bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18403: Effect of Dabigatran on the Ability to Generate Fibrin at a Wound site and its Reversal by Idarucizumab, the Antidote to Dabigatran, in Healthy Volunteers: An Exploratory Marker of Blood Loss
Authors: van Ryn Joanne , Schmoll Michael , Pillu Haiko , Gheyle Lien , Brys Joline , Moschetti Viktoria , Glund Stephan , Reilly Paul , Stangier Joachim
Published: July 2021

Background:
Idarucizumab is a humanized antibody fragment (Fab) that specifically and potently binds dabigatran to neutralize its anticoagulant activity. Assessing whether reversal of anticoagulation also reverses bleeding is challenging. This healthy volunteer (HV) study explored dabigatran’s ability to inhibit fibrin formation in blood at a non-penetrating wound site by measuring fibrinopeptide A (FPA) generation and to test whether idarucizumab restores wound site fibrin formation.

Methods:
The study followed the Declaration of Helsinki with HV written informed consent. Dabigatran etexilate (DE, 220 mg bid) was given for 4 days. FPA was assessed before DE and on day 3 and 4 at 2.5 and 6 hrs post morning DE dose. On day 4, HV received 5 min infusion of 1, 2 or 4 g of Fab or placebo 2 hrs post morning DE dose (n=8-9/group). Incisions were made with a scalpel device (Surgicutt®) on the forearm volar surface. Blood was collected from the wound at each time point over 4 min into vials containing stop solution and frozen until assayed. FPA was measured via commercial ELISA, ecarin clotting time (ECT) and diluted thrombin time (dTT) using standard methods. Plasma dabigatran levels were measured by LC-MS/MS. Data expressed as mean ± SE and analyzed using two way ANOVA, p<0.05 as significant.

Results:
Fab and dabigatran were well tolerated. Mean FPA before DE was 3980 ± 1735 ng/ml (n=35). There was almost complete inhibition of FPA to 208 ± 28 ng/mL 2.5 hrs post DE day 3, corresponding to peak dabigatran levels (210 ± 17 ng/mL). Six hrs post DE, levels were 127 ± 10 ng/mL and FPA was still significantly reduced to 328 ± 35 ng/mL (pooled day 3 data). There was a significant, dose-dependent return of fibrin formation with increasing doses of Fab to 24, 45 and 63% of pre DE values 30 min after 1, 2 and 4 g Fab, respectively (p<0.05). Anticoagulation (ECT and dTT) was significantly prolonged with dabigatran and reversed to control levels after dosing with 2 and 4 g Fab.

Discussion:
This study demonstrates that idarucizumab reverses dabigatran-induced inhibition of wound site fibrin formation in HV and this correlated with reversal of systemic anticoagulation. Translation into reversal of bleeding in patients requires further clinical investigations, which are currently ongoing.
Abstract 18412: Long Non-coding RNA Meg3 Regulates Senescence-associated Genes and Controls Endothelial Cell Function
Authors: Boon Reinier , Hofmann Patrick , Michalik Katharina , Knau Andrea , Ponomareva Yuliya , Zeiher Andreas , Uchida Shizuka , Dimmeler Stefanie
Published: July 2021

The majority of transcribed RNAs does not encode proteins, but function as regulatory RNAs. Non-protein-coding RNA are classified in short (<200 nt) and long (>200 nt) non-coding RNAs (lncRNAs). lncRNAs have been described to play an important role in many biological processes, including epigenetic regulation of gene expression.

To determine the expression and functional role of lncRNAs in endothelial cells, we performed RNA deep sequencing of human umbilical venous endothelial cells (ECs). Among the highest expressed lncRNAs, we identified Maternally Expressed 3 (Meg3, 35.3±0.6 RPKM), which has been correlated to VEGF expression. In HUVECs, Meg3 localizes to the nucleus and is induced by hypoxia (4.08±0.78-fold, p<0.05). Interestingly, Meg3 was also found to be induced in the intima of aged mice and correlates with age in human hearts (p=0.016). Meg3 levels are also induced in replicative senescent HUVECs in vitro (passage 16/17 vs 2/3, 2.9±0.99-fold).Conversely, silencing of Meg3 using LNA-GapmeRs induced angiogenic sprouting of endothelial cells in vitro (1.4±0.14-fold, P<0.05) but did not affect caspase-3 activation. Mechanistically, RNA immunoprecipations showed that Meg3 associates specifically to H3K27me3, a silencing chromatin mark. Silencing of Meg3 in HUVECs induces a robust repression of global gene expression, as measured by exon array analysis, with a highly significant repression of the anti-senescent HMGA2.

In summary these results demonstrate, that the lncRNA Meg3 is highly expressed in endothelial cells and is up-regulated by hypoxia and aging. Functionally, Meg3 inhibits sprouting angiogenesis in vitro. Meg3 depletion leads to a general repression of gene expression and the senescence marker HMGA2 likely by inducing the recruitment of silencing H3K27me3 marks to the promoters Therefore, modulating Meg3 may be a potential strategy to reduce endothelial senescence or increase regenerative angiogenesis.
Abstract 18540: Heme Oxygenase 1 Activity and Expression Suppresses a Proinflammatory Phenotype in Monocytes and Correlates With Endothelial Function in Mice and Humans
Authors: Wenzel Philip , Rossmann Heidi , Müller Christian , Kossmann Sabine , Simsek Canan , Kröller-Schön Swenja , Schulz Eberhard , Oelze Matthias , Daiber Andreas , Lackner Karl , Schnabel Renate , Blankenberg Stefan , Zeller Tanja , Wild Philipp , Münzel Thomas
Published: July 2021

Background:
Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 activity and expression determine the extent of vascular dysfunction in mice and humans.

