bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17019: Two Distinct mechanisms by which Na+/Ca2+ dysregulation contributes to Arrhythmogenic Diastolic Ca2+ Release
Authors: Radwanski Przemyslaw , Veeraraghavan Rengasayee , Knollmann Björn , Györke Sándor
Published: July 2021

Na
+
and Ca
2+
imbalance is associated with triggered arrhythmias resulting from diastolic Ca
2+
release (DCR) from sarcoplasmic reticulum (SR). Recent evidence suggests Na
+
channel blockade to be a promising therapy for pathologies, including catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the specific mechanism(s) as to how Na
+
/Ca
2+
dysregulation contribute to arrhythmias is unknown.

Confocal microscopy of ventricular myocytes isolated from CPVT mice lacking the cardiac calsequestrin was used to assess Ca
2+
handling response to isoproterenol (Iso) and various pharmacological interventions, while electrocardiograms were acquired during catecholamine challenge to assess the roles of various pools of Na
+
channels in CPVT.

We identify two pools of Na
+
channels: one composed of cardiac-type Na
+
channels localized to cell periphery, and a ‘
local pool
’ comprised of neuronal Na
+
channels colocalizing with RyR2 in the T-tubules. Augmenting function of both Na
+
channel pools with ATX-II in the presence Iso resulted in SR Ca
2+
overload and activation of Ca
2+
/calmodulin-dependent protein kinase II (CaMKII), which precipitated DCR. These, in turn, translated into frequent arrhythmias in CPVT mice. Selectively augmenting function of ‘local pool’ neuronal Na
+
channels with β-Pompilidotoxin (β-PMTX) precipitated DCR on the cellular level causing frequent arrhythmias during catecholamine challenge
in vivo
. However, increasing local Na
+
fluxes reduced SR Ca
2+
load suggesting that local elevation in cytosolic Ca
2+
rather than global SR Ca
2+
overload underlies DCR and arrhythmias under such conditions.

These data suggest two distinct mechanisms for Na
+
/Ca
2+
dysregulation-mediated arrhythmias. The first relies on SR Ca
2+
overload and CaMKII activation and the other on local contribution of Na
+
-Ca
2+
exchange to DCR. Consideration of these divergent mechanisms may enhance individualized approach to arrhythmia management.
Abstract 17038: A Role of Invasive Left Ventriculography during Cardiac Catheterization for Predicting Incidence of Major Cardiovascular Events
Authors: Kuwata Shingo , Yoneyama Kihei , Suzuki Kengo , Izumo Masaki , Ishibashi Yuki , Takahashi Eiji , Mitarai Takanobu , Kamijima Ryo , Koyama Kohei , Tanabe Yasuhiro , Kongoji Ken , Harada Tomoo , Akashi Yoshihiro J
Published: July 2021

Introduction:
We have developed the new index of left ventricular longitudinal axis shortening (LAS) using contrast left ventriculography (LVG) during Cardiac Catheterization.

Objective:
The purpose of this study was to evaluate whether LAS provided additive prognostic information beyond traditional ejection fraction (EF).

Methods:
Nine hundred and ninety eight consecutive patients who had undergone conventional catheters based on clinical indications between 2009 and 2012 were followed retrospectively from our clinical chart. LAS was assessed from LVG (see Figure). Cox regression analysis was used to predict the endpoints of all-cause mortality and congestive heart failure (HF). Receiver operating characteristic curve analysis was used for the discrimination ability of LAS for event beyond traditional EF.

Results:
Sixty-two events were observed during the follow-up period for mean 3.1±1.1 years. In the adjusted model, the endpoints were associated with lower LAS (hazard ratio 0.89; 95% confidence interval 0.80 to 0.90 per 1% LAS increment, p=0.036) after adjustment for the Framingham risk score, history of myocardial infarction and HF, number of stenosis vessels, EF, left ventricular end-diastolic pressure and Log brain natriuretic peptide (BNP). LAS improved ROC area by 7% compared with EF, and LAS combined with EF and log BNP by 13% (see Figure).

Conclusion:
LAS by LVG can be a predictor of death and congestive HF and appears to be a better parameter than traditional EF in patients who underwent invasive coronary angiography for clinical indications.
Abstract 17072: Disruption of mTORC2 Integrity Underlies Increased Myocardial Susceptibility to Ischemia/reperfusion Injury in Chronic Renal Failure
Authors: TOBISAWA TOSHIYUKI , YANO TOSHIYUKI , MIKI TAKAYUKI , TANNO MASAYA , KUNO ATSUSHI , KOUZU HIDEMICHI , MURASE HIROMICHI , OGASAWARA MAKOTO , MURATSUBAKI SHINGO , MIZUNO MASASHI , NISHIZAWA KEITARO , ISHIKAWA SATOKO , YOSHIDA HIDEAKI , MIURA TETSUJI
Published: July 2021

Objective:
Chronic renal failure (CRF) worsens prognosis after myocardial infarction, but its impact on myocardial injury remains unclear. We recently found that mTORC2, a kinase complex promoting phosphorylation of Akt at Ser473, plays a pivotal role in cardioprotection. Here, we tested the hypothesis that CRF increases myocardial susceptibility to ischemia/reperfusion injury by disrupting mTORC2 activation.

Methods and results:
Rats underwent 5/6 nephrectomy (subtotal nephrectomy, SNx) or a sham operation (Sham). Levels of serum creatinine at 4 weeks after the operation were higher in SNx (n=7) than in Sham (n=8) (0.72±0.05 vs. 0.33±0.05 mg/dl, p<0.05), confirming the development of CRF in SNx. Infarct size after 20-min coronary occlusion/2-hr reperfusion was larger in SNx than in Sham (53.2±5.8 vs. 41.1±2.4% of risk area, p<0.05) and was positively correlated with serum creatinine levels (r=0.54, p=0.01), indicating that severity of CRF is a determinant of infarct size. Using separate groups of rats, the effect of CRF on cellular signaling was examined by immunoblotting. Reperfusion-induced phosphorylation of Akt-Ser473 was significantly lower by 32% in SNx than in Sham, with attenuated phosphorylation of p70S6 kinase and GSK3β, downstream substrates of Akt. On the other hand, phosphorylation levels of Jak2, Akt-Thr308, and ERK were comparable between the two groups. Although expression levels of mTORC2 components (mTOR, Rictor, Sin1, and Deptor) and PTEN, a negative regulator of Akt activity, were similar in SNx and Sham, interaction of mTOR and Sin1 determined by immunoprecipitation was 17% less in SNx than in Sham, indicating partial disruption of mTORC2 integrity in CRF. In neonatal cardiomyocytes, mTOR-Sin1 interaction was reduced by treatment with H2O2 (100 μM).

