bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17733: Some Epilepsy Patients Die Suddenly Without a Preceding Seizure Episode: What are the Mechanisms?
Authors: Stecker Eric C , Chua Kelvin , Uy-Evanado Audrey , Teodorescu Carmen , Reinier Kyndaron , Gunson Karen , Jui Jonathan , Chugh Sumeet S
Published: March 2022

Introduction:
Epilepsy is associated with a significantly increased risk of sudden cardiac arrest (SCA), and we have previously reported that this devastating outcome does not always require a preceding seizure. Based on the hypothesis that the pathophysiology of SCA for epilepsy patients may be heterogeneous, we compared the clinical profile of epilepsy patients with and without seizure activity prior to SCA.

Methods:
Subjects of all ages with SCA occurring in the setting of prior documented epilepsy were identified from a large, ongoing, population-based study of SCA in the Northwest US (community pop. approx. 1 million). We explored the relationships between baseline demographics, lifetime medical history and SCA circumstances among those who had a witnessed seizure within 24 hours of the SCA event (seizure-dependent) and those who did not (seizure-independent). Data were obtained from multiple sources (first responders, medical practitioners and medical examiner) between 2002 and 2015. Patients with terminal illnesses and non-cardiac causes of arrest were excluded, as well as those with infantile febrile seizures or alcoholic withdrawal seizures.

Results:
Among 142 subjects with SCA and seizure disorder, 64 (45.1%) were witnessed during the event and, among these, 26 (40.6%) were seizure-dependent while 38 (59.4%) were seizure-independent. The seizure-independent subjects were significantly older (mean age 61.9 years; 95% CI, 43.1 to 80.7 years; vs 47.6 years; 95% CI, 27.0 to 68.2 years; p=0.006). However the younger seizure-dependent group had higher prevalence of cardiac arrest due to pulseless electrical activity (PEA) or asystole (81.0% vs 58.3%; p=0.081). There was no notable difference in the burden of comorbidities (Charlson index 1.92 vs 2.37; p=0.941), periarrest characteristics, ECG and echo parameters.

Conclusions:
Seizure-independent SCA occurs at an older age, supporting the hypothesis that over time, neuro-cardiac remodeling may lead to cardiac arrest in the absence of hypoxia. In younger, seizure-dependent patients hypoxia may be a pre-requisite, but both hypotheses warrant further detailed investigation.
Abstract 17781: Surgical Revascularization in Acute Coronary Syndromes: Minimally Invasive Hybrid Strategy versus Conventional Coronary Artery Bypass Grafting
Authors: Harskamp Ralf E , Liberman Henry A , Mehta Rajendra H , Jaber Wissam , Vassiliades Thomas A , Samady Habib , Halkos Michael E
Published: March 2022

Background:
Hybrid coronary revascularization (HCR), which combines minimally invasive bypass surgery and percutaneous coronary intervention of non-LAD vessels, constitute a less invasive alternative to conventional coronary artery bypass grafting (CABG). The safety and effectiveness of HCR in acute coronary syndromes (ACS) as a surgical coronary revacularization strategy is unknown.

Methods:
Patients presenting with ACS who underwent HCR at a U.S. academic center (1/2008-9/2013) were included. These patients were matched 1:4 to similar individuals who underwent CABG using a propensity-score matching algorithm. Conditional logistic regression and Cox regression stratified on matched pairs were performed to evaluate the association of HCR versus CABG on the outcomes of 30-day MACCE (a composite of mortality, myocardial infarction (MI) and stroke), peri-procedural complications, and 3-year mortality.

Results:
Of 585 patients (HCR=117, CABG=468) in the propensity-score matched cohort, the 30-day MACCE was comparable after HCR and CABG (4.3% vs. 3.6%, odds ratio: 1.19, 95%-CI:0.43-3.19, p=0.75). Compared with CABG, HCR resulted in fewer procedural complications (7.7% vs. 16.0%, p=0.037), fewer blood transfusions (0 95%-CI:0-0 vs 1 95%-CI:0-2, p<0.001), lower chest-tube drainage (760cc 95%-CI:555-1090 vs. 890cc 95%-CI:660-1130, p<0.001) and shorter length-of-stay (4, 95%-CI:3-5 versus 5, 95%-CI:4-7 days, p<0.001). Over a 3-year follow-up period, mortality was similar after HCR and CABG (6.0% vs. 7.0%, hazard ratio: 0.92, 95%-CI:0.33-2.54, p=0.87).

Conclusion:
In this exploratory analysis we found that among patients with ACS the use of HCR appeared safe, with fewer procedural complications, less blood product use, and faster recovery with similar longitudinal outcomes relative to conventional CABG surgery. Future multi-center studies involving a large number of patients with ACS are needed to confirm these findings.
Abstract 17789: Comprehensive Optical Imaging of Macrophages Associated With Intraplaque Hemorrhage Using the Integrated Dual Modal OCT-NIRF Structural-Molecular Imaging
Authors: Lee Jae Joong , Lee Min Woo , Kim Tae Shik , Song Joon Woo , Oh Dong Joo , Park Kyeongsoon , Oh Wang-Yuhl , Yoo Hongki , Kim Jin Won
Published: March 2022

Introduction:
Intraplaque hemorrhages (IPHs) are associated with rupture-prone plaques. Within IPHs, macrophages differentiate into a specific phenotype characterized by the expression of mannose receptors. The purpose of this study was to investigate the feasibility of intravascular optical coherence tomography (OCT)-near infrared fluorescence (NIRF) structural-molecular imaging combined with a NIRF probe targeting mannose receptors to estimate IPHs in vivo.

