bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19320: Protein Kinase G Oxidation Blunts Its Suppression of Cardiac Hypertrophy by Diminishing Phosphorylation of Tuberin and Consequent Autophagy
Authors: Ranek Mark J , Nakamura Taishi , Holewinski Ronald , Lee Dong-ik , Zhu Guangshuo , Chakir Khalid , Eaton Philip , Van Eyk Jennifer , Kass David A
Published: July 2021

Stimulation of protein kinase G (PKG) suppresses maladaptive cardiac hypertrophy in part by blunting signaling cascades such as calcineurin/NFAT (Cn) and calcium-calmodulin dependent kinase II (CamKII). Here we report PKG stimulation also enhances autophagy as an anti-hypertrophic mechanism, identify a novel phosphorylation target for this effect, and show this signaling is blunted when PKG becomes oxidized at cysteine 42 (C42). Mice with knock-in expression of mutant PKG (C42S) or littermate controls were subjected to pressure-overload. C42S mice were protected, with reduced hypertrophy and fibrosis, improved function, and blunted Cn, CamKII, and hypertrophic gene activation. Neonatal rat ventricular myocytes (NRVMs) expressing C42S-PKG exposed to 48hr endothelin-1 (ET1) also displayed less hypertrophic responses. In both C42S mice and NRVMs expressing C42S, autophagic flux was increased over WT, determined by autophagic flux assays, which was associated with inhibited mammalian target of rapamycin (mTOR) signaling. Control mice improved responses similar to C42S mice if autophagic flux was stimulated by inhibiting mTOR with everolimus. Analogous findings were obtained by mTOR suppression in NRVMs. To determine how PKG activation influences mTOR-regulated autophagy, we performed unbiased phospho-proteome analysis using mass spectrometry that revealed a unique PKG targeted site on tuberin (TSC2) at S1343. To test the functional importance of this site, we expressed a mutated TSC2, serine to glutamic acid (phospho-mimetic, S1343E), which depressed mTOR signaling, increased autophagic flux, and blunted hypertrophic signaling and cell enlargement stimulated by ET1 in NRVMs. By contrast, the cardio-protection elicited by PKG C42S was lost when TSC2 or a downstream critical autophagy protein, ATG5 were silenced. Taken together, these results provide the first evidence that PKG activation augments autophagy via targeting of TSC2 as a mechanism of anti-hypertrophic signaling, and that this occurs much more when PKG is in a reduced state (e.g. no C42-disulfide). Loss of this mechanism in myocardium under oxidative stress may play a role in the decline in protection from PKG in cardiac disease which often involves an oxidative environment.
Abstract 19334: Responses to a Pre-PCI Screening Questionnaire Influence Stent Type Used During PCI
Authors: Chung Matthew J , Rao Sunil V , Povsic Thomas J , Jones W S , Schulteis Ryan D
Published: July 2021

Introduction:
The strong correlation between early termination of dual antiplatelet therapy and stent thrombosis in patients treated with drug-eluting stents (DES) warrants emphasis on appropriate selection of patients for DES. Using a simple questionnaire administered pre-procedurally, we aimed to determine which clinical factors might predict the use of DES during PCI.

Hypothesis:
A “yes” response to any item on the pre-PCI questionnaire (table 1) will decrease the odds of DES use during PCI.

Methods:
Using the Durham Veterans Affairs electronic health record, we identified 1202 patients who underwent PCI from July 2008 to January 2013. We excluded patients without a complete pre-PCI questionnaire within 14 days of PCI, repeat procedures and those who received both DES and BMS or no stent during PCI, leaving 864 patients. Using logistic regression we performed univariate analyses of age, sex, diabetes, PCI indication (stable angina, unstable angina/NSTEMI or STEMI) and target vessel type (vein graft or native). Only age and PCI indication were significant predictors of DES use (p < 0.10). Adjusting for age and PCI indication with multivariate logistic regression, we then determined the association between “yes” responses to questionnaire items and DES use.

Results:
Of the 864 patients receiving stents, 661 received DES and 203 received BMS. Increasing age, presenting with STEMI, and a “yes” response to any item on the questionnaire decreased the odds of DES use, however, this was not significant for questions 2 and 6 (table 1). Presenting with unstable angina or NSTEMI, as compared with stable angina, significantly increased the odds of DES use.

Conclusions:
Age, PCI indication and responses to 4 of 6 items on a questionnaire administered pre-PCI were associated with stent type used during PCI. Future studies should investigate whether implementation of this questionnaire leads to lower rates of stent thrombosis through appropriate patient selection for DES.
Abstract 19336: Chronic Vagal Nerve Stimulation Causes Weight Loss by Reducing Food Intake and Feeding Efficiency in Mice
Authors: Stauss Harald M , Dias Daniel P , Morgan Donald A , Rahmouni Kamal
Published: July 2021