Conclusion:
Taken together with previous reports that CRF up-regulates oxidative stress level in the myocardium, the present results suggest that oxidative stress-mediated disruption of mTOC2 integrity, leading to impaired phosphorylation of Akt at Ser473 upon reperfusion, underlies the increased myocardial susceptibility to ischemia/reperfusion injury in CRF.
Abstract 17082: Carotid Body Denervation Improves Autonomic Balance and Prevents the Worsening of Heart Failure in Rats After Large Myocardial Infarction
Authors: Saku Keita , Kishi Takuya , Nishizaki Akiko , Fujii Kana , Akashi Takuya , Takehara Takako , Oga Yasuhiro , Kakino Takamori , Ikeda Masataka , Ide Tomomi , Sunagawa Kenji
Published: July 2021

Introduction:
Carotid body denervation (CBD) abolishes the carotid body hypersensitivity induced sympathoexcitatory hypertension. Since the carotid body hypersensitivity is a salient feature and predicts poor outcome of chronic heart failure (CHF), we hypothesized that CBD restores normal autonomic balance, thus improves CHF in rats after large myocardial infarction (MI).

Methods:
We created MI in 8 weeks Sprague-Dawley rats. Surviving rats at 2 weeks after MI were randomized into CBD (n=11) and sham-operated (Sham; n=13) groups. We removed the tissues around the carotid bifurcation and established CBD. In some rats (Sham; n=5, CBD; n=5), we telemetrically recorded heart rate (HR). One month after CBD, we compared physiological, histological and immunochemical findings between CBD and Sham.

Results:
CBD significantly reduced HR (337±15 vs. 364±12 bpm, p<0.05). CBD markedly increased the power spectral density of HR in the high frequency range (81.0±9.5 vs. 29.0±8.2 n.u., p<0.05) and decreased that of the low frequency/high frequency ratio (0.6±0.2 vs. 1.8±0.5, p<0.05) indicating the restoration of autonomic balance. CBD significantly reduced biventricular weight (3.1±0.3 vs. 3.7±0.3 g/kg, p<0.05) and left ventricle (LV) end-diastolic pressure (22±5 vs. 33±5 mmHg, p<0.01) and increased maximum LV dp/dt (5118±809 vs. 4217±472 mmHg/sec, p<0.05). CBD reduced lung weight (a marker of pulmonary edema) (6.8±2.0 vs. 12.4±1.5 g/kg, p<001). Furthermore, CBD reduced plasma brain natriuretic peptide (70±43 vs. 166±71 pg/ml, p<0.01) and plasma norepinephrine as an index of sympathetic drive (384±202 vs. 1048±997 pg/ml, p<0.05). CBD significantly reduced the number of inflammatory macrophages (345±45 vs. 474±73 counts/mm2, p<0.05) in the LV and the plasma concentration of interleukin-1β (14.3±4.7 vs. 24.5±11.8 pg/ml, p<0.05) indicating that CBD also suppressed the inflammatory response in CHF.

Conclusions:
CBD restores normal autonomic balance and prevents the worsening of heart failure in rats after large myocardial infarction. CBD may serve as a novel neuro-modulatory therapy for CHF patients.
Abstract 17166: Myeloid-specific Deletion of the Glucocorticoid Receptor Increases Mitochondrial Oxidative Stress and Impairs Wound Healing After Myocardial Infarction
Authors: Neuser Jonas , Fraccarollo Daniela , Tuckermann Jan P , Galuppo Paolo , Bauersachs Johann
Published: July 2021

Background:
Glucocorticoid administration impairs ischemic wound healing by inhibiting inflammation and angiogenesis via a glucocorticoid receptor (GR)-mediated transcriptional response. However, there are also apparently contradictory reports claiming protective effects of glucorticoid administration after myocardial infarction (MI). We investigated the role of the GR in myeloid cells for infarct wound healing, using GR deficient mice (GRLysMCre).

Methods and Results:
MI was induced by permanent left coronary artery ligation in GRflox (wild-type [WT] controls) and GRLysMCre mice. The 7-day mortality was significantly lower in WT compared with GRLysMCre mice. At 7 days post MI, GRLysMCre mice exhibited significantly enhanced thinning and dilatation of the infarcted wall, LV chamber enlargement and functional deterioration. This was associated with altered granulation tissue formation and impaired neoangiogenesis at the site of ischemic injury. Multicolor flow cytometric analysis and immunohistochemical studies revealed at the 2nd day post infarction less infiltrating mononuclear cells [CD11bhigh and (CD49b, NK1.1, B220, CD90, Ly6G)low] in the healing myocardium of GRLysMCre mice. Mononuclear cells were identified as monocytes (F4/80, I-Ab, CD11c)low and as macrophages/dendritic cells (F4/80, I-Ab, CD11c)high. Monocytes lacking GR, isolated from peripheral blood and spleen by magnetic-activated cell sorting 1 day after MI, displayed reduced migration capacity and increased superoxide anion production in mitochondria, which was detected by HPLC-electrochemical analysis of Mito-2-hydroxy-E+. Moreover, at day 2 and 3 we found enhanced cellular and mitochondrial oxidative stress in the healing myocardium of GRLysMCre mice.