Methods and results:
Decreasing HO activity was parallelled by decreasing aortic HO-1, eNOS and phospho-eNOS (ser1177) protein expression in HO-1 deficient mice, whereas aortic expression of nox2 showed a stepwise increase in HO-1+/- and HO-1-/- mice as compared to HO-1+/+ controls. Aortic superoxide formation increased depending on the extent of HO-1 deficiency and was blunted by the PKC inhibitor chelerythrine, indicating activation of the NADPH oxidase. When subjected to disease models of vascular dysfunction - angiotensin II-infusion (ATII, 0.1mg/kg/d for 7d), streptozotocin-induced diabetes mellitus and aging - HO-1 deficient mice showed an increased vascular dysfunction (shown by isometric tension studies) that was inversely correlated with HO activity. In a primary prevention population based cohort (the Gutenberg Health Study, GHS), we assessed length polymorphisms of the HO-1 promoter region, established a bipolar frequency pattern of allele length (long vs short repeats) in 4937 individuals and found a moderately significant association with flow mediated dilation of the brachial artery (FMD) in individuals with arterial hypertension. Monocytic HO-1 mRNA expression was positively correlated with CD14 expression indicating proinflammatory monocytes (p<0.001) and inversely with FMD in 733 hypertensive individuals of the GHS. ATII-infused HO-1+/+ mice had a significant infiltration of proinflammatory CD11b+Ly6Chi monocytes into the aortic wall, which was sharpely increased in HO-1+/- and HO-1-/- mice, providing a mechanistic link of the monocyte phenotype determined by HO-1 and vascular dysfunction in arterial hypertension.

Conclusions:
We here present evidence that HO activity and expression and inversely correlates with vascular dysfunction and NADPH oxidase mediated oxidative stress in mice and humans. We conclude, that HO-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes.
Abstract 18557: Low Galectin-3 Identifies Heart Failure Patients at Minimal Risk for Death or Rehospitalization
Authors: Meijers Wouter C , de Boer Rudolf A , van Veldhuisen Dirk J , Jaarsma Tiny , Maisel Alan S , Somma Salvatore D , Peacock W. F
Published: July 2021

Introduction:
Acute heart failure (AHF) patients have a very high mortality and unplanned hospital readmission rate approaching 25% within 30 days, up to 30% within 90 days. Stratification tools that predict a (very) low risk for mortality or rehospitalization would be potentially useful as such patients may be discharged early. We aimed to determine if the emerging biomarker galectin-3 could identify AHF patients at low risk for death or rehospitalization compared to BNP after discharge.

Methods:
This was a substudy of the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Enrollment of AHF patients occurred prior to discharge. We evaluated the relationship between percentiles of galectin-3 (and BNP) and the prediction of low risk in 592 patients.

Results:
In this cohort, the median [IQR] age, BNP and left ventricular ejection fraction were 73 years [64-79], 448 pg/mL [197-911], and 30% [23-43], respectively. Overall, the median [IQR] galectin-3 level was 20 ng/mL [15-26], with a maximum of 67 ng/mL. Patients with elevated galectin-3 levels had more severe disease, reflected by higher age, worse renal function, and higher BNP. No patient died within 30, 90 or 180 days with a galectin-3 level <11.8 ng/mL (10th percentile). No patient below this value was rehospitalized during 90 days follow-up and only one patient within 180 days. In comparison, the 10% lowest BNP levels (<96 pg/mL) failed to identify patients who died (N=7) or were rehospitalized (N=8) within 180 days. Also in higher percentiles (20-50th), galectin-3 remained superior over BNP in identifying low risk patients. We created a cox-hazard regression model, and this showed that galectin-3 level <11.8 remained a significant predictor of death or rehospitalization, also after adjustment for age, sex, (log) BNP, eGFR, NYHA class and LVEF: HR (CI) 0.32 (0.15-0.70); p<0.01). On top of these predictors for outcome, galectin-3 <11.8 ng/mL added significantly to the receiver operator characteristic curve for the composite outcome of 180 day death and rehospitalization (p<0.05).

Conclusion:
A galectin-3 level <11.8 ng/mL identifies discharged AHF patients without 30, 90 and 180 day mortality, and with a minimal risk for repeated HF rehospitalization.
Abstract 18597: Systemic, Non-cerebral, Arterial Embolism in 21,105 Patients with Atrial Fibrillation Randomized to Edoxaban or Warfarin: Results from the ENGAGE AF-TIMI 48 Trial
Authors: Geller Bram J , Ruff Christian T , Giugliano Robert P , Murphy Sabina A , Hanyok James J , Jin Jianqing , Mercuri Michele , Antman Elliott M
Published: July 2021

Background:
Atrial fibrillation (AF) is widely recognized as a major risk factor for stroke and systemic embolism. Multiple trials comparing warfarin with factor specific oral anticoagulants have demonstrated that the newer agents are at least as effective as and generally safer than warfarin. However, none of these studies has provided a detailed analyses regarding systemic embolism, the less frequent component of the primary endpoint.

Methods and Results:
We did a prespecified analysis of data from the 21,105 patients with AF enrolled into ENGAGE AF-TIMI 48, a randomized trial comparing two once-daily regimens of edoxaban (high- and low-dose) with warfarin for the prevention of stroke and systemic embolism. Of the 1,016 patients who met the primary endpoint, 67 (6.6%) had a systemic embolic event (SEE) of which 13% were fatal. Risk factors for systemic embolism versus stroke include age (78 versus 74 years; P=0.005), permanent atrial fibrillation (72% versus 54%; P=0.009), and creatinine clearance ≤ 50 mL/min (42% versus 27%; P=0.01). Of the 73 total SEEs (includes multiple events), 62 involved the extremities (85%) and 30 required a surgical or percutaneous intervention (41%). In a meta-analysis of the four major trials comparing novel oral anticoagulants (NOACs) versus warfarin, the NOACs reduce the risk of SEE compared to warfarin (relative risk, 0.63; 95% confidence interval, 0.43 to 0.91; P=0.01), with less bleeding and a better safety profile.