Chronic electrical vagal nerve stimulation (VNS) has emerged as a new tool to treat human diseases including obesity. Indeed, chronic VNS has been shown to cause weight loss in humans and in experimental animal models. However, the mechanisms for VNS-induced weight loss are largely unknown. We hypothesized that an increase in metabolic rate together with reduced caloric intake and reduced feeding efficiency (body weight gain per calories consumed) contribute to chronic VNS-induced weight loss or reduced weight gain. To test this hypothesis, we developed a miniaturized microprocessor-operated nerve stimulator for chronic use in conscious mice. Effectiveness of the stimulator was verified by bradycardia at stimulation frequencies above 5 Hz (3V, 1mA, 1ms pulses). Male C57Bl/6 mice (16 weeks old, standard mouse chow diet) were instrumented with nerve stimulators (3V, 1mA, 1ms pulses at 5 Hz) on the right cervical vagal nerve and body weight, food intake and metabolic rate (indirect calorimetry) were determined at baseline and weekly thereafter. After the initial post-surgical weight loss, sham animals (n=9, stimulators off) regained pre-surgical body weight within 16 days (100.0±2.7%). In contrast, mice with chronic VNS (n=12) never reestablished pre-surgical body weight (94.5±0.9% on day 16, P<0.05 vs. sham). Caloric intake was significantly reduced in mice with chronic VNS compared to sham animals (74.7±2.4 vs. 84.6±4.2 kcal/week, P<0.05). Likewise, mice with chronic VNS showed significantly reduced feeding efficiency compared to sham mice (2.6±2.0 vs. 10.6±2.4 mg body weight gain per kcal consumed). Oxygen consumption tended to be elevated (2734±152 vs. 2490±124 mL/kg/h, P=0.23) during the first week, but not thereafter. In conclusion reduced food intake and lower feeding efficiency contribute to reduced weight gain in mice with chronic VNS. We speculate that an initial increase in metabolic rate (assessed by oxygen consumption) may be antagonized by compensatory mechanisms in response to chronic VNS.
Abstract 19355: Lower Heart Rates are Associated with Better Mid-term Outcomes in Fontan Patients
Authors: Kurishima Clara , Senzaki Hideaki , Shinohara Tokuko , Nakanishi Toshio
Published: July 2021

Background:
In adult heart failure, higher heart rates (HR) are known to be associated with increased risks of myocardial infarction and sudden cardiac death. Thus, HR modulation has been increasingly recognized as a potentially effective therapy for heart failure. HR may also be a useful therapeutic target in patients after the Fontan surgery, in which effective treatment to improve prognosis remains to be established. We hypothesized that lower HR is associated with better mid-term outcomes in Fontan patients.

Methods:
We retrospectively analyzed 24-hour Holter ECG in 56 consecutive patients in the chronic phase (at least 1 year) after the Fontan operation and in the sinus rhythm (mean age; 19 years, range; 9-49 years). Data for minimum, maximum, and average HR were extracted. We then examined the relationships between HR values and mid-term hemodynamic and clinical (6-min walk-distance) outcomes. Mid-term outcomes were assessed both at 1-3 years (mean 1.5 years) after the initial Holter recording (Group 1) and at more than 3 years (mean 4.9 years) after the initial Holter recording (Group 2).

Results:
Lower values of mean and minimum HR were significantly correlated with lower CVP in both groups (P<0.05, for each). Mean and minimum HR were also significantly and negatively correlated with the 6-min walk-distance in Group 2 (P <0.05 for each). The results were similar after controlling for age by multivariate analysis. Importantly, lower HR was not associated with decreased cardiac output.

Conclusions:
The present study demonstrated for the first time that lower HR can lead to better mid-term outcomes of hemodynamics and exercise capacity in Fontan patients. HR can be an important therapeutic target to improve the prognosis after the Fontan operation.
Abstract 19361: Reversal of Anticoagulant-induced Bleeding in External and Internal Bleeding Models by PER977, a Small Molecule Anticoagulant Antidote
Authors: Bakhru Sasha , Laulicht Bryan , Jiang Xuan , Chen Lirong , Grosso Michael , Morishima Yoshiyuki , Brown Karen , Mercuri Michele , Masumoto Hiroshi , Costin James , Steiner Solomon
Published: July 2021

The new oral anticoagulants (NOACs) offer significant advantages over heparins and warfarin therapies. However, concern over serious bleeding and potential over-dosage is heightened with the lack of a specific reversal agent. PER977 is a synthetic small molecule in clinical development as an anticoagulant reversal agent. In the current studies, PER977 reversal was evaluated in two preclinical bleeding models, recapitulating the clinical scenarios of reversal in actively bleeding cutaneous wounds and internal large organ lacerations. Reversal of anticoagulation-induced, active bleeding was demonstrated in a rat tail transection model. Rats were dosed with the direct factor Xa inhibitor, edoxaban, resulting in large increases in blood loss mass. Briefly, the rat was orally dosed with edoxaban. After 75 min, rat tails were fully transected 2 mm from the tip. Immediately after tail transection, PER977 solution or saline was administered through the jugular vein. Blood from the tail was collected for 7.5 minutes and then transferred into a second collection tube for an additional 7.5 minutes. PER977 significantly decreased bleeding in vivo in rats treated with edoxaban (Figure 1a) within the first 7.5 minutes after PER977 administration. Additionally, bleeding was evaluated in a rat liver laceration model of internal bleeding. Following calibrated cuts to the medial lobe of the exposed liver, bleeding time was determined to the nearest 15 seconds. This rat liver laceration internal bleeding model demonstrated that edoxaban can significantly increase the bleeding time after the rat liver is lacerated. Moreover, the i.v. administration of PER977 can fully reverse the anticoagulant effect of edoxaban 10 minutes after PER977 administration (Figure 1b). In conclusion, PER977 is a synthetic small molecule that reverses NOAC anticoagulation in animal models of external and internal bleeding, and is currently in phase 2 clinical studies with edoxaban.
Abstract 19384: Favorable Association Between a Mediterranean Dietary Pattern and Cardiovascular Risk Factors in Patients with Stable Coronary Heart Disease in the STABILITY Study
Authors: Stewart Ralph A , Wallentin Lars , Benatar Jocelyne , Danchin Nicolas , Hagström Emil , Harrington Robert A , Held Claes , Husted Steen , Lonn Eva , Stebbins Amanda , Vedin Ola , Watson David , White Havey D
Published: July 2021

Introduction:
A ‘Mediterranean’ dietary (MD) pattern has been associated with lower cardiovascular mortality, but the reasons for benefit are uncertain.

Hypothesis:
Greater adherence to a MD pattern is associated with more favorable cardiovascular risk factors.

