bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13015: Cardiac Tamponade as a Rare Presentation of Chronic Lymphocytic Leukemia
Authors: Abdul Ghaffar Yasir , Haider Imran , Salih Mohsin F , Musunuru Teijo N
Published: July 2021

An 89 year old male with a past medical history of CAD , diastolic HFpEF, HTN, HLD, DM, sick sinus syndrome with permanent pacemaker, OSA presented to the office with complaints of fatigue and progressive exertional dyspnea for 2 weeks. On examination his BP was 86/61mm Hg with a systolic drop of 20mmhg during inspiration by palpatory method, RR was 24 breaths/min, HR was 64 bpm, O2 sat. was 85% on RA. JVP was raised at 15cm. Cardiopulmonary examination revealed distant heart sounds, bibasilar crepitations and mild bilateral pedal eema. No lymphadenopathy was palpable. Initial lab assessment showed Hb of 9.5gdl, WBCs of 14.3 K/ul, potassium of 6.2mmol/, increased BUN/Creatinine ratio of 67/1.7, LDH of 642 U/L, Troponin I of 0.04ng/ml and BNP of 338pg/ml. EKG demonstrated av-paced rhythm without any evidence of electrical alternans or low voltage. CXR showed significant cardiomegaly. Transthoracic echocardiogram revealed normal LV cavity size, wall thickness and systolic function. A large pericardial effusion with early right ventricular diastolic collapse suggesting tamponade. The patient underwent emergent closed pericardiocentesis with complete resolution of symptoms. . Pericardial fluid analysis showed glucose of 78mg/dl, protein of 4.2g/dl, PH of 7.21, LDH of 1913 U/L, 1195000/uL RBCs, 212427/uL nucleated cells(Differential count N 3%, L 93%, M 2%, E 2% and B 0). Cytology was positive for PAX-5, CD-5 and negative for Cyclin-D1 & CD-10 which was consistent with CLL. The patient was evaluated by the oncologist and he was started on rituximab and bendamustine. Follow up echocardiograms did not show any recurrence of effusion. The presence of pulsus paradouxs with other signs including hypotension, muffled heart sounds and raised jugular venous pressure greatly increases its sensitivity for cardiac tamponade which was evident in this case. Our case is unique because cardiac tamponade is rarely reported as an initial presentation of Chronic Lymphocytic Leukemia.
Abstract 13022: Second-generation versus First-generation Drug-eluting Stents in Patients With Calcified Coronary Lesions: Pooled Analysis From the RESET and NEXT Trials
Authors: Nishida Koji , Nakatsuma Kenji , Shiomi Hiroki , Kawai Kazuya , Hamashige Naohisa , Morimoto Takeshi , Kimura Takeshi
Published: July 2021

Background:
The impact of second-generation drug-eluting stents (G2-DES) implantation as compared with first-generation drug-eluting stents (G1-DES) for calcified coronary lesion has not been yet adequately addressed.

Methods:
This pooled analysis compared 2-year clinical outcomes between G1- and G2-DES according to the presence or absence of coronary lesion calcification, using individual patient-level data from 2 large-scale prospective multicenter randomized trials, RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) and NEXT (Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent). Among 4583 patients enrolled in the 2 trials, G1-DES (sirolimus-eluting stent) and G2-DES (everolimus- or biolimus-eluting stent) were used in 299 and 1033 patients, respectively, in the Calc stratum (at least 1 moderate to severe calcification), and 1208 and 3550 patients, respectively, in the Non-calc stratum (no or mild calcification). Coronary calcification was assessed by an independent angiographic core laboratory. The primary endpoint of the study was clinically driven target-lesion revascularization (TLR) at 2-year follow-up.

Result:
In the Calc stratum, the cumulative incidence of clinically driven TLR was significantly lower in G2-DES than in G1-DES (5.7% vs. 9.4%, P=0.03), while it was not significantly different between G1- and G2-DES in the Non-calc stratum (3.6% vs. 4.2%, P=0.35). Cumulative incidence of definite stent thrombosis was not significantly different between G1- and G2-DES in both strata (Calc stratum, 0.6% vs. 1.0%, P=0.44, and Non-calc stratum, 0.2% vs. 0.2%, P=0.98). After adjusting for confounders, the lower risk of G2-DES relative to G1-DES for clinically driven TLR remained significant in the Calc stratum (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35-0.87; P=0.01). There was significant interaction between the generation of DES and presence or absence of calcification (P interaction=0.01).