Methods and Results:
IPH was induced by injecting centrifuged autologous erythrocytes through a micro-infusion catheter into rabbit aortic plaques. Normal chow diet was continued for an additional 6 weeks for macrophage differentiation. 48 hours after intravenous injection of our newly synthesized NIRF labeled nanoprobe (ex/em 750/773 nm) targeting macrophage mannose receptors at a dose of 10 mg/kg, OCT-NIRF imaging demonstrated highly enhanced NIRF signals in IPH lesions characterized by black-dotted neovessels surrounded with heterogenous OCT signals (asterisk), suggesting the association of mannose receptor positive macrophages with intraplaque hemorrhagic transformation (Figure). FM and histologic findings from the corresponding sister sections corroborated the in vivo imagings, which demonstrated the co-localization of NIRF signals with macrophage mannose receptors and hemorrhagic compositions.

Conclusions:
OCT-NIRF imaging with a NIRF probe targeting mannose receptors could provide a promising novel strategy to estimate IPH-associated macrophages and detect high-risk plaques.
Abstract 17799: Have We Abandoned Therapeutic Hypothermia Prematurely?
Authors: Bray Janet , Bloom Jason , Stub Dion , Segan Louise , Mitra Biswadev , Smith Karen , Finn Judith , Bernard Stephen
Published: March 2022

Introduction:
Following the recent Targeted Temperature Management (TTM) Trial, many worldwide cardiac arrest centers have adjusted target temperatures from 330C to 360C. The aim of this study was to examine quality of post-arrest care in an expert cardiac center following the adoption of a TTM protocol.

Methods:
We conducted an audit of consecutive ventricular fibrillation out-of-hospital cardiac arrest (VF-OHCA) patients of presumed cardiac etiology, admitted to a quaternary referral cardiac hospital in Australia.

Results:
Over the two-year period there were 70 VF-OHCAs admitted (28 before TTM change and 42 after). Patient demographics, arrest features including witnessed arrest, bystander CPR and arrest duration were all similar, between the two periods. Post-arrest care including cardiology consults (93% vs 100%, p=0.15), coronary angiography (79% vs. 76%, p=0.82) and documented orders for TTM were all equivalent. Compliance, however, with temperature management was significantly worse in the 360C period; the average time at target temperature was significantly lower in this time (22hrs vs. 8hrs, p<0.001). 50% of patients recorded temperatures >37.1o in the first 24-hours in the 360C, compared to 0% of patients during the 330C period. Survival to hospital discharge (75% vs 69%, p = 0.59) and rates of discharge to home among (59% vs 45%, p = 0.32) were similar between 330C and 360C periods. After adjustment for arrest duration, an abnormal temperature (>37.10C) in the first 24hours following hospital admission was associated with hypoxic brain injury (AOR=4.55, 95%CI: 1.08-19.09, p=0.039).

Conclusion:
Revision of the TTM protocol in an expert cardiac centre was associated with significant non-compliance with target temperatures, leading to increased febrile patients in the post arrest period and possible poorer outcomes.
Abstract 17806: Clinical Outcomes of Patients Treated With First Generation vs. Second Generation Drug-eluting Stents for Left Main Coronary Artery Disease: A Meta-analysis
Authors: Gongora Carlos A , Casso Dominguez Abel , Bavishi Chirag , Pena Jacobo , Chavez Patricia , Arora Shilpkumar , Moreno Pedro , Tamis-Holland Jacqueline
Published: March 2022

Introduction:
The second generation drug-eluting stents Everolimus and/or Zotarolimus (S-DES) have been proven to be superior to the first generation drug-eluting stents Sirolimus and/or Paclitaxel (F-DES) when treating non-left main coronary artery lesions. Previous studies have come to inconsistent results regarding the efficacy of these two stent types in patients treated for left main coronary artery disease (LMCAD).

Hypothesis:
We hypothesized that the use of S-DES would results in better outcomes than F-DES in patients with LMCAD.

Methods:
We performed a meta-analysis to summarize the up-to-date evidence on this subject. We included studies comparing clinical outcomes for S-DES vs F-DES in patients with LMCAD. We examined the following end-points: Mortality, myocardial infarction (MI), and target-vessel revascularization (TVR). In addition we examined the rates of stent thrombosis and major adverse cardiac events (MACE). MACE was defined according to the definition used by each of the included studies. Pooled risk ratios (RR) and their 95% confidence intervals (CI) were calculated for all the clinical outcomes using a random-effect model.

Results:
A total of 4 studies met our search criteria and were included in the analysis. Among these studies 701 patients were treated with F-DES and 753 patients were treated with S-DES. There was no significant difference in all-cause mortality or MI in the group of patients treated with S-DES as compared with those treated with F-DES. TVR was lower with S-DES. (Figure 1). In addition, S-DES was associated with lower MACE rates (RR: 0.63; 95% CI: 0.48 to 0.82; p <0.05) and there was a trend toward a lower rate of stent thrombosis (RR: 0.40; 95% CI: 0.13 to 1.20; p 0.10) with S-DES.

Conclusions:
The use of S-DES for the treatment of LMCAD is associated with improved clinical outcomes as compared with F-DES. S-DES should be the stents of choice when treating patients with LMCAD.
Abstract 17820: Overexpression of Nos1ap Alters Qtc Intervals and Risk of Arrhythmias in Mice
Authors: Williams Tatjana , Oppelt Daniel , Arias-Loza Paula Anahi , Abesser Marco , Schmitt Joachim , Schuh Kai , Ritter Oliver
Published: March 2022

Rationale:
The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death.

Hypothesis:
We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders.

Methods and results:
We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). NOS1AP overexpressing animals were investigated with the main focus upon electrophysiology. Heart rates were similar in induced and non-induced animals. NOS1AP overexpression resulted in arrhythmia already under basal conditions; we observed ventricular fibrillation and tachycardia. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleled by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. QTc alterations and accompanied deaths subsided upon readministration of doxycycline.

We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans.

Conclusion:
Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals.