Methods:
Associations between a MD pattern and cardiovascular risk factors were evaluated at the baseline assessment in 15,482 (97.8%) patients with chronic coronary heart disease from 39 countries who participated in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial. From a food frequency questionnaire a Mediterranean Diet Score (MDS) was calculated by

assigning points for more consumption of whole grains, fruits and vegetables, legumes, fish and alcohol, and for less consumption of meat (0 to 4 points in each food category). Cardiovascular risk factors at baseline are reported by approximate quartiles of MDS.

Results:
See table. For all risk factors p was <0.0001 for differences by MDS group.

Conclusions:
In a global population of patients with stable CHD greater adherence to a MD pattern was associated with less obesity, less hypertension, improved glucose tolerance and less inflammation.
Abstract 19437: Elevated Platelet Turnover in Patients Receiving Dual Antiplatlet Therapy Could Permit the Formation of Uninhibited Platelet Clusters That Act as Seeds for Thrombus Formation
Authors: Hoefer Thomas , Warner Timothy D
Published: July 2021

Introduction:
ACS patients who also have conditions associated with increased platelet turnover, such as diabetes or chronic kidney disease, are at increased risk of atherothrombotic events despite receiving dual-antiplatelet therapy (DAPT). It may well be that aspirin and thienopyridines, such as clopidogrel or prasugrel, prescribed once daily as pharmacologically short-lived but irreversibly acting agents, are less effective in these patients because of the daily emergence of a significant subpopulation of uninhibited platelets.

Hypothesis:
Here we investigated the potentially crucial roles of subpopulations of uninhibited platelets in overcoming DAPT and driving aggregation.

Methods:
Aliquots of platelet rich plasma were incubated with aspirin, prasugrel active metabolite (PAM) plus aspirin, or vehicle and platelets were differently labelled with membrane dyes. Aliquots were then combined in various proportions and platelet responses measured in standard light transmission aggregometry. Aggregates formed in response to platelet agonists were then fixed and detailed structural analyses made by advanced imaging techniques, including confocal microscopy and ImageStream flow cytometry, to determine the interactions of different platelet populations.

Results:
Platelet aggregation responses and images of platelet aggregates demonstrated complex, dynamic relationships between platelet subpopulations. Summary analysis indicated that aggregates containing aspirin-treated (90-60%) and drug-free (10-40%) platelets had random distributions of drug-free platelets in response to ADP or AA. In contrast, aggregates containing DAPT-inhibited (90-60%) platelets and drug-free (10-40%) platelets showed marked clustering of drug-free platelets at aggregate cores surrounded by recruited DAPT-inhibited platelets.

Conclusions:
We show that a subpopulation of drug-free platelets can provide seeds for the formation of aggregates that then recruit DAPT-inhibited platelets. Such interaction between platelet subpopulations are of direct relevance to ACS patients with underlying conditions associated with elevated platelet turnover and may well provide an explanation for the failure of DAPT with aspirin and thienopyridines.
Abstract 19474: Clinical Characteristics and Outcomes of Patients With and Without Diabetes in the Surgical Treatment for Ischemic Heart Failure (STICH) trial
Authors: MacDonald Michael R , She Lilin , Doenst Torsten , Binkley Philip , Rouleau Jean , San Tan , Lee Kerry , Sopko George , Szalewski Dominika , Velazquez Eric , Petrie Mark C
Published: July 2021

Introduction:
Diabetes mellitus (DM), coronary artery disease (CAD) and heart failure commonly coexist. Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with a left ventricular ejection fraction (LVEF) of 35% or less and CAD amenable to CABG. Patients were randomised to CABG and optimal medical therapy (OMT) or OMT alone.

Hypothesis:
We assessed the hypothesis that patients with DM enrolled in the STICH trial would have greater benefit of CABG than patients without DM.

Methods:
We compared the characteristics and clinical outcomes of patients with and without DM randomized to CABG and OMT or OMT alone. Cox-proportional hazards analyses were used to assess treatment effect.

Results:
Diabetes was present in 40.3%. At baseline, patients with DM had more triple vessel CAD (66% v 57%, p<0.001), higher LVEF [median 29% (IQR:22,35) vs 27% (IQR:22,33), p=0.015] and smaller left ventricular end diastolic volume index [median 105 ml/m2 (IQR:85, 128) vs 117 ml/m2 (IQR:93, 146) (p<0.001)]. Among patients with DM, there was a higher proportion of females, higher BMI on average, worse renal function, and more hypertension. Patients with DM undergoing CABG spent longer on cardio-pulmonary bypass [median 97 (IQR:71,126) vs 87 (IQR:65, 115) minutes, p=0.029], and were more likely to develop perioperative AF (23% vs 11%, p<0.001) and worsening renal function (9% vs 4%, p=0.021). Patients with DM on OMT had similar outcomes as those on OMT without diabetes (Table 1). A statistically significant or near statistically significant improvement in clinical outcomes with CABG compared to OMT was documented in patients without DM, but not in patients with DM. However, there was no significant interaction between DM and treatment group on formal statistical testing.

Conclusions:
Patients with and without DM enrolled in the STICH trial had similar outcomes at 5 years, and CABG did not exert greater benefit in patients with DM.
Abstract 19492: Novel Assessment of Pulmonary and Systemic Pressures During Treadmill Testing via Implantable Telemetry in a Rat Model of Pulmonary Arterial Hypertension
Authors: Zinn Abigail , Novack Rachel , Fisher Amanda , Presson Robert , Zaretsky Dmitry , Rusyniak Daniel , Lahm Tim , Brown Mary Beth
Published: July 2021

Objectives:
1) To determine if pulmonary arterial pressures (PAP) may be measured simultaneously with systemic blood pressures (BP) during exercise testing in laboratory rats using implantable telemetry; and 2) To determine the relationship of exercise intensity to acute PAP exercise responses over the course of PAH development.