Conclusion:
G2-DES as compared with G1-DES was associated with lower risk for clinically driven TLR in patients with calcified coronary lesions.
Abstract 13025: Deficiency of Interleukin-1 Receptor Antagonist Promotes Angiotensin II-induced Aortic Inflammation and Aneurysm
Authors: Akita Koji , Isoda Kikuo , Isobe Sarasa , Niida Tomiharu , Daida Hiroyuki
Published: July 2021

Introduction:
Angiotensin II (AngII) increases arterial pressure and induces inflammation. Although interleukin-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines, the role of IL-1Ra in AngII-induced aortic inflammation and aneurysm remains unknown.

Methods and Results:
To determine the contrition of IL-1Ra to AngII-induced aortic inflammation, male wild-type (WT) (n=18) and IL-1Ra-deficient (IL-1Ra-/-) (n=18) mice were infused with AngII (3000ng/kg per minute) using subcutaneous osmotic pumps for 28 days. 7 days after infusion, real-time PCR of abdominal aorta in IL-1Ra-/- mice revealed significantly increased mRNA levels of IL-6 (2.1-fold, p<0.01), TNF-α (4.1-fold, p<0.01), and MMP-9 (20.3-fold, p<0.05) compared with WT mice. 14 days after infusion, both systolic blood pressure (178±21 vs 135±21 mmHg, p<0.01)and abdominal aortic width (1.02±0.12 vs 0.82±0.05 mm, p<0.01) in IL-1Ra-/- mice significantly increased compared with WT mice. Moreover, AngII infusion into IL-1Ra-/- mice also led to a significant increased occurrence of fatal aortic rupture (IL-1Ra-/-: 89% vs WT: 6%, p<0.01). Next, WT (n=6) and IL-1Ra-/- (n=6) mice were infuse with AngII for only 14 days, and histological analyses were performed at 28 days after operation. Interestingly, the abdominal aortic width in IL-1Ra-/- mice more significantly increased than those in WT mice (1.57±0.34 vs 0.80±0.04 mm, p<0.01), although IL-1Ra-/- and WT mice did not differ with regard to systolic blood pressure (105±15 vs 109±13 mmHg, p=0.61) at 28 days after operation. Histological analyses revealed there were numerous inflammatory cells around the abdominal aorta in IL-1Ra-/- mice, but not in WT mice. Furthermore, elastin staining showed destruction of the elastic lamina of abdominal aorta in IL-1Ra-/- mice. TNF-α protein expression also increased significantly in IL-1Ra-/- mice compared to WT mice at 28days.

Conclusions:
The present study shows that IL-1Ra deficiency in mice led to increase inflammation and the development of aortic aneurysm after AngII infusion. Furthermore, our results also showed IL-1Ra deficiency continued the AngII-induced inflammation even though blood pressure was improved after cessation of AngII infusion.
Abstract 13060: Abrogation of miR-195 Improves Function in Aged Heart by Preventing Telomere Shortening and Mitochondrial Dysfunction
Authors: Okada Motoi , Kim HaWon , Ashraf Muhammad , Kawabe Jun-ichi , Hasebe Naoyuki
Published: July 2021

Background:
Recently, we discovered a distinct microRNAs profile in young and old MSCs by microarray which led us to hypothesize that senescence-associated microRNA(miR)-195 plays a critical role in stem cell aging through telomerase reverse transcriptase (tert) deactivation and determined whether direct inhibition of miR-195 in aged myocardium restores juvenile characteristics and improves cardiac function.

