thoracotomy (length 5 cm) with placement of a flexible 128-channel-MEA (32x32 mm, 100 μm electrodes with 2.7 mm distance) on (a) healthy, (b) infarcted and (c) peri-infarcted areas of the left ventricle. Animals were stimulated with predefined pacing protocols.

Results:
We assed global as well as regional function after MI confirming its efficacy and impact. Application of the MEA - electrode was safe and feasible, showing reproducible results in all animals. Analyzing different ventricular regions in 2D- reconstruction maps we found the inhomogeneity of conduction velocity to be significantly increased creating a characteristic pattern in the peri-infarcted region (

Figure
A

). At each electrode the local ECG was registered to calculate differences in activation time. In comparison to recordings prior to the MI the peri-infarct tissue exhibited significant aberrations in spontaneous impulse propagation (

Figure
B

) as well as in pacing protocol measurements.

Conclusions:
We applied and demonstrated the feasibility of
in-vivo
epicardial MEA - mapping in a swine large animal model of MI. We believe this tool holds great potential for evaluating conduction velocity and impulse propagation for testing regenerative and anti-arrhythmic therapeutic strategies.
Abstract 14072: Incidence of Stent Thrombosis and Its Predictors After Endovascular Therapy for Femoropopliteal Artery Disease
Authors: Tsujimura Takuya , Iida Osamu , Fujita Masashi , Masuda Masaharu , Okamoto Shin , Nanto Kiyonoori , Kanda Takashi , Shiraki Tatsuya , Sunaga Akihiro , Okuno Shota , Matsuda Yasuhiro , Yanaka Koji , Ohashi Takuya , Uematsu Masaaki
Published: July 2021

Background:
Stent thrombosis (ST) in the coronary artery has been associated with a high mortality rate (45%). Despite its broad use, incidence of ST and its impact on clinical outcome following endovascular therapy (EVT) for femoropopliteal (FP) lesions have not been systematically studied.

Methods:
Five hundred and fifty-nine consecutive patients (74±9 years; 33% female; 47% with critical limb ischemia; 31% TASC C/D) who underwent stent implantation (81% bare metal and 19% drug-eluting stents) in FP lesions (length, 157±100 mm) were retrospectively studied. ST was diagnosed when the following criteria were met: 1) initial procedural success; 2) rapid symptom occurrence; 3) thrombus present at procedure; and 4) lesion resolved with <50% diameter narrowing by thrombolysis. We evaluated the incidence of ST and its impact on major adverse limb event (MALE)-free survival by Kaplan-Meier analysis and by Cox proportional hazard model.

Results:
Rate of ST linearly increased during the follow-up and reached 1.6% (7/559) at 36 months following stent implantation. MALE-free survival rate was 74.6% at 36 months after stent implantation. The independent predictors were age (HR), body mass index (HR), CLI (HR), hemodialysis (HR), and chronic heart failure (HR), while ST (0.99; [0.14-7.33] was not significantly associated with MALE-free survival.

Conclusion:
ST, which occurred in 1.6% at 36 months after stent implantation, was not an independent predictor of MALE-free survival in patients with PAD in FP lesions.
Abstract 14116: Effects of Statin Intensity and Low-density Lipoprotein Cholesterol Lowering in Korean Patients With Chronic Ischemic Heart Disease and Very Low Low-density Lipoprotein Cholesterol
Authors: Lee Soo Youn , Youn Jong-Chan , Park Sungha , Kang Seok-Min , Choi Donghoon , Oh Seung Jin , Kim Eung Ju , Lee Sang-Hak
Published: July 2021

Introduction:
Current guidelines on lipid management emphasize LDL-C lowering >50% of baseline levels with intensive statin regimens in patients with coronary artery disease. However, whether this strategy is beneficial also in patients with very low LDL-C has not been proven. Furthermore, controversy remains on the optimal statin intensity for Asians in whom outcome data of lipid therapy are highly limited.