Methods:
A specialized implantable transmitter (Data Sciences International); via telemetry following thoracotomy with right ventricular (RV) and abdominal aortic catheter positioning, respectively enabled simultaneous systolic, diastolic and mean PAP and BP recordings. Following recovery, an incremental treadmill test measured maximal aerobic capacity (VO
2
max) via analysis of expired gases. Steady state exercise testing was then performed for 3 different submaximal relative intensities: 50, 75, and 90% VO
2
max. Pressures were recorded during each test, as well as pre- and post- exercise. At 2.5 weeks following monocrotaline (MCT, 40 mg/kg) administration (mild PH) and 7 weeks post-MCT (advanced PH), VO
2
max and steady-state exercise tests were repeated.

Results:
Compared to pre-MCT, at 2.5 weeks post-MCT systolic PAP increased from 25 to 41 mmHg at rest; from 105 to 117 mmHg at peak exercise; and from 40 to 58 mmHg, 46 to 65 mmHg, and 55 to 75 mmHg during running at 50, 75, and 90% VO
2
max, respectively. At 7 weeks post-MCT, PAP further increased at rest (to 59 mmHg), and during steady state running (to 69, 70, and 73 mmHg, at 50, 75, and 90% VO
2
max, respectively). During recovery from steady state exercise, the fall in PAP occurred more rapidly post-MCT, bringing PAP to even lower than resting from 10 min to 2h into recovery.

Conclusions:
Using implantable telemetry we have accomplished dual pressure recordings during serial exercise tests before and after PAH induction. The rise in PAP relative to exercise intensity is steeper in PAH but is accompanied by a post-exercise window of normalized PAP, which may be attributed to pronounced acute pulmonary endothelial activation. Future work will investigate how these acute effects translate to wall stress and RV remodeling with chronic exercise training and may allow for optimized exercise prescription for patients affected with PAH.
Abstract 19514: Race and Willingness to Participate in Cardiovascular Clinical Research
Authors: Zhang Xiaotao , Bazzano Lydia A , Gavin Stephen G , Gaudreau Stephanie , Breault Joseph
Published: July 2021

African Americans (AA) are underrepresented in clinical trials in the United States for a variety of reasons. The majority of studies examining this issue were conducted >10 years ago and since then, efforts have been implemented to improve AA enrollment in research. We took advantage of the cardiovascular research data of a large community academic center in New Orleans, Louisiana to examine whether race was associated with participation in cardiovascular research. We used a nested case control design with 80% power to detect a doubling in odds of non-participation. Individuals could be included if they were offered participation in any of the 4 largest studies conducted in 2012, were White or AA and were American citizens (n=974). Median income household income was inferred using postal codes. Cases were defined as individuals who declined to participate and did not sign a consent form. Controls were defined as individuals who agreed to participate and signed a consent form. We identified 100 cases and selected 200 controls matched on age (within 1 year) and sex using a random selection algorithm. Of the 974 eligible for analysis, mean (SD) age was 65 (14)

years, median household income in thousands was 51.92 (19.9), and 65.3% were men. Of those who agreed to participate, 32.2% were AA while of those who refused, 31.0% were AA. The unadjusted Mantel-Haenszel odds ratio for non-participation by race was 1.06 (95% CI: 0.60 to 1.94) for AA individuals compared to their White age and sex matched counterparts. Using multivariable conditional logistic regression, the odds ratio for participation in a study was 1.04 (95% CI: 0.56 to 1.92) for AA as compared to their White age and sex matched counterparts, after adjustment for median household income, employment, and marital status. Our findings suggest that, at a large community academic center, race does not significantly affect willingness to participate in cardiovascular research independent of age, gender, socioeconomic and marital status.
Abstract 19519: Closing the Cardiac Intensive Care Unit: Cost-Savings Associated with a “Closed” versus “Open” Model of Critical Care Delivery
Authors: Das Arun K , Harden Jacqueline M , Ravichandran Mathi M , Lishmanov Anton , Raftery Linda , van Diepen Sean , Katz Jason N
Published: July 2021

Introduction:
A recent AHA scientific statement highlighted the evolving complexity of critical care delivery for cardiac patients, and the emerging need for novel staffing models. In this document, a “closed” unit structure - in which a dedicated intensive care team treats all admitted patients - was specifically advocated. However, in light of escalating critical care costs within US hospitals, there is a pressing need to better understand the financial impact of different care platforms.

Methods:
In July 2013, our academic cardiac intensive care unit (CICU) was transitioned from an “open” to a “closed” model of care. In a before-and-after study design, consecutive admission records were reviewed from Aug 2012-Dec 2012 (“open” unit) and from Aug 2013-Dec 2013 (“closed” unit). Routinely collected financial and demographic data were examined, and the impact of case-mix index (CMI) on cost was evaluated.

Results:
In the “open” and “closed” models, there were 333 patient-visits accounting for 1,891 patient-days and 397 visits accounting for 2,558 patient-days, respectively. While demographics, payor mix, and fixed vs. variable cost distribution were unchanged (Table), the total cost-per-patient and cost-per-patient-day were lower within the “closed” CICU ($8,676 vs. $10,118 and $1,346 vs. $1,782, respectively) despite a greater average CMI (4.6 vs. 3.6). Total and 30d CICU readmission rates were also lower in the “closed” unit (Table). Readmissions in the "closed" unit resulted in greater cost-per-patient-day than new admits ($1,576 vs. $1,339).