Methods and Results:
To examine the mechanistic participation of miR-195 in cardiac aging and function, we directly injected lentivral miR-195 inhibitor into the normal mice heart through open chest surgery. Interestingly, we observed a significant telomere re-lengthening in myocardium injected with anti-miR-195 as examined by Q-FISH analysis. In addition, heart tissues treated with miR-195 inhibitor markedly restored the expression of anti-aging factors such as Tert, telomeric repeat-binding factor 2 (Trf2) and Sirt1, whereas expression of pro-aging markers including p53 and p16 were reduced. Additionally, we found that mitochondrial activity was significantly improved in miR-195 knocked down heart as examined by cytochrome c oxidase activity assay. To investigate whether abrogation of miR-195 in myocardium improves cardiac function, we performed echocardiography at 4 weeks after injection. The cardiac function was markedly improved in miR-195 knocked down myocardium as evaluated by cardiac performance index, a useful marker for heart failure (0.24±0.05 vs 0.44±0.13, p<0.05, n=6), whereas there was no significant change in systolic function . Furthermore, histological analysis showed that transfection of miR-195 inhibitor markedly reduced fibrosis as well as expression of connective tissue growth factor (CTGF), a fibrogenic master switch, in the aged myocardium as compared to scramble transfected heart.

Conclusions:
These results demonstrate that abrogation of miR-195 improves cardiac function through restoration of anti-aging factors as well as amelioration of mitochondrial dysfunction. Suppression of miR-195 in aging myocardium is a novel therapeutic strategy for treatment against age-dependent cardiovascular diseases.
Abstract 13172: Gender Differences in Impact of Vascular Endothelial Dysfunction or CYP2C19 Polymorphism on Clinical Outcome Following Coronary Stenting in Patients with Coronary Heart Disease
Authors: Hokimoto Seiji , Akasaka Tmonori , Tabata Noriaki , Arima Yuichiro , Kaikita Koichi , Nakagawa Kazuko , Ogawa Hisao
Published: July 2021

Background:
Vascular endothelial dysfunction and CYP2C19 polymorphism are associated with increased risk of cardiovascular event in patients with coronary heart disease (CHD). The aim was to examine the gender differences in vascular endothelial dysfunction or CYP2C19 genotype on clinical outcomes following stent implantation.

Methods:
We enrolled 600 patients following stent implantation, taking dual antiplatelet therapy. Patients were divided into male (n=426) and female (n=174) groups. Platelet reactivity (PR) by a light transmission aggregometry, reactive hyperemia index (RHI) using reactive hyperemia peripheral arterial tonometry as an index of endothelial dysfunction, and CYP2C19 polymorphism were examined. CYP2C19 genotype was classified into carrier (at least one CYP2C19 loss-of function allele carriage) and non-carrier. Cardiovascular event (cardiovascular death, myocardial infarction (MI), stroke, unstable angina, revascularization, intraprocedural thrombotic event and heart failure) was assessed according to male or female over 18 months follow-up.

Results:
There were no significant differences in distribution of CYP2C19 carrier and non-carrier (78.9 vs. 64.3%, P=0.126), PR (4474 vs. 4223 AU*min, P=0.485) and clinical outcomes (17.8 vs. 16.7%, P=0.731) between male and female. In male group alone, the incidence of cardiovascular event was significantly associated with CYP2C19 carrier, renal failure, high PR, previous MI, and peripheral artery disease. While in female group alone, low RHI was significant (0.47 vs. 0.61, P=0.015). Multivariate analysis identified CYP2C19 carrier (HR, 1.908, 95% CI, 1.043-3.489; P=0.032), previous MI (HR, 1.918, 95% CI, 1.125-3.269, P=0.017), and peripheral artery disease (HR, 1.872, 95% CI, 1.079-3.247, P=0.026) as predictors of cardiovascular events in male group, while low RHI alone was a predictor in female (HR, 0.129, 95% CI, 0.021-0.811, P=0.029).

Conclusions:
The impact of CYP2C19 polymorphism on clinical outcome is more significant in male, not female, while effect of endothelial dysfunction is more significant in female, not male, respectively. There are gender differences in impact of CYP2C19 genotype or endothelial dysfunction on clinical outcome in CHD patients.
Abstract 13189: Clinical Presentation, Long-Term Follow-Up, and Disease Penetrance of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in 1001 Patients and Family Members
Authors: Groeneweg Judith A , Bhonsale Aditya , James Cynthia A , te Riele Anneline S , van der Heijden Jeroen F , Murray Brittney , Tichnell Crystall , Sawant Abhishek , Doevendans Pieter A , Tandri Harikrishna , van Tintelen J P , Judge Daniel P , van Veen Toon A , Dooijes Dennis , Wilde Arthur A , Hauer Richard N , Calkins Hugh
Published: July 2021

Introduction:
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is a hereditary progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic ARVD/C cohort of 1001 individuals.