Conclusions:
Myeloid-specific deletion of the GR increasing mitochondrial oxidative stress alters wound healing and promotes infarct expansion. Our results suggest that the GR in myeloid cells play a crucial role during cardiac repair after myocardial infarction.
Abstract 17233: Implantable Loop Recorder Monitoring Detects a High Incidence of Bradycardia Leading to Pacemaker Implant in Hemodialysis Patients: Preliminary Results From the Monitoring in Dialysis (MiD) Study
Authors: Koplan Bruce A , Charytan David M , Podoll Amber S , Reddy Vikranth , Roy-Chaudhury Prabir , Tiwari Suresh C , Tumlin James , Williamson Don E
Published: July 2021

Introduction:
Hemodialysis (HD) pts have an increased incidence of syncope and sudden death. A greater understanding of the incidence of bradyarrhythmias as a potential risk factor for these events is needed. The MiD study enrolled maintenance HD pts to undergo implantable loop recorder (ILR) placement to determine the arrhythmia incidence in this population.

Hypothesis:
ILR monitoring will be useful in detecting bradyarrhythmias and guiding treatment in ESRD patients

Methods:
MiD is a prospective, multi-center study to characterize arrhythmias in HD pts during 12mo of ILR monitoring. All ILR-detected events with stored ECG are visually reviewed for confirmation during the initial 6mo. Clinically significant arrhythmias include bradycardia <=40bpm for 6sec, asystole >=3sec, or sustained VT >=130bpm for >=30sec.

Results:
Follow up is available for 45 pts [mean follow-up 6.4mo (0.6-12.0mo), mean age 56 (27-76yrs), 36% female]. Bradycardia events occurred in 16/45 pts (36%) with an incidence of 28.7 (95% CI 10.1-81.7) events per patient month in these 16 pts. Bradycardia was confirmed by visual review in 408 out of 456 ILR-detected brady events with stored ECG occurring during the first 6mo for a positive predictive value (PPV) of 89.5%. An additional 27 of these ILR-detected “brady events” were found to contain either premature ventricular contractions or atrial arrhythmias (PPV for any arrhythmia 95.5%). 4 of 45 subjects (8.9%) have undergone permanent pacemaker implant for bradyarrhythmias or symptomatic tachy-brady syndrome. In comparison, only one patient (2.2%) has been observed to have ventricular tachycardia (VT>=130bpm for >=30seconds). There was no association between timing of dialysis and bradyarrhythmias.

Conclusions:
ILR monitoring detects bradyarrhythmias with high PPV in > 1/3 of HD pts and is associated with a high incidence (9%) of permanent pacemaker implant. With improvement in ILR technology with respect to size and wireless capability, clinicians should have a low tolerance to evaluate HD patients for bradyarrhythmias. These findings may also have implications when considering ESRD patients at increased risk of sudden cardiac death for subcutaneous-only defibrillators that do not currently have permanent pacing capability.
Abstract 17257: The Association Between Diet Quality After Diabetes Diagnosis and Major Cardiovascular Events in Women With Type 2 Diabetes Mellitus
Authors: Shin Hyun J , McCullough Peter A , Li Shanshan , Cho Eunyoung , Rimm Eric , Rosner Bernard , Manson JoAnn E , Hu Frank B
Published: July 2021

Introduction:
The role of dietary choices in the prevention of cardiovascular hard-outcome among type 2 diabetes patients has not been studied well. We examined whether there is an association between dietary quality after diagnosis of type 2 diabetes and major cardiovascular events among women using long-term prospective cohort study.

Hypothesis:
Healthy dietary pattern after type 2 diabetes diagnosis is associated with decreased risk for major cardiovascular events among women.

Methods:
The women with type 2 diabetes (n=6,895, mean age 64 years old) from the Nurses’ Health Study with no baseline cancer or cardiovascular disease were selected. Cox proportional hazard model was used to assess the multivariate association between the alternate Healthy Eating Index (aHEI) and the first episode of major cardiovascular events (coronary heart disease (CHD) or stroke).

Results:
During 26 years of follow-up (75, 276 person-years), a total of the 705 major cardiovascular events (432 cases of CHD, 314 cases of stroke, 41 cases of both CHD and stroke) were documented. The age-adjusted relative risks of major cardiovascular events across quintiles of aHEI score (Q1, Q2, Q3, Q4, Q5) were 1, 0.99 (95% CI, 0.80 to 1.22), 0.84 (CI, 0.67 to 1.05), 0.57 (CI, 0.44 to 0.72), and 0.66 (CI, 0.52 to 0.84) (P < 0.0001 for trend). These figures did not change materially after adjustment for body mass index, physical activity, smoking and other cardiovascular risk factors (1, 1.00, 0.91, 0.63, and 0.80, respectively; P = 0.008 for trend). The multivariate relative risks for stroke and CHD across quintiles of aHEI score were 1, 0.72, 0.80, 0.46, and 0.72 (P = 0.028 for trend) and 1, 1.21, 0.96, 0.72, and 0.73 (p=0.014 for trend), respectively.

Conclusions:
Healthier dietary habits after the diagnosis of diabetes are associated with a reduced risk of cardiovascular events including stroke and coronary heart disease.
Abstract 17276: Implantable Cardioverter-Defibrillator Therapy in Women: Population-based Outomes
Authors: Cowan Simone , Grubisic Maja , Ding Lillian , Hawkins Nathaniel , Raymakers Adam , Novak Paul , Gao Min , Bashir Jamil
Published: July 2021

Background:
Due to the low enrolment of women in implantable cardioverter-defibrillator (ICD) trials, there is controversy whether the survival benefit of ICDs applies to both sexes. Population-based data examining sex differences in ICD outcomes may provide further clarification.

Methods:
Study data were derived from a provincial registry in British Columbia (BC), the Cardiac Services BC Registry, where all ICD recipients are recorded. Patients ≥18 years with a new ICD implant from Jan 2003 to Dec 2012 were included. Data were linked to BC Vital Statistics to determine all-cause mortality. Survival was assessed using Kaplan-Meier methods stratified by sex and compared using the log-rank test. The Cox proportional-hazards model was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) between sexes. The effect of demographics, comorbidities and medication use were explored and only factors with a p-value < 0.15 were included in the final model. Statistical analyses were performed with SAS software, version 9.3 (Cary, NC).