Conclusions:
A “closed” CICU staffing model is associated with lower health care costs. This may be partly explained by lower CICU recidivism, but likely is multifactorial. Additional study will focus on the influence of resource use, critical care delivery to key sub-populations, and the development of effective strategies for further cost containment.
Abstract 19525: Knockout of CD38 Preserves Endothelial Function in the Postischemic Heart through Reduced Nicotinamide Adenine Dinucleotide Phosphate Salvage
Authors: Boslett James J , Chini Eduardo N , Zweier Jay
Published: July 2021

Introduction:
Cardiac ischemia/reperfusion (I/R) injury causes dysfunction in the coronary endothelium, resulting in loss of vascular relaxation and decreased tissue perfusion. Prior data with pharmacological inhibitors suggests that CD38 plays a role in I/R-induced vascular endothelial dysfunction (VED) through consumption of NADPH precursor NADP, limiting the supply of NADPH for nitric oxide (NO) production from endothelial NO synthase (eNOS) and decreasing NOS-dependent coronary flow (NDCF). In order to definitively determine the role of CD38 in cardiac I/R injury and endothelial dysfunction, we performed studies on hearts of wild type (WT) and CD38
-/-
mice.

Methods:
Isolated Langendorff perfused hearts of WT (n=9) and CD38
-/-
mice (n=7) were subjected to 30 min ischemia (I) and contractile function and coronary flow were monitored through 30 min reperfusion (R) with an intraventricular balloon and Doppler flow probe, respectively. At 30 min R, NDCF was measured with administration of NOS inhibitor L-NAME and then hearts were frozen for high performance liquid chromatography (HPLC) measurements of NADP(H) and NAD(H).

Results:
There was no difference in contractile function recovery between groups. However, hearts from CD38
-/-
mice had enhanced recovery of both NADP(H) and NAD(H) (47.4 +/- 3.2 and 42.2 +/- 3.3% higher). Furthermore, at 30 min R, hearts from CD38
-/-
mice had much higher post-ischemic recovery of coronary flow (14.64 +/- 3.50% higher) and NDCF (48.7 +/- 5.5% higher) compared to WT mice (Fig 1 & 2).

Conclusion:
Thus, we observe that CD38 activation is a key mechanism contributing to NADP(H) depletion and VED in the postischemic heart.
Abstract 19539: Obstructive Sleep Apnea Screening Resulting in Improved CVD Risk Score
Authors: McLaughlin Mary Ann , Iyengar Rupa L , Beebe Heather N , Jamar Bianca , Woodward Mark , Crowley Laura , Maceda Cynara
Published: July 2021

Introduction:
Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder with a prevalence of 15 - 20% in the general population. OSA is related to numerous disorders and increases risk of cardiovascular disease (CVD) and CV events including myocardial infarction and cerebrovascular accidents. Behavioral modification is a quintessential component of treatment for OSA.

Hypothesis:
We sought to evaluate and quantify the impact of Law Enforcement Cardiac Screening (LECS) program on change in OSA risk.

Methods:
Patients seen in World Trade Center (WTC) LECS from 2008 - 2010 were reevaluated in WTC CHEST from 2012 - 2014. We analyzed 959 patients’ anthropometric measurements and CV risk factors against status of high risk for OSA (OSA+) defined as never met, only met criteria in LECS, only met criteria in CHEST and met criteria in both LECS and CHEST. OSA+ was defined as 2 or more positive categories on the Berlin Questionnaire (BQ). Independent t-test, ANOVA, and multivariate regression analyses were used to assess the impact of WTC LECS on OSA+ as it relates to body mass index (BMI), waist circumference, and high sensitivity CRP (hsCRP)

Results:
We found that those who only met high risk for OSA criteria in 2008 - 2010 (LECS only) had a significant decrease in BMI when reevaluated in 2012 - 2014 (CHEST) (41.5 kg/m2 vs. 38.4 kg/m2 respectively; p < 0.001). Patients only diagnosed in 2008 - 2010 had a significant decrease in hsCRP compared to those diagnosed in 2012 - 2014 (-1.44 vs -0.37 respectively, p = 0.040).

Conclusions:
Using the BQ as screening tool for OSA in a large population of asymptomatic middle aged participants allowed identification approximately 40% of the initial screening population to be at OSA+. Identifying these participants allowed us to counsel and advise patients of pertinent behavioral modifications known to improve risks for OSA. These efforts resulted in significant reduction in anthropometric measurements and improved CVD 10 year risk.
Abstract 19557: Novel Stress Signaling JNK Regulates Pro-arrhythmic Molecular CaMKIIδ Activity and Expression in Aged Human Atrium
Authors: Wu Xiaomin , Zhao Weiwei , Corrillo Elena , Chen Weizhe , Yan Jiajie , Bers Donald M , Robia Seth L , Ai Xun
Published: July 2021