In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.
Abstract 17829: Frequency-domain Optical Coherence Tomography Findings of Population With High Skin Auto Fluorescence
Authors: Fujino Yusuke , Tahara Satoko , Naganum Toru , Yabushita Hiroto , Wang Wei , Nakamura Sunao
Published: March 2022

Objective:
We aim to assess the coronary artery plaque features in patients with high skin auto fluorescence (SAF) using frequency-domain optical coherence tomography (FD-OCT).

Background:
SAF, a non-invasive measurement of the accumulation for glycation end products (AGEs) level of skin, has been reported as a useful marker for micro/macro vascular complications. Moreover patients involved with coronary artery disease (CAD) with higher SAF show worse clinical outcome compared to patients with lower SAF. Due to its unprecedented high resolution (~10μm axial), optical coherence tomography (OCT) has been increasingly used for plaque assessments. In this situation, there is no data evaluating the OCT findings of high SAF population.

Methods:
We prospectively enrolled 108 consecutive patients with de novo coronary artery disease underwent percutaneous coronary intervention (PCI) with FD-OCT images at pre-PCI. SAF was measured before PCI procedure. We divided the population into two group high SAF group (greater than or equal to 2.6) and low SAF group (less than 2.6), then compared FD-OCT findings between high and low SAF group. Furthermore we evaluated the predictor of thin cap fibroatheroma (TCFA) and plaque rapture by FD-OCT.

Results:
High SAF group shows much more TCFA and plaque rapture compared to low SAF group (63.9% vs 31.9%, p<0.001 and 32.8% vs 12.8%, p<0.001, respectively). In multivariable analysis, age (odds ratio [OR]: 0.96; 95% confidence interval [CI]: 0.92 to 1.00; p = 0.046) and SAF (<2.6 as reference) (odds ratio [OR]: 5.89; 95% confidence interval [CI]: 2.39 to 14.51; p < 0.001) were considered to be the predictor of TCFA and SAF (odds ratio [OR]: 4.23; 95% confidence interval [CI]: 1.23 to 14.51; p = 0.022), gender (male as reference) (odds ratio [OR]: 0.12; 95% confidence interval [CI]: 0.03 to 0.56; p = 0.007) and LDL (odds ratio [OR]: 1.2; 95% confidence interval [CI]: 1.02 to 1.42; p = 0.029) were considered to be the predictor of plaque rapture.

Conclusion:
Based on FD-OCT imaging, high SAF group shows the association with TCFA and plaque rapture compared to low SAF group. These OCT findings may explain the worse clinical outcomes of high SAF patients.
Abstract 17836: The Regenerative Capacity of Explant-derived Cardiac Stem Cells Inversely Correlates With Patient Risk for Future Cardiac Events
Authors: Mayfield Audrey , Fitzpatrick Megan , Latham Nicholas , Tilokee Everad L , Villanueva Melanie , Mount Seth , Davis Darryl R
Published: March 2022

Background:
Although recent trials have demonstrated that cardiac-derived cell products repair damaged myocardium, the influence of age and medical co-morbidities is unknown. Therefore we investigated the effect of medical comorbidities on the functional activity of human explant-derived cardiac stem cells (EDCs).

Methods/Results:
Human EDCs were cultured from atrial appendages obtained during cardiac surgery. The Long Term Stratification model (LTS) was chosen as the best means of discriminating between patients with few or extensive comorbidities. Increasing LTS score demonstrated a moderate negative correlation with: 1) EDC conditioned media HUVEC tubule formation (R
2
=0.53; r=-4±1, p=0.003), 2) transwell recruitment of circulating angiogenic cells (R
2
=0.48; r=-15±5, p=0.016), 3) decreased echocardiographic ejection fraction (R
2
=0.64, r=-0.7±0.2, p=0.003) and increasing scar burden (R
2
=0.59, r=-0.5±0.2, p=0.04) 3 weeks after myocardial injection of EDCs into a SCID mouse model of myocardial infarction. These effects may be attributable to LTS score dependent decreases in SDF-1 (R
2
=0.33; r=-0.2±0.1, p=0.02) or exosome (R
2
=0.59; r=-2.4±0.8X10
7
, p=0.02) content within conditioned media. Interestingly, the most abundant cytokine in EDC conditioned media (IL-6) demonstrated a positive correlation with increasing LTS scores (R
2
=0.33, r=1.2±0.5, p=0.03). Lentiviral mediated knock down of IL-6 (IL-6KD) by EDCs suggests that IL-6 supports therapeutic regeneration as intra-myocardial injection of IL-6 KD EDCs from low (<3) and high (>5) LTS score patients reduced improvements in ejection fraction by 1.4±0.1 fold (p≤0.05) while increasing scar burden by 1.3±0.1 fold (p≤0.05). Immunohistochemistry demonstrated that IL-6KD reduced newly generated BrdU+ myocytes (p=0.03 vs. scramble treated EDCs) while promoting the persistence of maladaptive myofibroblasts (p=0.01 vs. scramble treated EDCs).

Conclusions:
The regenerative performance of the earliest cell population cultured from human tissue declines with accumulating medical co-morbidities. This effect is associated with diminished production of pro-cardiogenic cytokines and exosomes while IL-6 plays a novel pivotal role in EDC-mediated repair of damaged myocardium.
Abstract 17876: Risk Factors and Thirty-day Adverse Events in Emergency Department Patients With Symptoms of Myocardial Ischemia With and Without Diabetes
Authors: Rose Bovino Leonie L , Jefferson Vanessa , Feinn Richard S
Published: March 2022

Objective:
To evaluate the association between diabetes and demographic and clinical characteristics and 30-day adverse cardiovascular events (return to the emergency department [ED] with signs and/or symptoms of acute myocardial ischemia, all-cause admission, acute myocardial infarction, use of reperfusion therapy, and all-cause mortality) in patients presenting to the ED with chest pain and/or symptoms suggestive of acute myocardial ischemia.