Conclusion:
Although less frequent than stroke, systemic embolism results in significant morbidity and mortality in patients with AF. In a meta-analysis, NOACs reduce the risk of SEEs compared to warfarin.
Abstract 186: Patient Positioning Improves Direct Laryngoscopy First-Attempt Success in Patients with Cardiac Arrest
Authors: Escott Mark , Gleisberg Guy , Traynor Kevin , Jenks Shane , Vartanian Levon , Aaron-Wood Casey , Cosper Jared , Monroe Brett
Published: July 2021

Introduction:
Multiple endotracheal intubation (ETI) attempts can facilitate complications and adversely affect patient outcomes. According to the AHA, in out-of-hospital urban and rural settings, patients intubated during resuscitation had a better survival rate than patients who were not intubated. Published literature on cardiac arrest (CA) patient positioning during ETI and its significance on first attempt success rate (FASR) are scarce.

Objective:
To compare direct laryngoscopy (DL) intubation FASR and glottic exposure with patient position during CA.

Methods:
An institutional review board approved, multi-agency prospective analysis was conducted comparing video laryngoscopy to DL from March 18, 2013 through March 17, 2014 performed by consented paramedics. Subsequently, a subgroup analysis was performed on CA patients, examining the effect of provider positioning on FASR during DL. Throughout this study, patient airways were managed in the following optional positions: (1) supine - floor (Floor), (2) supine stretcher - ambulance (Ambulance), and (3) supine stretcher - elevated (Elevated). We recorded the FASR, Cormack- Lehane and Percentage of Glottic Opening views within each intubation position.

Results:
A total of 190 first attempt DL intubations were recorded, of these 120 (63%) were successful. The DL intubation FASR by positions was: (1) Floor 37 (55%) compared to Ambulance 19 (58%) (95% CI: -0.179 - 0.216), (2) Ambulance 19 (58%) compared to Elevated 64 (71%) (95% CI: -0.047 - 0.323), (3) Floor 37 (55%) compared to Elevated 64 (71%)(95%: CI: 0.008 - 0.304). The Cormack- Lehane view grade mean was: Floor 2.6, Ambulance 2.4, and Elevated 2.0. The Percentage of Glottic Opening mean was: Floor 52%, Ambulance 53%, and Elevated 66%.

Conclusions:
This analysis demonstrated a 16% increase and superiority in DL intubation FASR from the Floor to the Elevated position on CA patients. The Elevated position offers an enhanced view of the airway anatomy and improved Cormack- Lehane and Percentage of Glottic Opening scores. The position of intubation should be considered when evaluating the appropriate stage in cardiac arrest to provide advanced airway management, particularly with anticipated difficult airways.
Abstract 18627: Monocyte Subsets in Patients With Severe Aortic Valve Stenosis Undergoing TAVI
Authors: Hewing Bernd , Au Sebastian C , Ludwig Antje , Stangl Verena , Baumann Gert , Stangl Karl
Published: July 2021

Introduction:
Aortic valve stenosis (AVS) shares profound similarities with atherosclerotic plaque progression, including the presence of macrophages in the valve tissue. Monocytes are the precursor of macrophages and various studies have shown associations of individual monocyte subsets with cardiovascular risk. Therefore, we assessed the hypotheses that monocyte subsets differ in the presence of severe AVS compared to an AVS-free setting and change by intervention of the AVS.

Methods:
Classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++) CD86 positive monocyte subsets and monocyte activation (median fluorescent intensity of CD11b) were determined by flow cytometry in peripheral blood from patients with severe AVS (n=32) and matched AVS-free controls (n=28). A follow-up evaluation of monocyte subsets and activation was performed in AVS patients undergoing transcutaneous valve implantation (TAVI) 3 months after the procedure (n=9).

Results:
There were no significant differences in the absolute monocyte counts between AVS patients and controls. In contrast, AVS patients exhibited a shift towards CD16+ monocytes subsets with significant higher proportion of the intermediate monocyte subset compared to controls (median [IQR] 7.0% [5.5-8.7%] versus 5.8% [4.7-6.6%]; p=0.015). Classical and non-classical monocyte subsets and monocyte activation did not differ significantly between the groups. There was no significant change in the distribution of monocyte subsets or in monocyte activation 3 months after TAVI compared to baseline.

Conclusions:
We found preliminary evidence for a significant difference in the distribution of monocyte subsets in patients with severe AVS compared to AVS-free controls indicating an involvement of monocyte subsets in the pathogenesis of AVS. Monocyte subsets and activation did not change after treatment of AVS by TAVI.
Abstract 18678: Transcutaneous Aortic Valve Replacement -Is Anticoagulation Protective?
Authors: Rajamanickam Anitha , Mucci Kaylan , Basnet Sandeep , Rao Ravinder , Yee Jimmy , Baber Usman , Dangas George , Kini Annapoorna , Adams David , Sharma Samin
Published: July 2021

INTRODUCTION:
Stroke continues to be the most dreaded and quality of life limiting complication of transcutaneous aortic valve replacement [TAVR]. We sought to describe the effects of Anticoagulation[AC] on post TAVR rates of stroke/transient ischemic attack[TIA] and death.