The c-Jun N terminal kinase (JNK) is an important member of the MAP kinases family, activated in response to stress and implicated in the development of cardiovascular diseases (CVDs). We have previously shown that JNK plays a pivotal role in development of atrial arrhythmia in aged hearts. However, the underlying mechanism remains incompletely understood. Accumulating evidence suggests that CaMKIIδ is another critical kinase in the development of arrhythmias and CVDs. In human atrial tissue, we discovered that enhanced phosphorylation of JNK (JNK-P) was associated with an increased ratio of phosphorylation of CaMKIIδ Thr286 (CaMKII-P) to total CaMKIIδ (immunoblotting assay) with increasing age (19-82yrs; n=12), while the level of CaMKIIδ mRNA expression (qPCR) was also up-regulated. To further characterize the JNK-CaMKIIδ relationship, we used a unique HL1 atrial myocyte line. CaMKIIδ activation status was assessed using a specific CaMKIIδ-P antibody (immunoblotting assay) and a CaMKIIδ biosensor camui (FRET imaging assay). We found that atrial myocytes treated with JNK activator anisomysin (24hrs) exhibited significantly increased CaMKIIδ-P (56% vs sham controls; p<0.01; n=4,4) that was associated with markedly elevated JNK-P. In JNK activated live HL-1 myocytes, the activation of CaMKII (ratio of CFP to YFP fluorescence (FCFP/FYFP)) was increased by 35% (vs sham controls; p<0.05; n=4,4 monolayers). This suggests that JNK activation caused enhanced CaMKII activation in atrial myocytes. Overexpression of inactivated JNK2 (dominant negative; JNK2dn) attenuated JNK-induced CaMKIIδ activation (both CaMKII-P and camui FRET assays). Moreover, we found that the amount of CaMKIIδ protein and mRNA expressions in JNK-activated myocytes was up-regulated by 103% and 75%, respectively (p<0.05; n=3,3). Finally, overexpressed JNK2dn markedly suppressed JNK-induced CaMKIIδ up-regulation at both protein and mRNA levels (n=4,4). In conclusion, we report here for the first time that the novel stress signaling JNK regulates not only activity but also expression of the pro-arrhythmic signaling molecular CaMKIIδ in aged atrium. Modulation of JNK signaling could be a novel therapeutic approach to prevent and treat arrhythmias and CVDs in the elderly.
Abstract 19565: SAMeTT2R2 Scores Predict Stroke Risk After Initiation of Vitamin K Antagonist Therapy for Atrial Fibrillation: a Real-world Practice Study
Authors: Martinez Carlos , Katholing Anja , Reitbrock Stephan , Lip Gregory Y , Freedman Ben
Published: July 2021

Introduction:
Quality and duration of anticoagulation reflected by high proportion of Time in Therapeutic INR range (TTR) is associated with reduced thrombo-embolic and bleeding events in atrial fibrillation (AF). SAMeTT2R2, a novel score incorporating age, sex, ethnicity, smoking, co-morbidities, and interacting drugs, predicts inadequate anticoagulation control (TTR <0.6) after commencing Vitamin K Antagonist (VKA) for AF, with scores ≥2 suggested as a cut-off to predict inadequate control.

Aims:
To determine whether SAMeTT2R2 score ≥2 at VKA inception is associated with an increased stroke risk in real-world practice.

Methods:
A cohort of VKA-naïve patients with incident non-valvular AF between 2001 - 2010 was formed from a large UK primary care database (Clinical Practice Research Datalink, CPRD) with linkage to hospital discharges, and death registry. SAMeTT2R2 score was calculated in a subset of 4468 in whom VKA treatment was initiated within 90 days of AF diagnosis, and scores 0-1, ≥2 were related to 3-year stroke incidence. Competing risk analysis accounting for death was performed to compare the risk of stroke between the two groups in an intention-to-treat analysis.

Results:
Of 4468 patients with incident AF commenced on VKA (mean age 70.7, 41.2% female), 3422 (76.6%) had a SAMeTT2R2 score of 0-1, and 1046 (23.4%) a score of ≥2. During 3-years 138 patients had a stroke and 58 of these occurred in the year following AF. Cumulative risk estimates for stroke in patients with scores ≥2 compared to 0-1 were significantly increased at 1, 2 and 3 years (log rank test, p<0.01)(Figure). The proportion with TTR≥0.6 was 37.1% for scores ≥2 compared to 44.1% for scores 0-1 (p<0.01).

Conclusions:
SAMeTT2R2 scores ≥2 predict increased stroke risk in the 3 years following incident AF in patients commenced on VKA treatment. These findings suggest that patients with high SAMeTT2R2 scores may require intensified anticoagulation control or use of oral non-VKA anticoagulants.
Abstract 19568: Hemodynamic Assessment of an Augmented Aorta: a Rapid Prototyping Technique
Authors: Gralewski Kevin A , Whitehead Kevin K , Dori Yoav
Published: July 2021

Introduction:
Interest in high fidelity aortic flow phantoms remains significant even with advancements in computational fluid dynamic methods. We present a process for creating a patient-specific, compliant aortic arch and valve (AoV) along with our corresponding validation efforts.

Methods:
A rendered aortic volume was created by threshold-based segmentation in Mimics (Materialise, Leuven, Belgium) and edited in 3-matic to create a 3D printed mold (Object Connex 5000, Stratasys, Edina, Minnesota) into which a polyurethane based resin (Smooth-on, Easton, Pennsylvania) was cast. The AoV was created in a similar manner and ultimately seated in the distal end of an inlet port designed to induce laminar flow. The arch, with fixed inlet, was then constrained to the correct anatomical conformation by a custom rapid prototyped chamber. An MRI-compatible pump programmed to match the patient’s flow profile managed flow of a 40% glycerin-aqueous solution. Both through-plane and 4D phase contrast velocity mapping MRI sequences were acquired and compared to the patient data with time-elapse flow streamlines calculated by GTFlow version 2.0.1 (GyroTools, Zurich Switzerland).

Results:
The phantom remained robust and compliant throughout the dynamic loading occurring under pulsatile flow. Registration revealed good alignment of the phantom lumen to the segmented patient aorta. 4D flow analysis showed an unusual left-handed helical flow pattern in both the in vivo patient data and derived phantom flows. Flow measurements in the ascending and descending aorta of the model agreed within 5% of the actual patient measured flow.

Conclusions:
We have demonstrated a viable method to create patient-specific flow phantoms, which closely mimic the physiological system for which they are modeled. Further studies are needed to optimize the valve anatomy and wall compliance.
Abstract 19586: Impact of Dyspnea: From Validity Indices to the Clinical Utility of the French-canadian Version of the Modified Dyspnea Index
Authors: Dore Michel , Gallani Maria-Cecilia , Provencher Steeve , Poirier Paul , Gagné Camille , Gélinas Céline
Published: July 2021

Introduction:
Dyspnea is a cardinal symptom among patients with respiratory and cardiovascular diseases. Its underlying mechanisms are complex, including pathophysiological as well as psychological and environmental factors. There is no gold standard to its evaluation and it has been recognized that multidimensional tools could provide a more comprehensive evaluation of the symptom.