Methods and Results:
Totally, 3867 patients with chronic ischemic heart disease were initially screened. Among them, 393 subjects(age: 66 years; males: 68%) who showed baseline LDL-C <80 mg/dL without lipid lowering medications were finally included. Patients were retrospectively classified to 4 groups according to statin intensity they received : no (n=35), Moderate-low (atorvastatin 10mg or similar, n=135), moderate-high (atorvastatin 20 mg or similar, n=177), or high (atorvastatin 40-80 mg or similar, n=46) intensity. Patients took blood tests every 3-6 months and were clinically followed-up for major adverse cardiac events (MACE).

During the mean follow-up of 3.8 years, 41 patients (10.4%) experienced MACE. The event-free survival was higher in patients receiving higher dose statins (Figure, p=0.03). In the univariate analysis, age (p=0.05), the % change of LDL-C (p=0.01), and the statin intensity (p=0.03) were associated with MACE. In the multivariate analysis, the statin intensity was found to be an only independent predictor of clinical outcome (p=0.05). Interestingly, the beneficial effect of statins became significant at the moderate-high dose. The predictive value of the % change of LDL-C was not significant after controlling other variables.

Conclusions:
Our study demonstrated that higher dose statins (at least moderate-high intensity) were more beneficial in Asian patients with chronic ischemic heart disease even if their LDL-C is <80 mg/dL. This effect was independent of % change of LDL-C.
Abstract 14124: A Marked Increase in Myocardial Oxidative Stress Associated With Sympathetic Hyperactivity is Related to Transient Myocardial Dysfunction in Patients With Takotsubo Cardiomyopathy
Authors: Nanno Takuma , Kobayashi Shigeki , Oda Seiko , Ishiguchi Hironori , Myoren Takeki , Miyazaki Yosuke , Suetomi Takeshi , Ono Makoto , Mochizuki Mamoru , Oda Tetsuro , Okuda Shinichi , Yamada Jutaro , Okamura Takayuki , Yano Masafumi
Published: July 2021

Introduction:
Sympathetic hyperactivity is considered as one of the most likely pathogenic mechanism in takotsubo cardiomyopathy (TC). However, little is known about the relationship between sympathetic hyperactivity and myocardial oxidative stress (OS).

Hypothesis:
We hypothesized that cardiac sympathetic hyperactivity was associated with cardiac myocardial OS, and OS related to transient myocardial dysfunction in patients with TC compared with acute anteroseptal myocardial infarction (AMI).

Methods:
In 8 TC patients and 8 AMI patients (NYHA 3), ECG, echocardiography, cardiac catheterization and serial measurements of plasma catecholamines, urinary (U) 8-hydroxy-2’-deoxyguanosine (8-OHdG) as a marker of OS and plasma CPK were performed for two weeks from onset.

Results:
Blood sampling from coronary sinus (CS) and aorta (Ao) at 1st day showed that norepinephrine (NE) levels and 8-OHdG level in CS were significantly higher than those in Ao and peripheral blood, indicating that an increase in myocardial OS was associated with cardiac sympathetic hyperactivity. NE levels in peripheral blood were peaked out at 1st day and 2-times higher in TC than in AMI within a week, while the max CPK value in TC was significantly lower than that in AMI. Dual scintigraphy of 201Tl and 123I-meta-iodobenzylguanidine was performed at 7th day showed that cardiac sympathetic nervous injury was much larger than myocardial perfusion damage in all TC patients. U-8OHdG level (ng/mg Cr; normal range:<10.0) in TC was elevated in parallel with the profile of plasma NE level (1st day: 65.6±24.5, 4th day: 19.1±8.3, 7th day: 16.4±9.1), while it was decreased to almost normal range after percutaneous coronary intervention for left anterior descending artery in AMI (1st day: 24.3±13.8, 4th day: 9.8±3.4, 7th day: 12.3±2.7). Interestingly, difference in serum 8-OHdG levels (CS vs Ao) in TC increased proportionally with wall motion score (WMS) as an index of LV dysfunction (R=0.93, p<0.001), while difference in serum NA levels (CA vs Ao) in TC did not. U-8OHdG level in TC was positively correlated with WMS at each day (1st day, 7th day).