Methods:
We conducted a cross-sectional study of 163 adult patients presenting to the ED at a single hospital with symptoms of acute myocardial ischemia warranting evaluation with an electrocardiogram and a cardiac troponin test. We analyzed data collected 30±7 days after ED/hospital discharge from the index visit. Using chi-squared tests, we compared patients with a history of diabetes (n=65) to those without (n=98) on demographic and clinical characteristics and on 30-day adverse cardiovascular events.

Findings:
Patients with a history of diabetes were significantly more likely to be older (p<.001), overweight (p=.003), have a history of coronary artery disease (p<.001), heart failure (p=.016), and hyperlipidemia (p<.001) than patients without a history of diabetes. We found a significant association between a history of diabetes and a composite of 30-day adverse cardiovascular events (p=.036). We also found a significant association between a history of diabetes and admission to the hospital within 30 days of the index visit (p=.015).

Conclusion:
Study findings emphasize the predominance of more modifiable and non-modifiable cardiovascular risk factors in patients with diabetes compared to those without diabetes among patients presenting to the ED with signs and/or symptoms of acute myocardial ischemia. Past research has demonstrated a strong association of optimal weight, glycemic, and blood pressure management with protective benefits in patients with diabetes. Tailored educational interventions in the ED may reduce modifiable risks in these patients, their hospital return rate, and likelihood of 30-day adverse cardiovascular outcomes.
Abstract 17885: Pulmonary Vascular Compliance Predicts Mortality in the Acute Respiratory Distress Syndrome
Authors: Metkus Thomas , Tampakakis Emmanouil , Mullin Christopher , Houston Brian , Kolb Todd , Mathai Stephen , Damico Rachel , Hassoun Paul , Kass David , Brower Roy , Tedford Ryan
Published: March 2022

Introduction:
Novel markers of prognosis in the acute respiratory distress syndrome (ARDS) are needed.

Hypothesis:
We hypothesized that pulmonary vascular compliance would predict outcome in ARDS, and that higher left heart filling pressure would be associated with increased pulsatile loading of the right ventricle manifested as reduced RC time.

Methods:
We performed a retrospective analysis of 392 subjects with a complete hemodynamic data set on trial day 0 in the ARDS Network Fluid and Catheter Treatment Trial of PA catheter use in ARDS. Pulmonary vascular compliance (Cpa) was calculated as stroke volume divided by PA pulse pressure. Pulmonary vascular resistance (PVR) was calculated as mean PA pressure minus pulmonary artery wedge pressure (PAWP) divided by cardiac output. The RC time was calculated as the product of PVR and Cpa. Cox proportional hazard modeling and Kaplan-Meier survival analysis were performed with primary outcome of death.

Results:
The mean age was 50 ± 16 years. Mean PA pressure and PAWP were both elevated (29 ± 8 mmHg and 15 ± 5 mmHg, respectively) as was cardiac output (7.7 ± 2.7 L/m). The mean PVR was 2.1 ± 1.2 Wood units and Cpa 4.6 ± 2.5 ml/mmHg. Mean RC time was 0.47 ± 0.24 seconds (s). With each 5 mmHg increase in PAWP, RC time decreased by 0.06 s (p<0.0001 for slope). There was increased hazard of death per quartile decrease in Cp (HR 1.28, 95% CI 1.08-1.52; p = 0.004) and per quartile increase in PVR (HR 1.23, 95% CI 1.04-1.46; p = 0.02). Adjusted for APACHE III score, there remained a trend towards increased hazard of death per quartile increase in PVR (HR 1.2 95% CI 1.03-1.4, p = 0.02) and per quartile decrease in Cp (HR 1.18 95% CI 1.0-1.4, p = 0.055). Kaplan-Meier survival curves per quartile of Cp are shown in the Figure.

Conclusion:
Pulmonary vascular compliance predicts mortality in ARDS. Higher wedge pressure is associated with lower RC time in ARDS consistent with increased RV pulsatile loading.
Abstract 17895: Complementary Prognostic Value of Cardiac Metaiodobenzylguanidine Imaging and Diastolic Wall Strain in Patients With Preserved Left Ventricular Ejection Fraction Admitted for Acute Decompensated Heart Failure
Authors: Tamaki Shunsuke , Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Ishimi Masashi , Hakui Hideyuki , Ozaki Tatsuhisa , Sato Yoshihiro , Seo Masahiro , Ikeda Iyo , Fukuhara Eiji , Fukunami Masatake
Published: March 2022

Introduction:
Cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging has been reported to provide prognostic information in patients with heart failure with preserved ejection fraction (HFpEF). On the other hand, diastolic wall strain (DWS) has been recently introduced as a simple and feasible echocardiographic index in assessing left ventricular (LV) diastolic stiffness, and has been shown to be associated with poor outcome in patients with HFpEF.

Hypothesis:
We assessed the hypothesis that cardiac MIBG imaging and DWS might have a complementary prognostic value in HFpEF patients admitted for acute decompensated heart failure (ADHF).

Methods:
We studied 70 consecutive patients admitted for ADHF and discharged with survival whose LV ejection fraction measured by echocardiography was ≧40% (age: 77±12 years, male: 49%, NYHA class at discharge: 2.2±0.8). Cardiac MIBG imaging and echocardiography were performed just before discharge. The cardiac MIBG heart-to-mediastinum ratio (H/M) and washout rate were calculated from the chest anterior view images obtained at 20 and 200min after isotope injection. DWS was determined in the LV M-mode echocardiogram using a validated formula. The endpoints were unplanned hospitalization for worsening heart failure (WHF) and pump failure death (PFD).