Methods:
Clinical/genetic characteristics and follow-up data of ARVD/C index patients (n=439, fulfillment of 2010 criteria in all) and family members (n=562) were assessed. Genetic screening of desmosomal and TMEM43 and PLN genes was performed in index patients.

Results:
Mutations, predominantly in PKP2, were identified in 276/439 (63%). Index patients presented mostly with sustained ventricular arrhythmias (VA) (268/439, 61%). Recurrent sustained VA (in 301/416 (72%) patients presenting alive) characterized follow-up (median 7 years) with 10/63 (16%) sudden cardiac deaths (SCD) in patients without implantable cardioverter-defibrillators (ICDs) versus 2/335 (0.6%) in those with ICDs. Overall, cardiac mortality during follow-up (6%) and cardiac transplantation rate (4%) were low. Although disease onset was significantly earlier in index patients with mutations (first presentation 34 vs.38 years old, p<0.001), disease burden was similar in index patients with and without identified mutations. No phenotypic differences were found between index patients with familial and isolated ARVD/C. Of family members, 37% (207/562) had ARVD/C. Symptoms at presentation correlated with disease expression. Nonetheless, even 103/324 (32%) initially asymptomatic mutation-carrying family members, developed ARVD/C. Family members with mutations more often had ARVD/C (40 vs. 18%, p<0.001), sustained VA (11 vs. 1.3%, p<0.001), and cardiac death (2 vs. 0%) than those without.

Conclusions:
Long-term outcome in ARVD/C index patients was favorable when diagnosed and treated. Prognosis in family members was determined by symptoms and mutation status. One in three family members, including asymptomatic mutation carriers, developed ARVD/C.
Abstract 13233: Does Fetal Aortic Valvuloplasty alter the Natural History of Aortic Stenosis?
Authors: Kovacevic Alexander , Mellander Mats , Tulzer Gerald , Herberg Ulrike , Dangel Joanna , Öhman Annika , Gardiner Helena
Published: July 2021

Introduction:
Fetal aortic valvuloplasty (FV) is proposed as therapy to achieve biventricular circulation (BV) in fetuses where univentricular circulation (UV) is likely.

Hypothesis:
FV cannot alter natural history (NH) outcome.

Methods:
Hybrid of case-control and repeated samples cohort study. Fetuses with aortic stenosis (AS) were enrolled in a multicenter study (2005-2012). FV was considered in 70 / 214 AS and successful in 59/67 (88.0%) performed. Six salvage cases (hydrops) were excluded and 47 liveborn FV could be matched with 95 controls (NH) by scan closest to 23 +/- 3 weeks and +/- 1 Z-score for MV, LV and AV, producing a best match group for each.

Results:
Procedure-related death occurred in 7/67 (10.4%). Overall 151/214 (71%) were liveborn, but outcome unknown in 5. Serial left sided growth was similar in FV and NH: Z score differences MV = 0.11, LV = 0.08, AV = 0.11, p>0.90. Hazard ratio for FV survival was similar to NH at 30 d, 1 and 4 yrs after birth [0.68 (95% CI 0.347 - 1.315), p= 0.25]. Cohorts matched for MV, LV and AV did not show survival advantage after FV and survival with freedom from UV circulation showed fewer BV survivors in FV than NH. (Fig 1) Funnel plots show improved BV survival by center volume for FV, but more BV-UV conversions in one with limited surgical options where 17% vs 82% FV remain BV. (Fig 2)

Conclusions:
Data show no survival advantage or improved chance of BV at 4 years in fetuses matched for morphology at 23 wks undergoing FV. Centralization of FV may improve survival, but BV - UV conversion suggests a specialized surgical approach is also essential to maintain BV outcome. A carefully designed prospective study is indicated to better evaluate FV. procedure.
Abstract 13234: The Association Between Serum Potassium and Major Adverse Cardiovascular Events in Patients With Chronic Kidney Disease
Authors: Yang Alex , Luo Jiacong , Jensen Donna E , Brunelli Steven M
Published: July 2021

Introduction:
Patients with kidney disease often have high serum potassium (K) due to diminished excretory capacity.