METHODS:
196 patients [116 self expanding and 80 balloon expandable] underwent TAVR from December 2010 to August 2013 at our institution. 1 month follow up was completed on all patients and 1 year follow up was available on 105 patients[TAVR prior to September 2012]. Of these, 59 patients were discharged on AC [55 on Coumadin, 4 on Dabigatran] and 137 patients without AC [NO-AC]

RESULTS:
Atrial fibrillation/flutter[AF] incidence was higher with patients on AC vs NO-AC [ 73% vs 26% ,p <0.001] . There was no difference in diabetes, hypertension, hyperlipidemia, chronic kidney disease, prior MI or stroke, history of thromboembolism, prior gastrointestinal bleed , anemia or cirrhosis. Strokes/TIA after discharge on AC was seen in only 1 patient [subtherapeutic INR of 1.5] and 1 patient had an intracranial bleed on dabigatran vs 5 NO-AC patients [1.7% vs 3.7%, p=0.670].Mortality at I year [13.5 % AC vs 20.4% NO-AC p= 0.3167] - Figure 1. Statistical significance in primary outcomes was not met due to small number of patients

CONCLUSION:
AC patients showed a trend towards improved survival and stroke rates. This difference can be hypothesized by the reduction in thromboemboli formation at the level of the valve struts. Further studies randomizing TAVR patients to AC and NOAC is needed to see if this observed difference translates to reduction in mortality and strokes.
Abstract 18785: Should We Recommend Triple Therapy for Patients Undergoing Stent Implantation With a High Score HAS-BLED?
Authors: Sambola Antonia
Published: July 2021

Introduction:
Current clinical guidelines recommend the use of HAS-BLED score to assess the risk of bleeding in patients requiring oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stenting (PCI-S).

Hypothesis:
The use of OAC in patients requiring OAC with a high score HAS-BLED would be not safe.

Objective:
To evaluate the safety of OAC in patients with indication and a high risk of bleeding (HAS-BLED score ≥ 3) who undergoing PCI-s.

Methods:
A prospective multicenter study was conducted from 2007 to 2012 to identify patients requiring long-term OAC undergoing PCI-S. All adverse outcomes were analyzed at 1-year follow-up.

Results:
We identified 828 patients requiring OAC (77.3% male, 72.0±9.3 years) undergoing PCI-S. Five-hundred thirteen (62%) had a HAS-BLED ≥ 3. Of these, 329 (64.8%) received OAC. These patients had a mortality rate (10.1% vs. 10.3%) and major adverse cardiac events rate (MACE) (19.6% vs. 18.8%, p=0:46) similar to those who did not receive OAC. However, bleeding events rate was significantly higher (15.1% vs. 23.7%, p=0.01) with an excess of major bleeding (3.4% vs. 9.2%, p=0.01) in patients treated on OAC. In a multivariate analysis, in patients with a HAS-BLED ≥ 3: age (p=0.02) and renal failure (p <0.001) were predictors of mortality, but OAC was not associated with mortality. The only predictor of bleeding events was the use of OAC (p=0.01), while renal failure and use of drug eluting stents were not.

Conclusions:
A high percentage of patients undergoing PCI-S have a high bleeding risk (HAS-BLED ≥ 3). In these patients, the use of OAC does not seem to improve prognosis, but increases the incidence of major bleeding.
Abstract 18859: Staphylococcus aureus Infective Endocarditis is Associated with Worsened Clinical Characteristics than Non-Staphylococcus aureus Organisms
Authors: Han Sang Myung , Vasan Sowmya , Grbic Mark , Yerebakan Halit , Sorabella Robert , Najjar Marc , Castillero Estibaliz , Wu Yeu Sanz , Takayama Hiroo , Argenziano Michael , Gordon Rachel , Kalesan Bindu , George Isaac
Published: July 2021

Background:
Staphylococcus aureus remains a leading cause of IE, but it is unknown whether S. aureus is associated with more severe infections or worsened outcomes compared to other bacterial organisms. The primary purpose of this study was to compare the clinical characteristics and mortality in S. aureus (SA) versus non-S. aureus (NSA) IE patients undergoing valvular surgery.

Methods:
All patients undergoing valvular surgery for bacterial IE between 1995 and 2013 at our institution were included in this study. Clinical data were retrospectively collected from chart review. Patients were categorized according to causative organism: 1) SA: n=85, and 2) NSA: n=238, composed of coagulase-negative staphylococci (23%), streptococci (12% viridans; 19% non-viridans), enterococci (17%), and other (51%).

Results:
SA patients had a higher severity of illness compared to NSA patients due to higher rates of preoperative vascular complications (58.8% vs. 39.4%, p = 0.002), preoperative septic shock (23.5% vs. 13.9%, p = 0.039), preoperative embolic events (33.3% vs. 20.7%, p = 0.02), preoperative stroke (27.1% vs. 13.5%, p = 0.004), and annular abscess (44.7% vs. 27.3%, p = 0.003). There were no statistically significant differences in 30-day (9.4% vs. 8.0%, p = 0.68, OR = 1.20) or 1-year (20% vs. 14.3%, p = 0.22, OR = 1.50) post-operative mortality between SA and NSA IE patients, respectively. However, length of hospital stay, and 30-day post-operative development of new renal failure were higher in SA patients. There was a trend to more post-operative embolic events in SA patients.

Conclusions:
SA IE is associated with higher morbidity on presentation, such as pre-operative embolic events, stroke and annular abscess, compared to IE caused by other bacterial organisms, but does not lead to increased mortality after surgery. Further research is needed to investigate the differences in post-operative complications among patients.
Abstract 18890: An
MYH7
Mutation Causes Inherited Left Ventricular Noncompaction and Sudden Death in a Large Multigenerational Family
Authors: Morgan Gina M , Gutmann Rebecca , Klappa Anthony J , Zhu Xiaodong , Ahmad Ferhaan , Mehdi Haider , London Barry
Published: July 2021

Introduction:
Mutations in
MYH7
, encoding the cardiac β-myosin heavy chain, cause hypertrophic (HCM) and dilated cardiomyopathy (DCM). Recently, several mutations in
MYH7
were reported in patients with left ventricular noncompaction (LVNC), a rare cardiomyopathy characterized by increased trabeculation and sudden death (SCD). No large families with inherited LVNC caused by
MYH7
mutations have been reported.