Results:
During a follow-up period of 2.0±0.8 years, 20 patients had WHF and 7 patients had PFD. At multivariate Cox analysis, out of the variables including clinical, hemodynamic, biochemical, MIBG and echocardiographic parameters, H/M on delayed image (late H/M) and DWS were significantly independently associated with WHF (p=0.0058) and PFD (p=0.0160), respectively. Kaplan-Meier analysis showed that the patients with late H/M <1.73 (mean value) and those with DWS <0.292 (mean value) had a significantly higher risk of WHF and PFD, respectively (Figure).

Conclusions:
Cardiac MIBG imaging and DWS had a complementary prognostic value in HFpEF patients admitted for ADHF.
Abstract 17912: Health-related Quality of Life Outcomes in PARADIGM-HF
Authors: Lewis Eldrin , Zile Michael R , Swedberg Karl , Rouleau Jean L , Claggett Brian , Lefkowitz Martin P , Shi Victor C , Solomon Scott D , Packer Milton , McMurray John J
Published: March 2022

Introduction:
Heart failure with reduced ejection fraction (HF) patients have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and HF hospitalizations. In PARADIGM-HF, LCZ696 reduced morbidity and mortality compared with enalapril. Prior analysis demonstrated a significant difference in 8-month Kansas City Cardiomyopathy-Clinical Summary score (KCCQ-CSS) when imputing 0 for death (-2.99 vs. -4.63, p=0.0014). Given improvements in mortality with LCZ696, this analysis provides impact of therapy on
all domains
of HRQL in survivors only.

Hypothesis:
LCZ696 will improve HRQL

Methods:
Patients (after run-in phase) completed disease-specific KCCQ at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures ANCOVA model adjusting for treatment, region, & baseline values (primary efficacy pre-specified at 8 months), and association of KCCQ with mortality was assessed.

Results:
Among 8442 patients enrolled in PARADIGM-HF, 7623 (90%) completed KCCQ scores at randomization with complete data at 8 months on 7281 (86%). Baseline KCCQ scores were similar in LCZ696 and enalapril groups (73.5±20 vs. 72.3±19). Death increased with every 10 point decrement of baseline KCCQ-CSS [HR 1.11 (1.09, 1.14)]. At 8 months, LCZ696 group noted improvements in both KCCQ-CSS (+0.61 vs. -0.28, p=0.010) and KCCQ-Overall summary score (+1.10 vs. -0.15, p<0.001) in comparison to enalapril group with consistent trends in most KCCQ domains (Table). Adjusted change scores demonstrated consistent improvements in LCZ696 compared with enalapril through 36 months.

Conclusions:
Disease-specific HRQL is associated with survival. Changes in HRQL were better in patients treated with LCZ696 compared with enalapril with consistency in most domains. These findings suggest that LCZ696 leads to better HRQL in addition to morbidity & mortality in HF-reduced ejection fraction patients.
Abstract 17959: Is External Chest Compression Safe in Ventricular Assist Device Patients? A Case Series
Authors: ARORA BHASKAR , Radojevic Joseph , Darsaklis Konstadina , Hammond Jonathan , Huhn Nicole , Chomick Nicole , Devoe Tari , Ciesielski Thomas , Underhill David , Fusco Daniel , Gluck Jason
Published: March 2022

Introduction:
Current resuscitation guidelines do not address ventricular assist device (VAD) population. However, commonly adopted resuscitation algorithms discourage use of external chest compression (ECC). This deviation from convention is largely driven by the concern that ECC could dislodge the VAD inflow cannula. We present a case series of 4 patients with left ventricular assist device (LVAD) that underwent ECC during CPR without suffering any ill effects. One patient underwent targeted temperature therapy (TTT) after arrest and had successful neurological recovery.

Hypothesis:
1. ECC may be safe and effective in patients with VAD.

2. End tidal CO2 (ETCO2), a surrogate for cardiac output, can guide initiation of ECC in this population.

Methods:
This case series was performed at a single North American tertiary medical center. Clinical data was gathered by review of hospital chart. Autopsy data was used to verify integrity of VAD after ECC. Baseline characteristics are described in Table 1.

Results:
Three out of these four patients underwent ECC. One had a VAD implant within 60 days of this event. Autopsy showed that VAD circuit was intact in all three including the fresh implant. The fourth patient with respiratory failure didn’t receive ECC because ETCO2 value was higher than 20 mm Hg. ROSC was established in two patients with ETCO2 greater than 10 mm Hg, none survived to hospital discharge. TTT was performed in one patient with improvement in neurological status.Results are described in table 2.

Conclusions:
ECC can be safely performed in VAD patients. ETCO2 less than 20 mm Hg can be used to initiate ECC. ETCO2 could predict survival in this population. TTT can be safely performed in VAD. More evidence is needed to consolidate these findings.
Abstract 17990: Common PCSK9 Gain-of-function E32K Variant Carriers Reveal Milder LDL-C but Higher TG Elevation Compared With LDLR Mutations
Authors: Nohara Atsushi , Kawashiri Masa-aki , Tada Hayato , Yoshida Mie , Mori Mika , Nakanishi Chiaki , Yagi Kunimasa , Inazu Akihiro , Kobayashi Takeshi , Yamagishi Masakazu , Mabuchi Hiroshi
Published: March 2022

Background:
Proprotein convertase subtilisin kexin type 9 (PCSK9) gene is the third causal gene of familial hypercholesterolemia (FH), and is now an emerging therapeutic target. We have found Gain-of-function mutation E32K in PCSK9 gene is common in Japanese FH. We investigated clinical characteristics of gain-of-function PCSK9 variant carriers.

Methods:
A total of 940 Clinically diagnosed FH heterozygotes were investigated for LDLR, PCSK9, and APOB gene. High-resolution melting (HRM) method followed by Sanger sequence were used for point mutation, and multiplex ligation-dependent probe amplification methods were applied for large rearrangements in LDLR. Fasting lipid levels without lipid-lowering drugs were analyzed.