Conclusions:
These findings suggest that myocardial OS induced by cardiac sympathetic hyperactivity may play a critical role in transient LV dysfunction in TC.
Abstract 14157: Periodontal Microbiome Induces Inflammation and Atherosclerosis in Hyperlipidemic Atherogenic Apoe
Null
Mice
Authors: Chukkapalli Sasanka , Velsko Irina , Rivera-Kweh Mercedes , Zheng Donghang , Lucas Alexandra , Lakshmyya Kesavalu
Published: July 2021

Introduction:
Periodontal disease (PD) is a polymicrobial dysbiotic chronic inflammatory disease produced by a complex subgingival microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). American Heart Association supported the association between PD and ASVD but not causal association. Prior reports investigated the associations between these two diseases PD and ASVD. But the complex signaling molecules and mechanisms establishing a causal association are not well defined.

Methods:
To investigate how polybacterial infections initiate atherosclerotic plaque growth, ApoE
null
mice were orally infected with a polybacterial consortium of 4 well-characterized periodontal pathogens
Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia
and
Fusobacterium nucleatum
. We assessed PD characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression.

Results:
Polybacterial infections have enhanced gingival colonization and significantly induced alveolar bone loss ApoE
null
mice. Polybacterial infections were found to be invasive with hematogenous dissemination into heart and aorta. Polybacterial infection-induced significantly higher levels of serum risk factors (oxidized LDL, nitric oxide), altered lipid profiles (cholesterol, triglycerides, chylomicrons, VLDL) as well as accelerated aortic plaque formation in ApoE
null
mice. Polybacterial infection is associated with significant decreases in
Apoa1, Apob, Birc3, Fga, FgB
genes that are associated with atherosclerosis. Gingival infections after 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. At 24 weeks of chronic infection additional changes in inflammatory molecules were induced with reduced KC, MCSF, and enhanced GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, and RANTES.

Conclusions:
This is the first study demonstrating differences in the host immune response to a polybacterial infection with atherosclerotic lesion progression in a mouse model.
Abstract 14166: Cardiac Function is Protected From Ischemic Injury in African Spiny Mice
Authors: Qi YanFei , Vohra Ravneet , Zhang Juan , Wang Lei , Krause Eric , Guzzo Dominic S , Walter Glenn A , Katovich Michael J , Maden Malcolm , Raizada Mohan K , Pepine Carl J
Published: July 2021

Tissue regeneration is common in crustaceans, insects, reptiles and amphibians. African spiny mice (ASM) evolve to shed a large portion of skin to escape from predators. They have been recently reported as the first mammal to regenerate complete hair follicles, dermis, epidermis, sebaceous glands, adipose tissue, microvessels, smooth muscle, skeletal muscle of the panniculus carnosus and cartilage (
Seifert
et al.
Nature 2012
). However, the extent of regenerative ability of ASM with regard to their heart has not been investigated. The objective of this project is to determine the cardiac regenerative potential of ASM relative to another murine species (CD1 mouse) in a coronary artery ligation model. CD1 and ASM were divided into four groups (see table below). Similar ischemic area was induced for group 2 and 4. Cardiac function was assessed using echocardiography and MRI. Briefly, MI led to a 51% decrease in left ventricle ejection fraction (LVEF, 31.9±6.5 vs 64.5±3.7%) in CD1 mice following MI. Whereas, EF was preserved in ASM following MI (78.4±6.5 vs 61.71±1.8%). Collectively, it appears that ASM may be able to preserve and/or regenerate myocardium after ischemic injury. Our findings warrant additional studies to identify molecular pathways and genetic circuits that promote myocardial preservation/regeneration processes.
Abstract 14209: Association Between Atrial Septal Defects and Bronchopulmonary Dysplasia in Premature Infants
Authors: Hornik Christoph P , Hill Kevin D , Li Jennifer S , Laughon Matthew , Rowe Stevie , Clark Reese , Smith P Brian
Published: July 2021

Introduction:
Bronchopulmonary dysplasia (BPD) is a major cause of morbidity and mortality affecting 20,000 infants in the United States yearly. Known BPD risk factors include prematurity, respiratory support, oxygen use, and the presence of a patent ductus arteriosus (PDA). PDA increases BPD risk due to increased pulmonary blood flow which also occurs in the presence of an atrial septal defect (ASD). The extent to which an ASD impacts the risk of BPD is largely unknown.