Methods:
We identified a large family with LVNC and SCD (Pedigree). The proband is a 56 yo woman who presented at age 48 with heart failure, LVNC and a depressed ejection fraction (EF) by echocardiogram (TTE) and cardiac MRI (cMR). Medical records and blood samples were obtained from 20 adult family members, 8 clinically affected (6 LVNC; 2 DCM). DNA was isolated (PureGene), clinical genetic testing for known DCM/LVNC genes was performed on the proband’s affected daughter (GeneDx), and the mutation was identified in family members by direct sequencing. ECGs, TTEs, and cMRs were analyzed to determine PR/QRS/QTc intervals and EF; mutation carriers were compared to non-carriers in the family.

Results:
A heterozygous missense mutation in a hydrophobic coil in the myosin head was identified in exon 14 of
MYH7
(c.1400 T>C; p.Ile467Thr). This mutation was present in all 8 affected members, in 1 clinically unaffected obligate carrier, and in 1 symptomatic subject who had not undergone cardiac testing (penetrance ≥ 0.80). Three obligate carriers suffered SCD. Compared to noncarriers, the EF of mutation carriers was decreased (42 ± 13%, n=9, vs. 58 ±3%, n=4; p=0.03), the PR was borderline long (171 ± 33 vs. 149 ± 12 ms, n=10 each; p=0.06) and the QTc was prolonged (428 ± 32 vs. 405 ± 18 ms, n=10 each; p=0.05).

Conclusion:
The Ile467Thr mutation in
MYH7
causes inherited LVNC with high penetrance and SCD in a large family. Future studies are warranted to differentiate the mechanisms leading from this mutation to LVNC as contrasted with those leading from other
MYH7
mutations to HCM and DCM.
Abstract 18907: Relationships Between Renal Haemodynamics With Cardiac and Aortic Haemodynamics in the Early Stages of Essential Hypertension
Authors: Kintis Konstantinos , Tsioufis Costas , Mazaraki Anastasia , Koutra Evaggelia , Nikolopoulou Lefki , Kasiakogias Alexandros , Andrikou Ioannis , Thomopoulos Costas , Makris Thomas , Stefanadis Christodoulos
Published: July 2021

Introduction:
The relationship of renal haemodynamics with cardiac and aortic hameodynamics is still unclear.

Hypothesis:
We evaluated the relationship of increased renal resistive index (RRI) with Augmentation index (AIx) and cardiac haemodynamics by means of mitral annular early diastolic velocity (E/Ea) in untreated patients with essential hypertension.

Methods:
76 newly diagnosed untreated non diabetic patients with stage I-II essential hypertension [35 males, aged 50 years, office blood pressure (BP) = 143/ 91 mm Hg], underwent ABPM, complete echocardiographic study for determination of E/Ea and blood sampling for assessment of metabolic profile. Moreover, data on renal resistive index (RRI), obtained by Doppler ultrasound sampling of the intrarenal arteries, as well as augmentation index (AIx), were retrospectively analyzed.

Results:
Based on the mean value of RRI (0.60), hypertensives were classified into those with high and low RRI. Hypertensives with high RRI values compared to those with low values were older (55.6±9.8 vs 44.4±11.6 years, p < 0.001), had lower 24-hour diastolic BP (77.5±7.7 vs 84.3±6.7 mmHg, p < 0.001), lower 24-hour HR (71.2±10.3 vs 76.2±9.2 bpm, p < 0.05), higher levels of AIx (27.2±8.2 vs 17.8±14.8 %, p < 0.01), and higher values of E/Ea (lateral) (7.7±1.8 vs 6.2±2.3, p < 0.05). In the total population, RRI was negatively related to 24-hour diastolic BP (r = -0.523, p < 0.001) and 24-hour HR (r = -0.281, p < 0.05), while it was positively associated with CRP (r = 0.335, p < 0.05), TChol (r = 0.296, p < 0.01), age (r = 0.443, r < 0.001), AIx (r = 0.413, p = 0.001) and E/Ea(lateral) (r = 0.465, p < 0.05). Multiple regression analysis revealed that 24-hour diastolic BP and E/Ea (lateral) were independent associated with RRI (R2 = 0.434, p < 0.05).

Conclusions:
Increased vascular resistance of intrarenal arteries is associated with impaired aortic and cardiac haemodynamics, as reflected by increased AIx and E/Ea (lateral) values. RRI may be considered a useful surrogate of haemodynamics in essential hypertension.
Abstract 18946: A Complex Cardiac Rhythm and Conduction Abnormalities in Three Families Carrying a SCN5A Missense Mutation May Involve Single Nucleotide Polymorphisms in SCN5A and RYR2 genes
Authors: Antunez-Arguelles Erika , Medeiros-Domingo Argelia , Villarreal Teresa , Hernandez Jonathan J , Iturralde Pedro , Valdivia Hector H , Makielski Jonathan C , Valdivia Carmen R
Published: July 2021

Background:
Mutations in the gene encoding the cardiac sodium channel (SCN5A) have been implicated in arrhythmia syndromes including Brugada (BrS) and long-QT type 3 syndromes. Also, wide spectrums of mixed phenotypes, known as “overlap syndromes”, have been associated to SCN5A mutations. The contributions of single nucleotide polymorphisms (SNPs) add more complexity to the disease phenotype. Here we report a missense mutation in SCN5A (T1708N) in three Hispanic families with history of sudden cardiac death (SCD) and extensive variability and severity of symptoms, including syncope, atrial and ventricular tachycardia, and conduction abnormalities.