Results:
LDLR mutations were identified in 732 patients (78%) and 10% of them were large rearrangements. PCSK9 E32K mutation was identified in 56 patients (6%). No APOB mutations causing FH were identified, and 143 patients showed no known FH-gene mutations. LDLR mutation carriers showed significantly higher LDL-C (LDLR 268±73, PCSK9 198±82, No mutation 198±65 mg/dL,
p
<0.001) and higher apoB (183±51, 130±49, 148±42 mg/dL,
p
<0.001) compared with other two groups. On the other hand, PCSK9 and No mutation group had higher TG compared with LDLR mutations (126±94, 150±84, 145±74 mg/dL,
p
<0.05 in log-transformed TG). Hypertriglyceridemia was common in PCSK9 mutation (25%, 41%, 36%,
p
<0.01). HDL-C was higher in No mutation group (47±15, 51±51, 55±27 mg/dL,
p
<0.01). Achilles tendon xanthoma was more frequent in LDLR mutations. Lp(a) levels did not significantly different with PCSK9 mutation.

Results:
PCSK9 gain-of-function mutation E32K showed mild LDL-C elevation, but with frequent hypertriglyceridemia. This result will support basic reports that PCSK9 regulates not only LDL-R degradation but also VLDL metabolism.
Abstract 17998: Impairment of Vascular Bone Marrow Niche Predicts Death in Patients With Chronic Heart Failure
Authors: Sopova Kateryna , Palapies Lars , Leistner David , Stellos Konstantinos , Fichtlscherer Stephan , Seeger Florian , Dimmeler Stefanie , Assmus Birgit , Zeiher Andreas , Keller Till
Published: March 2022

Background:
The bone marrow vascular niche is essential for hematopoietic regeneration. Patients with chronic heart failure are characterized by myelosuppresion and anemia. Therefore, in order to investigate whether chronic heart failure is associated with an impairment in the vascular niche of the bone marrow, we measured in bone marrow plasma levels of the prototypical angiogenic factor PlGF (placental growth factor), as well as, its soluble inhibitor, sFlt-1 (Fms-like tyrosine kinase 1), which acts as a decoy receptor for PlGF, as a measure of the functional integrity of the vascular bone marrow niche.

Methods and Results:
Bone marrow plasma levels of sFlt-1 and PlGF were determined by ELISA in 187 patients (mean age: 62.2±11.3years) with chronic heart failure, who were enrolled in the Frankfurt Bone Marrow-Derived Mononuclear Cell Therapy Registry. Fifty-one patients died within the 5-year follow-up period. Patients with increased bone marrow-derived sFlt-1/PlGF ratio had a 1.35-fold increased risk for death (95%CI: 1.08 to 1.68, p=0.007). This association was robust after adjustment for age, gender, left ventricular ejection fraction (LVEF), eGFR and NT-proBNP serum levels (HR:1.3, 95%CI: 1.014 to 1.678, p=0.038) or the Seattle Heart Failure score (HR:1.38, 95%CI: 1.112 to 1.723, p=0.004). Importantly, this association remained significant even after adjustment for colony-forming unit capacity (HR:1.33, 95%CI: 1.051 to 1.675, p=0.018) and SDF-1-induced migratory capacity of bone marrow-derived cells (HR:1.35, 95%CI: 1.087 to 1.678, p=0.007).

Conclusions:
The present study for the first time discloses that an impairment of the angiogenic potential of the bone marrow microenvironment, defined as increased sFlt-1 to PlGF ratio in the bone marrow plasma, is independently associated with mortality in patients with chronic heart failure. These data further corroborate the importance of the bone marrow-heart axis to predict clinical outcome in patients with chronic heart failure.
Abstract 18010: Temporal Kinetics of Remote Ischemic Preconditioning: Transfer of Protection With Plasma Dialysate From Healthy Volunteers to an Isolated Mouse Heart
Authors: Hildebrandt Heike A , Kahlert Philipp , Erbel Raimund , Heusch Gerd , Kleinbongard Petra
Published: March 2022

Objective:
We aimed to analyze the temporal kinetics of cardioprotection by humoral factor(s) in healthy volunteers undergoing remote ischemic preconditioning (RIPC), a maneuver known to protect against myocardial injury, using infarct size in an isolated mouse heart as read-out.

Methods:
Ten healthy volunteers underwent RIPC by 3 cycles of 5 min upper-limb blood pressure cuff inflation and 5 min deflation. Venous blood samples were obtained at baseline before RIPC and after 5 and 30 min, 1, 6 and 24 h and daily up to 7 days. Plasma was dialyzed against the 20-fold volume of Krebs-Henseleit buffer for 24 h (cut-off: 12-14 kDa). Isolated mouse hearts were mounted on a Langendorff apparatus and perfused with Krebs-Henseleit buffer at a pressure of 100 mmHg. Before undergoing 20 min global ischemia and 120 min reperfusion, hearts were perfused with dialysate for 15 min. Infarct size was assessed by TTC-staining. The cardioprotective potential of the plasma dialysate obtained 5 min after RIPC was further evaluated by decreasing its dilution (1:10) in those samples, which did not induce cardioprotection in a dilution of 1:20.

Results:
The cardioprotective effect of RIPC was present in all cases 30 min after RIPC, lasted for at least 6 days and vanished thereafter (see Figure). Plasma taken 5 min after RIPC induced cardioprotection in only 50 % of cases, when using a dialysate with a 1:20 dilution. Decreasing the dilution to 1:10 induced cardioprotection in all cases (Figure insert).