Hypothesis:
Evaluate the association between ASD and BPD risk in premature infants.

Methods:
We used electronic medical record data from >950,000 infants in 362 neonatal intensive care units (NICUs) in the US managed by Pediatrix Medical Group (2004 - 2013) to identify infants 24-30 weeks gestational age (GA) and <1250 g birth weight (BW). We excluded infants with major anomalies including heart defects other than ASD or PDA. We defined BPD as the need for supplemental oxygen or respiratory support continuously from corrected GA 36-0 to 36-6 weeks. We predicted risk of BPD at 6 postnatal ages (1, 3, 7, 14, 21, and 28 days) using the NICHD Neonatal Research Network BPD risk calculator. We then developed separate logistic regression models conditioned on NICU center to evaluate the association between ASD and BPD adjusting for baseline BPD risk at the 6 time points. We repeated each model controlling for therapeutic interventions (PDA ligation, diuretics, pre- and postnatal steroids).

Results:
We identified 36,842 infants; 1257 (3%) had an ASD. Median GA and BW were 27 weeks (25th, 75th %ile 26, 29) and 940 g (765, 1091); 50% were male. BPD was more common in infants with ASD [593/1257 (47%) vs. 10,739/35,585 (30%), p<0.001]. Adjusted odds of BPD were higher in infants with ASD (Table).

Conclusions:
A diagnosis of ASD was associated with BPD risk in premature infants . Further studies should determine the impact of ASD size, pulmonary blood flow and resistance, and right ventricular compliance on the risk of developing BPD.
Abstract 14229: Accurate Infarct Identification by Combined Electromechanical Mapping and Magnetic Resonance Imaging to Improve the Targeting of Intramyocardial Injections in a Porcine Model of Chronic Myocardial Infarction
Authors: van Es René , van Slochteren Frebus J , Gyöngyösi Mariann , van der Spoel Tycho I , Koudstaal Stefan , Leiner Tim , Doevendans Pieter A , Chamuleau Steven A
Published: July 2021

Introduction:
For optimal success of cardiac regenerative therapy intramyocardial catheter guided stem cell transplantations are performed in infarct border zone areas i.e. the closest region of viable myocardium in the vicinity of the infarct area. To optimize the therapeutic effect this area should be accurately identified. The gold standard technique to determine the infarct size and location is late gadolinium enhanced (LGE) MRI. Nevertheless, the NOGA®XP electromechanical mapping (EMM) system is used to guide injections to the infarct border zone. Since EMM is expensive, time consuming and has a low spatial resolution, we have developed a practical and accurate technique to fuse the NOGA®XP electromechanical maps with LGE-MRI to guide injections based on high resolution MRI data.

Methods:
LGE-MRI and EMM were obtained in 17 pigs with chronic myocardial infarction. MRI and EMM datasets were registered using our in-house developed 3D CartBox image registration software toolbox. Comparisons between MRI and EMM were performed to assess: 1) feasibility of the 3D CartBox fusion technique, 2) the EMM values measured in the areas with a distinct infarct transmurality (IT).

Results:
Registration was successful in all datasets, and resulted in a mean error of 3.01±1.94mm between the MRI mesh and EMM points (Fig 1A). The highest sensitivity and specificity to identify infarct border zone of 50% IT was found for bipolar voltage between 1.2 and 1.7mV (Fig 1B).

Conclusions:
Our new 3D CartBox image registration toolbox enables real time registration of the EMM on MRI during the injection procedure. The optimal spatial resolution and the instant visualization of the MRI images enables users to easily guide injections to the most optimal injection location for cardiac regenerative therapy based on the gold standard infarct imaging technique. This technique allows physicians to harness the full therapeutic effect of the therapy.