Methods and Results:
We used the Ion Torrent platform and AmpliSeq panel to sequence 19 genes associated with arrhythmia syndromes. In addition to SCN5A-T1708N mutation, the patients carry two common SNPs, SCN5A-H558R and the cardiac ryanodine receptor RYR2-Q2958R, which we previously reported to be highly prevalent (~30%) in Hispanics and to increase the risk of SCD in homozygous individuals. To study the functional properties of SCN5A-T1708N, the mutation was engineered by site-directed mutagenesis into SCN5A with or without the SCN5A-H558R and expressed in HEK cells for voltage clamp experiments. SCN5A-T1708N showed a significant increase of late INa compared to WT. Also, the kinetic properties of SCN5A-T1708N showed slower time constants of recovery and increase in slow inactivation, which would tend to reduce INa; these effects were not modified by the presence of SCN5A-H558R. On the other hand, INa density for SCN5A-T1708N was reduced compared to WT (289± 63 and 387± 62 pA/pF, respectively), yet, for the double mutant H558R-T1708N, INa was more severely depressed (145± 32 pA/pF).

Conclusion:
The profound biophysical phenotype of T1708N with loss and gain of function could account for the variability and the severity of the clinical phenotype in these families. The RYR2-Q2958R polymorphism may function as a pro-arrhythmic genetic modifier and it is conceivable that it may predispose to SCD in some members of these families. The study of these polymorphisms in large cohorts may identify common haplotypes associated to cardiac arrhythmias and facilitate identification of patients at high risk for SCD.
Abstract 18972: Iron Quantification in Carotid Artery Atherosclerosis Predicts Downstream Injury by Magnetic Resonance Imaging
Authors: Sharkey-Toppen Travis P , Tran Tam , Smart Suzanne , McCarthy Beth , Nguyen Xuan , Raman Subha V
Published: July 2021

Introduction:
Luminal stenosis is the primary imaging parameter used to guide management of patients with carotid artery atherosclerosis (CAA). However, neuroimaging identifies subclinical events in patients with CAA not meeting anatomic guidelines for intervention. Strategies to characterize atherosclerotic plaque beyond %stenosis may help reduce the downstream ischemic burden of atherosclerotic disease.

Hypothesis:
Using noncontrast MRI T2* tissue mapping that we have previously validated for plaque iron characterization, we tested the hypothesis that carotid plaque T2* better predicts ischemic injury by brain MRI than symptom history.

Methods:
We enrolled 26 individuals with carotid artery stenosis ≥50%. Each subject underwent MRI that included carotid plaque T2* mapping (TR=75ms, 5 TEs, 20° flip angle, 0.44x0.44x2mm resolution), brain diffusion weighted imaging (TR=4436ms, TE=93ms, 0.9x0.9x3mm resolution) and brain fluid attenuated inverse recovery imaging (TR=13970ms, TE=2500ms, 150° flip angle, and 0.9x0.9x3mm resolution). Plaque T2* quantification and brain MRI were independently assessed by experienced observers blinded to patient history and other results. Brain MRIs with Wahlund score ≥2 were classified as positive for ischemic damage.

Results:
Patients with brain imaging positive for ischemic damage had shorter intraplaque T2* compared to patients with negative brain MRI (17.2±2.9 vs. 20.3±3.2ms, p=.012, Figure). Conversely, presence/absence of brain injury did not correlate with symptoms (p=.352).

Conclusions:
Noncontrast atherosclerosis imaging using an MRI biomarker of intraplaque iron in patients with carotid artery disease can discriminate between patients with vs. those without ischemic brain injury. Prospective studies that couple plaque characterization with anatomic and clinical factors may better identify at-risk patients with carotid artery disease before significant ischemic brain injury has accrued.
Abstract 19026: Libman-sacks Endocarditis: Can It Be Clinically Predicted?
Authors: Macias Leonardo , Snider Richard , Ratliff Michelle , Roldan Paola , Rodriguez Rodrigo , Qualls Clifford , Sibbitt Wilmer , Roldan Carlos A
Published: July 2021

Background:
Libman-Sacks endocarditis, characterized by Libman-Sacks vegetations (LSV), is common in patients with systemic lupus erythematosus (SLE) and is a strong predictor of stroke and transient ischemic attacks (TIA), cognitive dysfunction, and increased

mortality. Accurate detection of LSV may lead to early therapy and prevention of development or progression of embolic cerebrovascular disease. TEE is accurate for detecting LSV, but is semi-invasive. Thus, there is a need for identifying clinical variables with a high predictive value for LSV on TEE.

Methods:
76 SLE patients (69 women, 38 ± 12 years old) and 26 age-and sex-matched healthy controls underwent TEE and assessment of demographics, atherogenic risk factors, and parameters of inflammation,

platelet activity, coagulation, and fibrinolysis. Patients were also assessed for SLE duration, activity, injury, therapy, and autoantibodies including antiphospholipid antibodies. Multivariate regression and optimal receiver operator curve by Neyman-Pearson lemma were used to determine the best clinical predictors of LSV on TEE.

Results:
39 (51%) SLE patients vs 2 (8%) controls had LSV on TEE (p<0.001). In all 76 patients, acute stroke/TIA (OR 50.6, 95% CI = 6.8 - 374, p <0.001) and SLE duration (OR = 1.18, 95% CI = 1.05 - 1.32, p = 0.004) were the predictors of LSV. In 53 patients without acute stroke/TIA, SLE duration (OR = 1.16, CI =1.03 - 1.31, p = 0.01) and age (OR = 1.06, CI = 1.0 - 1.12, p = 0.05) were the predictors of LSV. A recruitment rule of performing TEE in SLE patients with acute stroke/TIA and in those without stroke/TIA if they have a disease duration of ≥12 years or a disease duration ≥5 years and age ≥32 provide high sensitivity (85%), specificity (81%), and positive (83%) and negative (83%) predictive values for

LSV on TEE (
Figure 1
).