Hypothesis:
The purpose of this study was to examine the validation of the scores of the French-Canadian version of the Modified Dyspnea Index(MDI), a multidimensional measure of dyspnea, among chronic cardiovascular and pulmonary patients.

Methods:
This study includes 137 patients: 79 with pulmonary arterial hypertension and 58 with interstitial lung disease. The cross-cultural adaptation and reliability of the MDI were already reported. The hypothesis guiding the test of convergent validity were that the final score of MDI, which reflects the intensity of dyspnea and its functional impact, would have correlations with: pulmonary function (forced vital capacity-FVC and FVC%), physical capacity (6 Minutes Walk Test-6MWT and Veterans Specific Activity Questionnaire-VSAQ), the practice of physical activity (Godin-Shephard Leisure-Time Physical Activity Questionnaire - GSLTPAQ) and quality of life (SF-12). Partial correlations were performed controlling theses variables: diagnosis, age, sex, BMI, and schooling.

Results:
The following correlations were observed between the total score of MDI and the reference variables: FVC 0.36 (
p<0.001
); FVC% 0.29 (
p=0.008
); 6MWT 0.58 (
p<0.001
); VSAQ 0.77 (
p<0.001
); GSLTPAQ 0.50 (
p<0.001
); SF12-Physical Component 0.73 (
p<0.001
); SF12-Mental Comp. 0.31 (
p<0.001
).

Conclusions:
The results confirmed the associations hypothesized. The total score of the MDI explained much more the variance of the quality of life and perceived physical capacity, than lung function explained the MDI score. It is aligned with the described impact of the symptom in the daily life of the patient and the complexity of the factors underlying its triggering and perception. The use of the MDI can be very helpful in the clinical follow-up, guiding the choice of the best therapeutic approach and evaluation the outcomes of the interventions implemented.
Abstract 19592: Predictors of Bleeding Complications in Patients Undergoing Percutaneous Coronary Intervention in an Australian Cohort
Authors: Tavella Rosanna , Worthley Matthew , Arstall Margaret , Zeitz Christopher , Beltrame John
Published: July 2021

Background:
Extensive studies have been undertaken to define clinical predictors of bleeding events in patients undergoing percutaneous coronary intervention (PCI). Few studies have included a large cohort of ‘real world’ patients undergoing PCI via a radial approach.

Methods:
The Coronary Angiogram Database of South Australia (CADOSA) captures all PCI procedures performed in each public hospital in the state of South Australia (population 1.675 million). CADOSA utilizes identical data specifications to CathPCI® Registry. Thus a significant PCI-related bleeding event was defined as blood loss from any location (percutaneous entry site, retroperitoneal, gastrointestinal, genitourinary) within 72 hours of procedure, resulting in a fall in haemoglobin > 3.0g/dL, transfusion, or prolonged hospital admission. Clinical determinants of PCI-related bleeding events were identified in a multivariable logistic regression model.

Results:
In 2012, there were 1,409 PCI procedures performed, with 80% undertaken for acute coronary syndrome, 56% via radial access, 14% using bivalirudin/enoxaparin and 5% utilizing novel anti-platelet agents (prasugrel 5%, ticagrelor 0.1%). Of these procedures, 1.7% had significant bleeding events. Univariate determinants of bleeding included increasing age, female, current smoker, prior PCI, ST elevation MI presentation, femoral access, cardiogenic shock, intra-aortic balloon pump insertion and administration of clopidogrel, glycoprotein IIb/IIIa inhibitors, verapamil or metaraminol prior/during procedure. The final model identified the following clinical determinants as significant independent predictors of bleeding with a C-index of 0.87: age over 80 years (OR=10.7; 3.4-34.0, p<0.01), current smoker (OR=5.7; 2.0-16.5, p<0.01), the use of glycoprotein IIb/IIIa inhibitor (OR=3.9; 1.4-10.6, p<0.01), use of clopidogrel (2.7; 1.0-7.1, p<0.05) and femoral access site (OR=10.6; 3.1-37.1, p<0.01).

Conclusion:
In a ‘real world’, representative PCI cohort where radial access approach is frequently used, there was a low prevalence of bleeding events. In addition to access site, several distinctive baseline clinical features along with administration of blood thinning agents predicted bleeding.
Abstract 19638: Short-Axis Echocardiographic Imaging of the Ascending Aorta is More Accurate than Long-Axis Imaging when Compared to Cardiac Magnetic Resonance Imaging and Computed Tomography
Authors: Kwan Tina W , Bornemeier Renee A , Best Thomas H , Tang Xinyu , Gossett Jeffrey , Collins Ronnie T
Published: July 2021

Introduction:
Parasternal long-axis echo imaging often underestimates aortic dimensions when compared to CT or MRI. More accurate and reproducible echo methods for determining aortic size would benefit care and reduce cost. We compared novel short-axis aortic echo images to standard long-axis and CT or MRI measurements.

Methods:
We retrospectively reviewed all cardiac CT/MRI performed in the setting of aortic dilation at Arkansas Children’s Hospital from September 2002 to September 2013. All CT/MRI exams with echocardiograms performed within 3 months were included. One blinded observer reviewed all CT/MRI studies, and measured lateral and anteroposterior dimensions of the aortic sinus (AoS), sinotubular junction (STJ), and ascending aorta (AsAo). Echo measurements were made by 3 independent, blinded observers, and included AoS, STJ, and AsAo in standard long-axis views, as well as novel short-axis measurements: anteroposterior sinus length; maximal left to non-coronary sinus length; and lengths from center right to left coronary sinus or non-coronary sinus. Short-axis anteroposterior and lateral measurements were made of the AsAo at the level of the right pulmonary artery from a high left-parasternal view. All echo measurements were compared to CT/MRI. Pearson product-moment correlation based on Fisher’s transformation was determined for each measure compared to CT/MRI.