Conclusion:
A single RIPC-maneuver induces the release of (a) dialyzable, humoral factor(s), which reduce(s) infarct size no later than 5 min after RIPC and remain(s) operative for up to 6 days. These results imply that cardioprotection is at least in part effected by (a) factor(s) which is/are quickly released/activated, long-lasting and/or continuously produced for quite a while after RIPC.
Abstract 18014: Did Patients With Peripheral Artery Disease Benefit From the Survival Improvement After Myocardial Infarction? Insights From the FAST-MI Program, 1995-2010
Authors: Aboyans Victor , Puymirat Etienne , Schiele Francois , Elbaz Meyer , Cattan Simon , Blanchard Didier , Henry Parick , Ferrières Jean , Simon Tabassome , Danchin Nicolas
Published: March 2022

Introduction:
Patients with peripheral artery disease (PAD) are at risk for acute myocardial infarction (AMI). The prognosis of patients after AMI has substantially improved over the last 20 years. Whether survival has similarly improved in patients with or without PAD is unknown.

Methods:
We compared the management and mortality after AMI according to clinical PAD status in 4 French nationwide registries conducted with similar methodology in 1995, 2000, 2005 and 2010. Each included during one month all patients admitted to cardiology departments in general, academic or private hospitals for AMI with symptoms onset ≤ 48 hours.

Results:
Among the 10,610 patients, 962 (9.1%) had PAD. PAD remained constant in NSTEMI patients (12%), while it decreased from 9.7% to 4.8% among STEMI patients. Median age increased in PAD patients (1995 vs 2010: 73 vs 75 years, P<0.05) but decreased in no-PAD patients (65 to 63 years, P<0.04). Women’s rates remained stable (PAD: 26 to 22%, no-PAD 29 to 27%). High cholesterol, obesity, diabetes, and hypertension rates increased significantly, irrespective of PAD status. Smoking rates decreased in PAD patients (29% to 23%, P=0.02), but increased in no-PAD patients (31 to 35%, P=0.02). The rates of early PCI (<72 hours) increased (PAD: 10% to 48%; no-PAD: 15 to 72%); so did the early use of antiplatelet drugs (PAD: 84% to 98 %; no-PAD: 92 to 98%), ACE-I or ARBs (PAD: 45 to 56%; no-PAD: 46 to 64%), beta-blockers (PAD: 48 to 71%; no-PAD: 66 to 80%) and statins (PAD: 10% to 85%; no-PAD: 10 to 88%).

In PAD patients, 30-day mortality decreased from 23.5% to 5.3% (HR 2010 vs 1995, adjusted for baseline characteristics: 0.23, 0.12-0.43). Their 1-year mortality decreased from 33 to 23% (HR 0.60, 0.41-0.88), but among 30-day survivors, no favorable trend was found for 1-year mortality (adjusted HR 2010 vs 1995: 1.54, 0.87-2.71). In no-PAD patients, adjusted HR for 30-day death (2010 vs 1995) was 0.33, (0.26-0.43), and 1-year survival also improved among 30-day survivors (adjusted HR 0.65, 0.50-0.85).

Conclusion:
After AMI, early survival has considerably increased in PAD patients as for no-PAD patients. However, no further survival improvement has been found in PAD patients beyond the 30 days, emphasizing the need for stronger secondary prevention.
Abstract 18019: Activation of Hepatic Hif-2a Signaling Perturbs Cholesterol Homeostasis in Mice
Authors: Ramakrishnan Sadeesh K
Published: March 2022

Cardiovascular disease (CVD) is the leading cause of death in the United States. Therefore, identifying novel pathways involved in the pathogenesis of CVD becomes imperative. Inflammation and hypercholesterolemia are the two hallmarks of CVD. Patients with chronic intermittent hypoxia or obstructive sleep apnea are at high risk for CVD due to aberrant cholesterol levels. Evolutionarily, cholesterol synthesis is a highly oxygen and energy dependent process. Therefore, the molecular mechanism involved in the paradoxical increase in cholesterol during hypoxia remains unclear. Hypoxia signaling is mediated through a well-conserved hypoxia driven transcription factors, hypoxia-inducible factor (HIF)-1 and HIF-2. Mice with a liver-specific disruption of the Von Hippel Lindau protein (

Vhl
LivKO

), a critical E3 ubiquitin ligase that degrades HIFs, exhibit increased levels of HIF-1 and HIF-2 protein and develop hepatic steatosis, systemic inflammation, hypercholesterolemia and have decreased survival. Moreover, we show that the transcription factor hypoxia-inducible factor (HIF)-2 is highly activated in the liver of rodent models of atherogenesis. Activation of HIF-2 in liver disrupts the circadian expression of cholesterol hydroxylases leading to hypercholesterolemia. Using a comprehensive metabolomic analysis, we identified an arginine metabolite, asymmetric dimethylarginine (ADMA) is highly induced in the serum and liver of C57BL/6 mice fed with high cholesterol diet. ADMA potently activates HIF-2 in human hepatoma HepG2 and colon-derived SW-480 cells. Our results demonstrate that metabolite induced HIF-2 signaling in liver perturbs cholesterol homeostasis leading to systemic inflammation and hypercholesterolemia.
Abstract 18064: Effect of Fluctuations in Glucose Levels on Vascular Endothelial Dysfunction and Clinical Outcomes in Coronary Artery Disease (CAD) Patients Without Diabetes Mellitus (DM)
Authors: Akasaka Tomonori , Hokimoto Seiji , Ogawa Hisao
Published: March 2022

Background:
Fluctuations in glucose levels give rise to inflammation and endothelial dysfunction by increasing oxidative stress. Mean amplitude of glycemic excursions (MAGE) is commonly used as a degree of fluctuations in glucose level, and play a significant role in vascular endothelial dysfunction in diabetes mellitus (DM) patients, but not so clear in non-DM patients. Vascular endothelial dysfunction is associated with an increased risk of cardiovascular events. Thus, we examined the impact of MAGE on vascular endothelial dysfunction and clinical outcomes in non-DM patients with CAD.