Results:
There were 3905 new ICD implants; of these, 704 were women (18%). Women were younger and had a lower prevalence of comorbidities. Except for beta-blockers, women were less likely to be prescribed cardiac medications. The overall survival of women was greater than men; however, women had a higher re-operation rate for complications (Figure). After adjusting for age, diabetes, coronary artery disease, congestive cardiomyopathy, peripheral vascular disease, acquired heart surgery, and anti-arrhythmic drug use, the sex difference in mortality was attenuated, adjusted HR 0.91, (95% CI: 0.75,1.12).

Conclusions:
Women may derive the same survival benefit as men but have a higher re-operation rate for complications. Ongoing analyses will determine whether the impact of sex on mortality differs among patients receiving an ICD for primary versus secondary prevention.
Abstract 17277: Myocardial Rescue by Mesenchymal Stem Cell via Tunneling Nanotube Formation
Authors: Yang Huaxiao , Runyan Raymond B , Borg Tom K , Markwald Roger , Xu Meifeng , Gao Bruce Z
Published: July 2021

Objectives:
Mesenchymal stem cell (MSC) shows promising therapeutic potentials for heart diseases in numerous animal studies and clinical trials. The cardiogenic transdifferentiation and paracrine factors delivery of MSCs are generally accepted mechanisms for myocardial rescue. Recent studies suggest that the rescue may also be achieved by direct delivery of subcellular organelles such as mitochondria. Tunneling nanotube (TNT) formation between MSCs and various damaged cell types has been observed both in vitro and in vivo for assisting organelle transfer. Based on our recent observation in a cell patterning-based in vitro assay, it is found that mitochondria are transferred from MSCs to neonatal cardiomyocytes (NCMs) through TNTs to enhance myocyte survival. Adequate investigation of hetero-paired TNTs is hampered by their random formation in standard cell culture and the difficulty of capturing them in vivo. Accordingly, a PDMS (polydimethylsiloxane) biochip-based coculture model was microfabricated to enable more consistent examination of TNT formation and mitochondrial transfer.

Methods:
Rat MSC (GFP tagged in green) and 3-day NCMs (w or w/0 treatment of 1 μg/ml lipopolysaccharide (LPS)) were introduced into a two-channel microfluidics-based biochip (Figure 1A) microfabricated with PDMS, and TNTs were guided to form in microchannels between the two cell types. The numbers of TNT formed between MSC and LPS treated or untreated NCM were counted per biochip after 24 hours coculturing. Then the sample was stained with annexin V to evaluate the cardiac stress of NCMs.

Results and Discussion:
It was observed that mitochondria were transferred unidirectionally from MSCs to NCMs via TNT (Figure 1B), irrespective of the TNT’s direction of formation. NCMs in stressed conditions triggered more TNT formation in red of annexin V staining with MSCs than the control (Figure 1C). It suggests that a rescue effect may be produced by TNT-mediated mitochondrial transfer.
Abstract 17292: Ulk1 Plays a Crucial Role in Mitochondrial Autophagy in Cardiomyocytes
Authors: Saito Toshiro , Monden Yoshiya , Sadoshima Junichi
Published: July 2021

Mitochondrial autophagy (MA) plays an important role in mediating mitochondrial (Mt) quality control. The molecular mechanism by which damaged mitochondria are removed during energy stress in cardiomyocytes (CMs) remains poorly understood. We investigated the roles of Atg7 and Ulk1, key regulators of autophagy, in mediating MA. Although cell viability, evaluated with CellTiter-Blue assays, was significantly lower (p<0.05) in Ad-shRNA-Atg7 (sh-Atg7)-transduced CMs than in Ad-shRNA-Ulk1 (sh-Ulk1)- or Ad-shRNA-Control (sh-Cont)-transduced CMs at baseline, those after glucose deprivation (GD) were significantly greater (p<0.05) in sh-Ulk1-transduced CMs than in sh-Atg7- or sh-Cont-transduced CMs. Although LC3-II and reduction of p62, markers of conventional autophagy, were indistinguishable in sh-Ulk1 and sh-Cont-transduced CMs, they were significantly suppressed in sh-Atg7-transduced CMs in comparison. GD significantly decreased (p<0.05) the amount of mtDNA and citrate synthase activity, markers of Mt mass, in sh-Cont- or sh-Atg7-transduced CMs, but not in sh-Ulk1-transduced CMs. More CMs with depolarized mitochondria were observed in sh-Ulk1-transduced CMs than in sh-Cont- or sh-Atg7-transduced CMs after GD. Thus, Ulk1 plays a more important role in mediating CM survival and Mt clearance in response to GD than Atg7. Clearance of MA through lysosomes was evaluated with mitochondria-targeted (Mito)-Keima, with a dual excitation spectrum peaking at 440 and 560 nm, corresponding to neutral and acidic pH, respectively. Knockdown of Drp1 or Beclin1 abolished the fluorescent dots with a high 560nm/440nm ratio, which represent lysosomal translocation of Mito-Keima, suggesting that the high-ratio dots represent MA. In control CMs, high-ratio dots represented 3.6±0.5 % of the area after GD, indicating stimulation of MA. Although knockdown of Ulk1 significantly reduced the area to 0.7±0.4 % (p<0.01, vs sh-Cont) after GD, that of Atg7 or p62 did not (4.9±1.3 % and 4.0±1.0 %). These results suggest that although Atg7 plays an important role in mediating autophagy at baseline, MA may take place even in the absence of Atg7 during energy stress. Furthermore, Ulk1 plays a major role in MA and CM survival in response to energy stress.
Abstract 17297: 9p21 CAD Risk Allele is Protective Against Calcific Aortic Stenosis
Authors: Musameh Muntaser D , Braund Peter S , Nelson Christopher P , Gracey Jay , Denniff Matthew , Thompson John , McCann Gerry P , Bown Matthew J , Sprigings David , Samani Nilesh J
Published: July 2021