Conclusion:
In SLE patients, acute stroke/TIA, or SLE duration ≥12 years, or SLE duration ≥5 years and age ≥32 provide a high diagnostic yield for detecting LSV on TEE.
Abstract 19080: Risk Stratification in Arch Surgery: When High Risk is Too High? Implications for Open or Endovascular Repair From a 15-Years Survey on Over 350 Patients
Authors: Iafrancesco Mauro , Ranasinghe Aaron M , Dronavalli Vamsidhar , Adam Donald J , Claridge Martin W , Riley Peter J , McCafferty Ian J , Pagano Domenico , Mascaro Jorge ,   Thoracic Aorta Multidisciplinary Team
Published: July 2021

Introduction:
At present, there are not risk scoring tools to predict in-hospital mortality for total aortic arch replacement (TAR),

Hypothesis:
To assess if Logistic Euroscore (LogES) is a useful tool for risk assessment in aortic arch surgery and which other operative factors may help to better identify high-risk patients.

Methods:
All patients who underwent open arch procedure between 1998 and 2013 were identified from our prospectively collected database which include 93 preoperative variables.

Results:
Three-hundred-fifty-seven open arch procedures were identified. Two-hundred-forty-two patients underwent TAR, 199 with conventional technique and 43 with frozen elephant trunk (FET) technique. Patients with higher LogES had higher in-hospital mortality (see table 1). Patient with a LogEs <20, 20-60 and >60 were classified as low-, high- or very high-risk, respectively. Complexity of surgery, defined as need for aortic root replacement (ARR) and/or mitral valve repair/replacement (MVR), increased significantly the risk of operation (27% vs. 4.2%, p:0.004) only in conventional TAR in high-risk patients. Low-risk patients were associated with low mortality regardless the extent of surgery whilst very high risk-patients had a high-risk of death even with simple operations. Mortality risk in FET was not increased by need for ARR/MVR. Rate of permanent neurological deficit remained low in all category of patients. Spinal cord injury (SCI) did not occur in any conventional TAR.

Conclusions:
Open surgery should remain the treatment of choice for patients with low/moderate LogES and high LogES without need for ARR/MVR. Patient with very-high LogES who do not need ARR/MVR should be consider for endovascular repair. Patient with high and very-high LogES and need for ARR/MVR cannot undergo endovascular treatment and remain a significant challenge. FET remains a procedure with an increase risk of death and SCI.
Abstract 19128: Acute Changes in Left Ventricular Contractility Following Mitraclip Implantation Depend on Left Atrial Volume
Authors: Dahlem Kristina M , Winkelmann Julia , Huntgeburth Michael , ten Freyhaus Henrik , Pfister Roman , Baldus Stephan , Rudolph Volker
Published: July 2021

Background:
The acute hemodynamic changes following elimination of mitral regurgitation is a much discussed issue, particularly in patients with severely compromised left ventricular function where the incompetent mitral valve was regarded as a pop-off valve. Herein, we investigated the acute changes of ventricular contractility in relation to left atrial volume.

Methods and results:
Echocardiographic left atrial and left ventricular longitudinal strain measurements before and 3 days after the procedure were performed in 19 patients (mean age: 77.9±7.9, 47% female, 73,7% functional mitral valve regurgitation, 26,3% degenerative mitral valve regurgitation) undergoing MitraClip implantation at our institution. Procedural success with reduction in MR to grade 2+ or less was achieved in all patients. Overall there was no significant change in left atrial or ventricular global or regional longitudinal strain after the procedure. However, a strong correlation was observed between worsening in left ventricular strain and left atrial volume (r: -0.72, p<0.01), i.e. there was a greater reduction in left ventricular contractility after clip implantation in patients with larger left atrial volumes. Multivariate, linear regression analyses revealed that left atrial volume predicted the change of left ventricular longitudinal strain following MitraClip implantation (r2: -0.07, p<0.01) independently of left ventricular ejection fraction (r2: -0.05, p=0.40), mitral regurgitant volume (r2: -0.09, p=0.09) and left atrial strain (r2: -0.03, p=0.85).

Discussion:
Our data suggest that enlarged left atria act as a low-resistance reservoir in mitral regurgitation. As a consequence elimination of mitral regurgitation in these patients leads to worsening of left ventricular contractility whereas in smaller atria left ventricular contractility is not negatively affected by elimination of MR.
Abstract 19203: A Case of New Supraventricular Tachycardia During Pregnancy, With the Development of Post-partum Eclampsia, Torsades De Pointes, and Long Qt Syndrome: Is There a Connection?
Authors: Rambhatla Tarak , Kodra Arber , Levine Evan , Mountantonakis Stavros , Bhasin Kabir , Skipitaris Nicholas
Published: July 2021

Background:
There is a mechanistic link between QT prolongation and the development of TdP. Women with LQTS have an increased risk of serious cardiac arrhythmias during the postpartum period,however,there is limited data on the effects of pregnancy on those without a prolonged QT prior to delivery.

Case Description:
The patient is a 22 y/o female with no history of arrhythmia.During pregnancy she had three episodes of SVT,each prompting hospital admissions.ECG showed a heart rate of 148-163bpm,a QTc of 390 to 410ms,and laboratory data a magnesium level of 1.6.On day 3 after a scheduled cesarean section, she suffered a eclamptic seizure and then a Tdp induced cardiac arrest.Magnesium was immediately given.CPR was performed for 31 minutes until return of spontaneous circulation was achieved.The patient had an extended ICU course but was eventually discharged home with her newborn twins,a subcutaneous implantable cardiac defibrillator (S-ICD),multiple postpartum ECGs showing QTc of 493 to 524ms,and a diagnosis of LQTS.