Methods:
We analyzed 48 CAD patients following percutaneous coronary intervention (PCI) during 12 months, and assessed the relation among MAGE measured by continuous glucose monitoring (CGM), the level of high-sensitivity CRP (hs-CRP), and reactive hyperemia index (RHI) measured from RH-PAT (reactive hyperemia peripheral arterial tonometry). Cardiovascular events were cardiovascular death, myocardial infarction, unstable angina, and revascularization.

Results:
In clinical characteristics, HbA1c and MAGE were 5.96±0.40% and 62.5±32.6mg/dl. MAGE correlated with hs-CRP (r=0.426; P=0.003) and RHI (r=–0.403; P=0.007), but not correlated with body mass index (BMI), HbA1c, LDL cholesterol, and systolic blood pressures. In short, high glycemic excursions (high MAGE) is associated with high inflammation (high level of hs-CRP) and vascular endothelial dysfunction (low RHI). When patients were classified into MAGE<65mg/dl (normal glycemic excursions) and MAGE>65mg/dl (high glycemic excursions), group of MAGE>65mg/dl showed significant higher hs-CRP (0.05±0.03 vs 0.15±0.15mg/dl, P<0.001) and lower RHI (1.98±0.45 vs 1.74±0.38, P=0.003) compared with group of MAGE<65mg/dl. Multivariate analysis for clinical outcomes identified high MAGE as predictive factors (OR4.7, P=0.032). In ROC curve, MAGE is predictive index for cardiovascular events (AUC 0.533, P=0.01).

Conclusions:
Fluctuations in glucose levels are associated with inflammation, endothelial dysfunction, and cardiovascular events. And, MAGE may be good predictive index for cardiovascular events in CAD patients without DM.
Abstract 18068: Trends in Proportionate Cardiovascular Mortality Among Adults With Human Immunodeficiency Virus in the United States: 1999-2013
Authors: Bahiru Ehete M , Feinstein Matthew J , Achenbach Chad J , Longenecker Chris T , Hsue Priscilla Y , So-Armah Kaku , Freiberg Matthew S , Lloyd-Jones Donald M
Published: March 2022

Introduction:
Due to the success of antiretroviral therapy, Human Immunodeficiency Virus (HIV)-infected individuals live longer and are at risk for cardiovascular disease (CVD). Whether the proportion of deaths due to CVD in the HIV-infected population has increased over time is unknown.

Hypothesis:
Our hypothesis was that proportionate mortality from CVD in the HIV-infected population has increased significantly since 1999.

Methods:
Using the publicly available CDC Wonder database of U.S. national mortality data, we assessed proportionate CVD mortality among adults aged ≥25 years with HIV. We compared these data to proportionate CVD mortality in two control groups: the general population and people with underlying inflammatory disease (i.e., inflammatory polyarthropathies (IPA)). For each group, we calculated proportionate CVD mortality by dividing deaths attributed to circulatory causes (based on ICD10 coding) by all causes of death for each year from 1999 to 2013.

Results:
Proportionate CVD mortality increased among HIV+ individuals from 1.9% of deaths in 1999 to 4.6% in 2013 (Figure 1); this pattern of increasing proportionate mortality was highly significant for men and women (P<0.01) and consistent across race groups. Meanwhile, proportionate CVD mortality declined in the general population (41% in 1999 to 32% in 2013; P<0.01) and IPA population (40% in 1999 to 29% in 2013; P<0.01). A sensitivity analysis including only in-hospital deaths also revealed a highly significant increase in proportionate CVD mortality for HIV-infected individuals, from 2.1% in 1999 to 3.9% in 2013 (P<0.01). Hypertensive and pulmonary heart diseases were 2-3 times more likely to be the cause of death in the HIV population than in the general population.

Conclusions:
Proportionate CVD mortality appears to have increased substantially in the HIV-infected population since 1999. Further studies are needed to guide risk assessment and prevention in this unique population.
Abstract 18086: Rates of Cardiovascular Events in Patients Receiving High-Intensity Statin Therapy in the United Kingdom
Authors: Taylor Benjamin , Danese Mark , Villa Guilllermo , Lothgren Mickael , Khunti Kamlesh , Ray Kausik
Published: March 2022

Background:
Cardiovascular (CV) event rates have declined, in part due to extensive use of treatments such as statin therapy, but rates in specific real-world populations are unknown. Our aim was to provide contemporary estimates of CV event rates across five high-risk cohorts receiving high-intensity statin therapy in the UK.

Hypothesis:
CV event rates will vary by cohort and over time.

Methods:
Five cohorts receiving high-intensity statins were studied in the Clinical Practice Research Datalink: (1) high-risk primary prevention (HRPP - diabetes with no other CV event), (2) evident CV disease (ECVD - CV disease excluding acute coronary syndrome (ACS), ischemic stroke (IS), and heart failure (HF)), (3) incident ACS, (4) incident IS, and (5) incident HF (in patients with ACS or IS). Patients were followed from 1/1/2005 (HRPP, ECVD) or qualifying index event (ACS/IS/HF) until the next CV event, death, or end of observation (12/31/2011). Outcome CV events were based on hospitalization primary diagnoses and cause of death data. These were combined to form a composite endpoint (ACS, IS, HF, or CV death) for all cohorts. For HRPP, the ECVD conditions were included as outcomes. Crude rates were estimated at 2-month intervals over time.

Results:
Cohort sizes ranged from 414 patients for IS to 9,411 for ECVD. Observation time ranged from 3.6 years for HF to 7.0 years for HRPP. Mean, unadjusted composite CV event rates per 1,000 person years were 37 for HRPP, 43 for ECVD, 107 for IS, 135 for ACS, and 201 for HF (Figure). The rates for secondary prevention cohorts were highest after the index CV event and then declined and became stable by one year.

Conclusions:
In the incident cohorts, event rates were highest in the first year and declined over time. However, rates were higher than the prevalent cohorts even at 1500 days after the index event. These rates are higher than in clinical trials and further research should identify methods of reducing CV risk in these high intensity statin patients.