The 9p21 locus has emerged as one of the strongest risk variants associated with coronary artery disease (CAD). The risk allele for CAD is also associated with other vascular pathologies, including abdominal aortic aneurysms and intracranial aneurysms. Calcific aortic stenosis (AS) and CAD share some risk factors and histopathologic features. However, a considerable proportion of severe AS patients have no significant CAD, indicating the presence of unique mechanisms underlying each condition. To date only one common genetic variant, rs10455872 in the LPA gene, has been robustly associated with risk of AS. Here we investigated the association of the lead CAD-associated variant (rs1333049) at the 9p21 locus with the risk of AS in 1044 cases and 4527 controls. We also typed the LPA SNP (rs10455872) as a validated variant. All cases had either echo confirmed AS of abnormal valve morphology and peak velocity across the aortic valve of more than 2.5 meters/second, or they had previously undergone surgery for severe AS. We used logistic regression analysis to investigate the additive effect of both variants on risk of AS, adjusting for CAD status. For the LPA locus, we observed the previously reported association of the G allele at rs10455872 with risk of AS (OR 1.23; 95% CI, 1.06 to 1.44, P= 0.008). Interestingly for the 9p21 locus, the CAD associated allele (C) for rs1333049 was associated with a lower risk of AS (OR 0.88; 95% CI, 0.80 to 0.98, P= 0.014). In an additional analysis, we examined the association of rs1333049 with AS in our 1044 cases against an independent set of 828 controls with no history of AS, and the results were consistent with the initial findings (OR 0.76; 95% CI, 0.66 to 0.87, P= 0.0001). This unexpected finding requires further validation, but suggests that the 9p21 locus CAD-associated variant is not uniformly deleterious for other vascular pathologies - and for AS may be protective. If the 9p21 finding is confirmed, then understanding the differential effect of this locus on AS and CAD may help to better understand the specific pathogenesis of each condition.
Abstract 17301: Increased Pulmonary Vascular and Systemic Response to Chronic Hypoxia in Sirtuin 1 Mutant Mice: a Role for Hypoxia-inducible Factor-3α?
Authors: Taha Mohamad , Deng Yupu , McBurney Michael W , Stewart Duncan J
Published: July 2021

Introduction:
Pulmonary Hypertension is caused by occlusive remodelling of pulmonary arterioles leading to increased pulmonary vascular resistance, right ventricle hypertrophy and eventually failure. Sirtuin-1 (Sirt1) is an NAD+-dependent deacetylase that has been strongly implicated in endothelium homeostasis in systemic vessels, but little is known about its role in hypoxia sensing.

Hypothesis:
We assessed the hypothesis that absence of Sirt1 catalytic activity is detrimental to the hypoxic response in mice.

Methods:
Mice lacking Sirt1 catalytic activity (sirt1Y/Y, H355Y) and their wild type (WT) littermates were exposed to chronic hypoxia (10% O2) for 1, 7 or 21 days.

Results:
Sirt1Y/Y exhibited an exaggerated increase in right ventricle systolic pressure, apparent within the first week of hypoxic exposure, which progressively increased over the 3 week CH exposure period (42±2 sirt1Y/Y vs. 30±1 WT; n=27/group, p< 0.001). Right ventricular hypertrophy, assessed by the RV/LV+S weight ratio, was also increased (Day 21: 0.56±0.01 sirt1Y/Y vs. 0.43±0.01 WT, n=27/group; p< 0.001). Hemtaocrit levels were similar in Sirt1Y/Y and WT mice at baseline; however, there was a delayed increase after three weeks of CH in Sirt1Y/Y mice relative to WT mice (71±2% sirt1Y/Y vs. 63±1% WT, n=17/group; p<0.001). Plasma levels of erythropoietin (EPO), assessed by ELISA at each time point, were markedly increased at Day 7 in Sirt1Y/Y vs. WT mice (492±240 vs. 81±16pg/mL, respectively; n=7-9, p< 0.05) but normalized at later time points (Day 21: 75±9 sirt1Y/Y vs. 96±12pg/mL WT; n=4/group). Surprisingly, expression of both HIF1α and 2α mRNA was decreased in mutant mice lungs during chronic hypoxia at all time points, as was the expression of several HIF1/2α responsive target genes. However, there was a dramatic increase in HIF3α in Sirt1 mutant vs. WT lungs, which has been implicated both in repression of other HIFs as well as in directly mediating hypoxic signaling.

Conclusions:
Loss of Sirt-1 deacetylation activity led to an exaggerated pulmonary and systemic response to hypoxia, consistent with a role for Sirt1 in hypoxia sensing and/or signaling. As well, our data suggest that HIF3α is a novel downstream target for Sirt1 in the regulation of the response to chronic hypoxia.
Abstract 17341: A 19-Year-Old Female with Recurrent Chylopericardium
Authors: Chen Cheng-Han , Kleiber Angela , Megerdichian Christine , Fonarow Gregg C , Baas Arnold S
Published: July 2021

A 19-year-old female initially presented to an outside hospital with worsening shortness of breath over the course of hours. Echocardiogram revealed a large pericardial effusion with tamponade physiology. An urgent pericardiocentesis followed by a pericardial window yielded 600cc of cloudy fluid, and work-up for infectious, auto-immune, and malignant etiologies was unrevealing. She was discharged home, but over the next four weeks developed a repeat pericardial effusion requiring another pericardiocentesis yielding 750cc of cloudy fluid.