Discussion:
Pregnancy increases or precipitate cardiac arrhythmias not previously present in otherwise healthy females. In women with LQTS, there have been studies that have shown significant increases in arrhythmias and SCD during the 9 months postpartum.Also recognized are silent forms of congenital LQTS in which patients are arrhythmia free until exposed to a precipitant.5-10% of patients who develop drug-induced TdP are silent carriers of gene mutations related to LQTS, suggesting a “second hit” can uncover the LQTS phenotype despite a “normal” QTc in the unprovoked state. This emphasizes the importance of other potential ‘hits’ that can uncover a LQTS, particularly relevant to this case, the postpartum period.To our knowledge,this is the first case of a simultaneously occurring eclamptic seizure and TdP induced cardiac arrest both successfully treated with IV magnesium.This is also the first report,to our knowledge,of multiple episodes of SVT occurring during pregnancy in a patient who subsequently developed postpartum eclampsia,TdP,SVT,and LQTS. Further studies are needed to identify patients at high risk for postpartum induced LQTS/TdP and if SVT during pregnancy is a risk factor, as well as twin births and Cesarian deliveries.
Abstract 19204: Symptoms of Depression and Posttraumatic Stress Disorder are Associated with Differential Autonomic Influences to Standing
Authors: Shah Amit J , Alkhoder Ayman , Obideen Malik , Ramadan Ronnie , Wilmot Kobina , Al Mheid Ibhar , Kutner Michael , Quyyumi Arshed A , Bremner J. Douglas , Vaccarino Viola
Published: July 2021

Introduction:
Depression and posttraumatic stress disorder (PTSD) are associated with impaired baroreflex sensitivity, a risk factor for sudden death. Unlike depression, PTSD is associated with hyperarousal. We hypothesized that, in patients with CAD, depressive and PTSD symptoms associate with different autonomic responses to standing (baroreflex response).

Methods:
We examined 178 patients with CAD for autonomic dysfunction with the ANSAR test (ANX 3.0, ANSAR Inc. Philadelphia, PA) in which heart rate variability was measured in both sitting (5 minutes) and standing (5 minutes) positions. Sympathetic (SNS) and parasympathetic (PNS) nervous system activity was measured using continuous wavelet transform and log-transformed. PTSD symptoms were assessed using the PTSD checklist scale (PCL), and depressive symptoms were assessed using the Beck Depression Inventory-II (BDI). Both BDI and PCL were examined in multivariate models simultaneously, adjusting for CAD risk factors, beta blockers, and antidepressants.

Results:
The mean (SD) age, BDI, and PCL scores were 62.4 (9.1), 7.2 (7.6), and 26.2 (10.2), respectively. For the group as a whole, the mean baseline SNS and PNS tones were -0.49 and -0.60 log beats per minute squared (log BPM
2
). In multivariable models, PCL score associated with higher baseline SNS tone (β=0.03, p=0.046). With standing, PCL score associated with decrease in the levels of SNS tone (β=-0.02, p=0.02) vs. sitting, and BDI associated with an increased PNS tone (β=0.03, p=0.03) vs. sitting. In both cases, these responses are the opposite of the expected autonomic response to standing, which is an increase in SNS tone and decrease in PNS tone vs. sitting.

Conclusion:
Depressive and PTSD symptoms have opposite autonomic pathologies in CAD patients. While PTSD symptoms are associated with higher SNS tone at baseline, they are also associated with lower sympathetic activation with standing. Depressive symptoms, on the other hand, are associated with reduced vagal withdrawal with standing. This suggests that both depressive and PTSD symptoms are associated with an abnormal baroreceptor function, but through different autonomic pathways.
Abstract 19210: Remote Ischemic Conditioning, Applied During Recurrent Coronary Thrombosis Mimicking Unstable Angina, Improves Coronary Patency
Authors: Przyklenk Karin , Whittaker Peter
Published: July 2021

Evidence from our group revealed that the benefits of preconditioning ischemia extend beyond infarct size reduction via up-regulation of cardioprotective signaling. We found that brief antecedent ischemia: i) attenuates molecular indices of platelet activation-aggregation (i.e., P-selectin expression, fibrinogen binding); and thus ii) improves arterial patency in models mimicking unstable angina. However, two issues limit potential translation of this endogenous anti-platelet effect: the conditioning stimulus was applied

directly

to the heart, as a

pretreatment

. Our current aim was to establish whether brief ischemia applied at a

remote

site (skeletal muscle),

after

the onset of recurrent coronary thrombosis, would improve subsequent coronary patency.

Methods:
Recurrent platelet-mediated coronary thrombosis was initiated in anesthetized dogs by application of a stenosis at a site of vessel injury. At 1 h after injury + stenosis, dogs received: i) remote ischemic conditioning (RIC: 4 5-min episodes of bilateral hindlimb ischemia); or ii) a time-matched sham-control period. Coronary blood flow was monitored throughout the 1 h before treatment and for 2 h after the RIC/sham stimulus. Primary endpoints were: i) area of the flow-time profile (index of coronary patency, expressed as % of baseline flow); and ii) % duration of total thrombotic occlusion (flow=0).

Results:
Both groups displayed poor coronary patency during the 1 h pretreat period: flow-time area averaged 31-32%, and duration of total thrombotic occlusion was 19-25%. Patency remained unchanged in controls throughout the protocol. In contrast, RIC evoked an immediate attenuation of recurrent thrombosis: flow-time area was increased to 63±10% (p<0.01) and duration of total occlusion was reduced to 4% (p=0.11).

Conclusion:
Remote ischemic conditioning, applied

during

episodes of recurrent platelet-mediated thrombosis mimicking unstable angina, improves subsequent coronary patency.