Results:
Fifty MRIs, 17 CTs, and 62 echocardiograms were identified and reviewed. Adequate imaging for long-axis aortic assessment was present in 48/62 (77%) echocardiograms, and 42/62 (68%) had adequate short-axis images. Fifty-three subjects median age 34.7 years met inclusion criteria. Long-axis measurements correlated well with CT/MRI for AoS (r=0.811), but poorly for AsAo (r=0.094). Short-axis measurements correlated equally well with CT/MRI for AoS (r=0.832), and AsAo (r=0.790).

Conclusions:
Parasternal short-axis echo measurements of the aorta are more accurate than conventional parasternal long-axis measurements when compared to CT/MRI. This simple and reproducible technique should be used routinely for echocardiographic evaluation of the aorta.
Abstract 19659: Early Detection of Right Ventricular Dysfunction Using Speckle-Tracking Echocardiography in Systemic Sclerosis Patients
Authors: Mukherjee Monica , Chung Shang-En , Hummers Laura K , Wigley Frederick M , Abraham Theodore P , Shah Ami A
Published: July 2021

Background:
Cardiac involvement in systemic sclerosis (SSc) adversely affects long-term prognosis, remaining undetectable despite frequent echocardiographic monitoring. Speckle tracking derived strain of the RV free wall was utilized to detect early changes in regional and global contractility in SSc patients.

Methods:
138 SSc patients who had technically adequate, clinically indicated 2D echocardiograms were studied, and compared with a cohort of 40 age-matched non-scleroderma controls (C). Conventional 2D and off-line strain analysis were performed using commercially available software. RV longitudinal systolic strain (RVLSS) was assessed in the basal, mid and apical free wall. RVLSS in each segment was compared between SSc and C using a Student’s t test. We modeled RVLSS as a function of segment and disease group (SSc vs. C). T-test was used to compare the group difference, and GEE to account for clustering of RV strain values across the 3 RV segments.

Results:
Global RVLSS was diminished in SSc compared to C (β 1.5, p=0.045). Regional differences in RVLSS were also noted: decreased in the apex (SSc -8.5 vs C -17.2, p<0.0001) and mid (SSc -12.4 vs. -17.8, p<0.0001) segments and increased in the base (SSc -32.2 vs. C -22.5, p<0.0001) in SSc vs C. Among C, regional differences in RVLSS were detected in the basal segment relative to the apex (base-apex β -5.4; p<0.0001) but not in the mid-apex comparison. In contrast, SSc had significant regional differences throughout (base-apex β -23.6, mid-apex β -3.9, both p<0.0001), especially when comparing the basal to apical segments. The base-apex difference was significantly greater in SSc compared to C (p<0.0001 for interaction). While SSc had a higher mean PASP than C (SSc 31.4 vs C 22.7 mmHg, p=0.0001), the differences observed in regional strain between SSc and C were unchanged when restricting our analyses to those with a PASP<35 mmHg.

Conclusion:
In SSc patients, basal segments of the RV free wall had increased RVLSS, in comparison to mid and apical segments, and the base-apex difference with significantly higher than that seen in non-scleroderma controls. This heterogenous pattern of regional strain in SSc patients, regardless of PASP, suggests regional remodeling of the RV prior to the onset of overt RV dysfunction.
Abstract 19717: Patient Characteristics Associated with False Arrhythmia Alarms in Intensive Care
Authors: Harris Patricia R , Zègre-Hemsey Jessica K , Mammone Tina , Schindler Daniel , Hu Xiao , Bai Yong , Paul Steven M , Drew Barbara J
Published: July 2021

Introduction:
A high rate of false arrhythmia alarms leads to clinical alarm fatigue, i.e. desensitization and inappropriate silencing of alarms.

Objective:
To determine patient characteristics associated with frequent false arrhythmia alarms in the intensive care unit (ICU).

Methods:
This descriptive, observational study prospectively enrolled every consecutive patient admitted to 1 of 5 adult ICUs (77 beds) at an urban medical center during March 2013. All monitor alarms and continuous waveforms were automatically stored on a secure server. Expert nurse scientists used a standardized protocol to annotate 6 clinically important arrhythmia alarms (asystole, pause, ventricular fibrillation, ventricular tachycardia, accelerated ventricular rhythm, ventricular bradycardia) as true or false. Medical records were examined to acquire patient characteristic data.

Results:
A total of 461 unique patients (mean age=60) were enrolled, generating 2,507,822 alarms, including all levels of arrhythmia, parameter, and technical alarms. There were 48,404 hours of patient monitoring time, resulting in an overall alarm rate of 52 alarms/hour. Investigators annotated 12,674 arrhythmia alarms; 11,137 were determined to be false (88%); 250 patients generated at least 1 of the 6 annotated alarm types; 2 patients generated 6,930 alarms (55%). Monitoring time for each patient was measured and number of false alarms/hour calculated for the clinically important arrhythmia alarms (range 0 - 8 false alarms/hour). Patient characteristics were compared with false alarm rates using nonparametric statistics to minimize the influence of outliers. Significant associations included: older age, ≥ 60 years (p=0.005), confused mental status (p<0.001), breathing with mechanical ventilation (p<0.001), and wide QRS complex due to bundle branch block, BBB (p=0.006) or ventricular paced rhythm (p=0.001).

Conclusion:
Patients likely to trigger a higher number of false arrhythmia alarms are those with confused mental status, on mechanical ventilation, or who have a wide QRS complex due to BBB or pacing. Algorithm improvements need to focus on better noise reduction (motion artifact with confused state) and distinguishing BBB and paced rhythms from ventricular arrhythmias.