She then presented to our hospital two weeks later with progressive shortness of breath. Echocardiogram revealed a large pericardial effusion with evidence of early tamponade physiology. Our differential diagnosis for her recurrent pericardial effusions remained broad, with infectious and malignant etiologies at the top of consideration. Computed tomography of the chest demonstrated the pericardial effusion and mild mediastinal adenopathy. She underwent another pericardial window with removal of 600cc of milky fluid, and fluid analysis was notable for a markedly elevated triglyceride level consistent with a diagnosis of chylopericardium. Work-up for malignancy as an etiology for recurrent chylopericardium was negative. A percutaneous lymphangiogram was then performed, which revealed a significant leak in the superior aspect of the thoracic duct into the pericardial space. Percutaneous embolization of the thoracic duct was performed using detachable coils along with embolic glue, resulting in resolution of the leak. She has since remained asymptomatic, and follow-up echocardiogram was without recurrence of any pericardial effusion.

This case of idiopathic recurrent chylopericardium as the cause for pericardial effusion represents a rare manifestation of a relatively common cardiac condition. It illustrates the importance of routine pericardial fluid analysis for triglycerides, as this led to her correct diagnosis of chylopericardium. The use of percutaneous thoracic duct embolization has only recently been reported as a novel approach for treatment of chylous leak, and may emerge as a useful alternative to surgery for recurrent chylopericardium.
Abstract 17360: Four Factors Explain Most of the Gender Disparity in Statin Therapy
Authors: Zhang Huabing , Plutzky Jorge , Shubina Maria , Turchin Alexander
Published: July 2021

Despite well documented gender disparities in statin therapy, the reasons underlying these differences remain obscure. Applying natural language processing to a retrospective cohort of 24,338 patients with coronary artery disease (CAD) treated in primary care practices (PCP) affiliated with two academic medical centers between 01/01/2000 and 12/31/2011, we studied contribution of smoking, age, cardiologist evaluation and adverse statin reactions to gender differences in statin use.

Two thirds of the patients were men (Table); 85.6% received statins during the study period and 69.7% had persistent statin therapy (active statin prescription at the last PCP visit). Women were less likely than men to have been treated with a statin but equally likely to have persistent statin therapy after statin initiation. Women were older, less likely to have ever smoked, less likely to have been seen by a cardiologist and more likely to have reported an adverse reaction to a statin.

In multivariable analysis of all subjects, patients with history of smoking (OR 1.304), younger age (OR 1.016), or cardiologist evaluation (OR 1.797) were more likely (p < 0.001 for all) to have persistent statin therapy. Direct estimations of the effect of the differences in joint distributions of the covariates between men and women showed the following contributions to gender differences in persistent statin therapy: age 51.7%, smoking 31.5%, cardiologist evaluation 24.2%, and adverse statin reactions 6.7%. Together, these four factors contributed 89.9% to the gender disparity in persistent statin therapy.

In 24,000 patients in whom statin therapy was clearly indicated, several specific factors appear to underlie differences in statin therapy and it’s persistent use between men and women. Identifying such drivers may facilitate interventions and further research to overcome gender differences in applying proven interventions for cardiovascular risk reduction.
Abstract 17378: Familial Spontaneous Coronary Artery Dissection - Evidence for Genetic Susceptibility
Authors: Goel Kashish , Tweet Marysia , Olson Timothy M , Maleszewski Joseph J , Gulati Rajiv , Hayes Sharonne
Published: July 2021

Background:
Spontaneous coronary artery dissection (SCAD) typically presents as acute coronary syndrome in young women with no cardiovascular risk factors. It is associated with high morbidity and mortality, and is underdiagnosed. Despite this, risk factors and pathophysiology associated with SCAD are not completely understood. The objective of the present case series was to assess family history as a risk factor in patients with SCAD.

Methods:
We reviewed the medical records and questionnaires of 335 participants in the Mayo Clinic SCAD Registry for history of MI, SCAD or CAD in another family member. Coronary angiograms of all affected family members were reviewed by a senior interventional cardiologist.

Results:
We identified 4 familial cases of SCAD comprised of affected mother-daughter, identical twin sister, sister and aunt-niece pairs, implicating both recessive and dominant modes of inheritance. The mother-daughter pair also reported history of fatal MI in 3 maternal relatives including grandmother, great grandmother and great aunt. One of the affected twin sisters died of SCAD, which was confirmed on autopsy. None of the subjects had other potential risk factors for SCAD including extreme exercise, polycystic kidney disease, connective tissue disorder, peripartum status or diagnosed non-coronary fibromuscular dysplasia. The details of their demographics, risk factors, presentation, location of SCAD and management are presented in the table.

Conclusions:
This series is the first to identify a familial association in SCAD suggesting a genetic predisposition. Recognition of SCAD as a heritable disorder has implications for at-risk family members and furthers our understanding of the pathophysiology of this complex disease. Whole exome sequencing in these families provides a unique opportunity to identify the molecular underpinnings of SCAD susceptibility.
Abstract 17410: A Multiperspective Analysis of the Influence of Medicare Part D on the Cost-effectiveness of Dabigatran versus Warfarin
Authors: Salata Brian M , Hutton David W , Levine Deborah A , Froehlich James B , Barnes Geoffrey D
Published: July 2021

Introduction:
Dabigatran and warfarin have been shown to be non-inferior for stroke prevention in atrial fibrillation (AF). We aimed to assess the cost perspectives of each payer (Medicare and patient) in relation to administration, monitoring and adverse outcomes for each medication.

Hypothesis:
We hypothesize that dabigatran 150 mg BID will be more cost-effective when compared to warfarin for both payers (Medicare and patient) regardless of Medicare Part D coverage.

Methods:
Using a Markov model, we performed a decision analysis comparing two treatment strategies in patients 65 years of age and older with AF: adjusted-dose warfarin and dabigatran 150 mg twice daily in Medicare patients with CHADS2 scores ≥ 1. Results are listed in 2013 US dollars, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). Patient movement between health states was modeled using 1-month cycles for 35 years or until death. Cost-effectiveness therapies were selected using a willingness to pay threshold of $50,000 per quality-adjusted life year gained.

Results:
For patients with Medicare Part D coverage, Quality-adjusted life expectancy was 10.74 QALYs with warfarin and 11.22 QALYs with 150 mg dabigatran BID. From Medicare’s perspective, total average costs were $59,684 and $59,284 for warfarin as well as $76,237 and $45,421 for dabigatran, in patients with and without Part D coverage, respectively. From Medicare’s perspective, the ICER comparing dabigatran with warfarin was $34,707 and -$29,065, for patients with and without Part D coverage, respectively. From the patient’s perspective, total costs were $33,466 and $33,866 for warfarin as well as $28,876 and $59,692 for dabigatran, in patients with and without Part D coverage, respectively. From the patient’s perspective, the ICER comparing dabigatran with warfarin was -$9,624 and $54,147, for patients with and without Part D coverage, respectively.

Conclusions:
In patients ≥ 65 years old with nonvalvular atrial fibrillation (NVAF) and at increased risk of stroke (CHAD2 score = 2), dabigatran 150 mg BID is more cost-effective for both Medicare and the patient, except for individual patients without Medicare Part D coverage.
Abstract 17415: Similar Improvements in Outcomes Following 36 Sessions of Cardiac Rehabilitation Irrespective of Duration
Authors: Gomadam Pallavi , Sacrinty Matthew , Douglas Christopher , Johnson Dominic , Addison Theresa , Martin Beverly , Paladenech Connie , Austin Natalie , Robinson Killian
Published: July 2021

Background:
Cardiac Rehabilitation (CR) improves functional capacity in patients with CAD. The standard program requires completion of 36 sessions most often in 12 weeks. For various reasons, many patients are unable to complete a CR program in this time. Data comparing outcomes from standard 12-week programs to those of a greater duration are sparse.

Hypothesis:
We predicted that patients completing 36 sessions of CR in our standard 12-week program would achieve similar improvements in exercise capacity and risk factors as those taking longer than 12 weeks.

Methods:
Between 2004 and 2013, 836 patients (mean age 63.3 ± 11.0 years, 222 females and 614 males) completed 36 sessions of CR in 12-15 weeks (n=507), 15-19 weeks (n=234), or 19-67 weeks (n=95). Exercise capacity in metabolic equivalents (METs) and risk factors were measured before and after CR. Analysis of variance was used to compare groups.

Results:
All patients showed similar improvements in exercise capacity, weight, BMI, LDL, and HDL cholesterol (see table and figure). Systolic pressures decreased, though not significantly, but diastolic pressures remained unchanged.

Conclusion:
Although standard of care for CR is usually to complete 36 sessions in 12 weeks, a longer program incorporating the same number of sessions may achieve similar outcomes in relation to exercise capacity and risk factors, with the exception of blood pressure. Such programs may be suitable for patients who are unable to complete a CR program within the standard time frame due to social, occupational, or medical constraints.
Abstract 17449: Left Ventricular Hypertrophy and Reduced Myocardial Function Are Associated with Aortic stiffness Measured by Cardiac MRI: the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Ohyama Yoshiaki , Ambale-Venkatesh Bharath , Chught Atul R , Teixido-Tura Gisera , Kim Jang Young , Donekal Sirisha , Yoneyama Kihei , Gjesdal Ola , Liu Chia-Ying , Redheuil Alban , Wu Colin , Hundley Gregory W , Bruemkie David A , Lima Joao A
Published: July 2021

Background:
Aortic pulse velocity (PWV) is generally considered an intrinsic marker of arterial stiffness. The association of central aortic PWV measured by MRI with cardiac structure and function remains poorly explored. We investigated how central aortic PWV assessed by MRI relates to LV structure and function in the population based study.

Method:
Multi-Ethnic Study of Atherosclerosis (MESA) participants at exam5 (2010-2012) were studied. Central aortic PWV was measured by phase contrast (PC) cine MRI at the level of the pulmonary artery bifurcation and black blood sagittal image. LV mass and volume indexed to height1.7, LV ejection fraction (LVEF), and LV mass volume ratio (M/V ratio) were determined by cine MRI. LV circumferential strain (Ecc), LV torsion, and early diastolic strain rate (SRe) were determined from tagged MRI. Linear regression models were used to evaluate the association between PWV and LV parameters after adjusting for demographics and cardiovascular risk factors.

Results:
A total of 2018 participants (age 70 ± 9 years, 53% women, 38% White, 10% Chinese, 28% African American, 24% Hispanic) were included in this cross-sectional study. Mean value of PWV was 8.9 ± 4.2 m/s. Distribution of PWV was skewed, so PWV was logarithmically transformed for linear regression models. In multivariable models adjusted for risk factors, higher PWV was associated with less/worse myocardial systolic and diastolic function parameters; LVEF, Ecc, torsion and SRe. Higher PWV was also associated with higher LV mass before and after adjusting multivariable models (Table).

Conclusion:
Our observations indicate that higher PWV is related to LV hypertrophy and subclinical myocardial systolic and diastolic dysfunction in multi-ethnic population.
Abstract 17459: Drug Eluting Balloon Angioplasty is a Safe Treatment Option for In-stent Restenosis: Meta-analysis of Current Evidence
Authors: Gaddam Sainath , Pandya Bhavi , Meghani Mustafain , Agarwal Vratika , Soomro Armaghan , Duvvuri Srinivas , Lafferty James , Royzman Roman , Kandov Ruben
Published: July 2021

Introduction:
Drug eluting balloons (DEB) were recently approved by FDA for peripheral artery interventions only. For coronary in-stent restenosis (ISR), the ACC/AHA/SCAI 2011 PCI guidelines have no recommendations on role for DEB. While ESC/EACTS 2010 PCI guidelines, have level IIa recommendation for DEB for ISR after a bare metal stent. The drug delivery kinetics with DEB allows shorter duration of dual anti-platelet therapy and has a potential role in ballooning side branches of a bifurcating lesion after stenting.

Aim:
To compare safety and efficacy of DEB angioplasty vs. plain old balloon angioplasty (BA) or drug eluting stent (DES) for treating coronary ISR.

Methods and Results:
A thorough search was performed on Pubmed, Embace and Google scholar databases for randomized control trials (RCT) comparing DEB vs. BA or DES for ISR. We compared target lesion revascularization (TLR) and MACE events for these groups. We also pooled data from registries and observation studies on DEB for outcome analysis.

Total number of patients with DEB’s in our study was 3465, with 693 DEB’s in 8 RCT’s. Mean follow up period was 11 months. Pooled analysis showed significant benefit for DEB compared to plain old BA, for events of target lesion revascularization (OR= 0.25, p<0.0001), and death (OR=0.31, p<0.0001). Comparing DEB to DES, there was no statistical difference in outcomes comparing TLR (OR=1.4, p=0.14), MI or death (OR=0.65, p=0.39). Cumulative incidence of target lesion revascularization (TLR) with DEB was 6.7%.

Conclusions:
For coronary ISR, drug eluting balloon angioplasty is superior to plain old balloon angioplasty in terms of safety and outcomes. However, comparing drug eluting balloons vs. drug eluting stents in ISR, the outcomes are comparable and will need larger studies powered to make definitive recommendation.
Abstract 17488: Effect of Cocaine on Coronary Microvasculature
Authors: Kumar Varun , Singh Mukesh , Gopalakrishnan Lakshmi , Kovacs Daniela F , Benatar Daniel , Gibson Charles M , Khosla Sandeep
Published: July 2021

Background:
Presence of coronary microvascular dysfunction despite normal epicardial coronary arteries is known to significantly impact mortality and morbidity. With the increasing number of cocaine users among urban population, it is imperative to assess its effect on the coronary microvasculature.

Method:
In this blinded, retrospective study, microvascular dysfunction was assessed using corrected Thrombolysis In Myocardial Infarction (TIMI) frame count (cTFC) and TIMI perfusion grade (TMPG), in an available consecutive series of 202 cocaine users in the absence of acute or recent MI, significant epicardial coronary artery disease (CAD) or vasospasm, among the 775 cocaine users who underwent coronary angiography at Mount Sinai Hospital, Chicago from 2005 to 2013. Applying the same criteria, the cTFCs and TMPGs were then compared with 210 randomly chosen non-cocaine users. Angiographers were blinded when determining the cTFC and TMPG.

Results:
The TMPG 0/1 for the left anterior descending (LAD), circumflex (LCx), and right coronary (RCA) arteries were statistically significant among cocaine users (LAD 22% versus 5%, p=<0.0001; LCx 25% versus 6%, p=<0.0001; RCA 42% versus 8%, p=<0.0001). For the cTFC, the LAD and LCx were significantly elevated among cocaine users (27.33 ± 10.9 versus 24.88 ± 10.05, p=0.03 and 41.11 ± 14.28 versus 38.23 ± 12.69, p=0.04; respectively). Additionally, there was a significant percentage of cocaine users with cTFC<14 (i.e. faster flow) observed in the RCA (9% versus 3%; p=0.008).

Conclusion:
Our study concludes that there is significant coronary microvascular dysfunction associated with cocaine use despite the absence of significant epicardial CAD.

Additionally, reduced coronary filling time might be the reason for the observed higher frequency of hyperemic flow in the RCA among cocaine users, which is associated with poorer clinical outcomes, particularly in the context of impaired myocardial perfusion.
Abstract 17491: Impact of Prehospital Administration of Antithrombotic Medications on Infarct-related Artery Patency in ST-elevation Myocardial Infarction: Results from the FAST-MI 2010 Registry
Authors: Puymirat Etienne , Cottin Yves , Montalescot Gilles , Bonnefoy-Cudraz Eric , Bonello Laurent , Belle Loic , Le Breton Herve , Steg Ph Gabriel , Ferrieres Jean , Simon Tabassome , Danchin Nicolas ,   for the FAST-MI investigators
Published: July 2021

Rationale:
The role of prehospital (PH) antithrombotic medications in STEMI is debated; real-world data are scarce. We used the FAST-MI 2010 data to assess TIMI flow before PCI, in relation to PH administration of antithrombotic medications and timing of coronary angiography.

Methods and Results:
FAST-MI is a nationwide French registry including consecutive AMI patients in 213 centers in November 2010. Of 2364 STEMI patients, 2035 had TIMI flow assessed pre-intervention (1458 primary PCI, 289 lysis, 288 no reperfusion therapy); 41% had TIMI flow 2/3. PH use of antithrombotics was: ASA 52%, clopidogrel 37%, prasugrel 7%, GP IIb-IIIa 4%; unfractionated heparin 24%, other anticoagulants 22%.

Mean age, risk factors, medical history, GRACE score, location of infarct did not differ between patients with TIMI 2/3 vs 0/1 flow. IRA patency was higher with time from onset to call less than 120min (45% vs 35%, P<0.001), and time from ECG to angio over 120 min (48% vs 33%,P<0.001).

In the whole population, % TIMI flow 2/3 was higher with PH lytics (78% vs 42%, P<0.001) and differed according to PH antithrombotic use: no antiplatelet 42%, ASA alone 39%, clopidogrel 53.5%, prasugrel 58%, GPIIb-IIIa 40%; no anticoagulant 43%, UFH 46%, other anticoagulants 55%. Lysis (OR 5.67, 3.67-8.77), and combination of dual antiplatelets and anticoagulants (OR 1.59, 1.20-2.12) were independent correlates of higher patency.

In patients with primary PCI, individual medications were not significantly correlated with IRA patency. Combined dual antiplatelet and anticoagulants, however, was a significant correlate of higher TIMI2/3 flow (adjusted OR 1.43, 1.05-1.96), as were shorter duration from onset to call (OR 1.53, 1.13-2.08) and longer time from ECG to angio (OR upper tertile vs lower tertile 1.65, 1.14-2.37).

ST-segment resolution, reinfarction, stent thrombosis and TIMI major bleeding did not differ according to PH antithrombotics.

Conclusion:
In the whole population of STEMI patients (including lytic-treated patients), as in patients with primary PCI, PH administration of combined antiplatelet and anticoagulants is associated with increased IRA patency. In contrast, none of the individual antithrombotic medications significantly improved IRA patency.