Hypothesis:
We evaluated the association of high K with rates of arrhythmia and major adverse cardiovascular events (MACE; composite of myocardial infarction, stroke, heart failure, and arrhythmia).

Methods:
We studied a retrospective cohort of patients with eGFR <60 mL/min/1.73m
2
between Jan-2009 and Jun-2013 (N=55,266). Patients were followed until the end of study (30-Jun-2013), death, end-stage renal disease, or transfer of care. Serum K, eGFR, and 13 covariates including demographics, prevalent comorbidities, and medication use (beta blockers, centrally acting calcium channel blockers, and loop and thiazide diuretics) were considered on a time-varying basis, updated for each K measurement.

Results:
At baseline, 15%, 4%, and 1% of patients had serum K 5.0-5.4, 5.5-5.9, and ≥6.0 mEq/L, respectively. Prevalence was greater in lower eGFR strata. Within each eGFR stratum serum K demonstrated U-shaped associations with rates of MACE and arrhythmia, displayed for eGFR <30 mL/min/1.73m
2
. Compared to K 4.5-4.9 mEq/L, incidence rate ratios (IRRs) of MACE for K ≥6.0 mEq/L were 2.11 [95%CI, 1.68-2.65], 1.44 [1.12-1.84], 1.56 [1.11-2.17], and 2.11 [1.53-2.89] in the eGFR <30, 30-39, 40-49, and 50-59 strata, respectively. K ≥6.0 mEq/L was associated with increased rate of arrhythmia in the lowest eGFR stratum (Figure); point estimates in other eGFR strata ranged from 1.39 to 1.53, but were not significant.

Conclusions:
K ≥6.0 mEq/L is associated with increased risk of MACE among patients with eGFR <60 mL/min/1.73m
2
and with arrhythmia among patients with eGFR <30 mL/min/1.73m
2
. Renal impairment should be considered when determining serum K targets with respect to cardiovascular risk.
Abstract 13243: Diminished Daily Fluctuation of Heart Rate Variability in Patients with Chronic Kidney Disease
Authors: Makimoto Hisaki , Fujiu Katsuhito , Shimizu Kohei , Amiya Eisuke , Asada Kazuo , Kojima Toshiya , Daimon Masao , Meyer Christian , Komuro Issei
Published: July 2021

Introduction:
Autonomic dysfunction is well known in patients with chronic kidney disease (CKD) and linked with cardiac death. In spite of a high incidence of morning death in CKD patients, circadian fluctuation in parasympathetic activation have not been studied in CKD.

Hypothesis:
We assessed the hypothesis that the cardiac autonomic circadian fluctuation is impaired in patients with CKD.

Methods:
The study population consisted of consecutive 101 patients (54 males, 70±10 years old) with CKD who underwent 24-hour Holter monitor. As a control group, 134 age and sex matched cases (66 males, 68±10 years old) without CKD who also underwent Holter monitor were recruited. Patients with diabetes orβ-blocker therapy were excluded. The high frequency component (HF), which reflected parasympathetic activity, and the low frequency to high frequency ratio (L/H ratio), which reflected, in part, sympathetic activity, were evaluated. To evaluate the contribution of CKD and other parameters to the cardiac autonomic fluctuation, the night (6PM-6AM) to day (6AM-6PM) ratio of HF and L/H ratio were analyzed utilizing a regression analysis.

Results:
The L/H ratio showed no significant difference during the night between the two groups, in contrast to the significant difference during the daytime. Patients with CKD showed significantly lower HF during the night as compared to control cases (P<0.05), although the daytime HF was not significantly different between the groups (Figure). Multivariate regression analysis demonstrated that CKD was independently associated with a lower night-to-day ratio of the HF and a higher night-to-day ratio of the L/H ration, even with the adjustment of age and comorbid hypertension.

Conclusions:
Our findings suggest that cardiac autonomic fluctuation is impaired in CKD patients. Whether a deterioration of autonomic activation might explain the high incidence of morning death in CKD patients needs to be clarified in future studies.
Abstract 13267: Age-Related Long-Term Benefit of Cardiac Resynchronization Therapy in LBBB Patients - a MADIT-CRT Long-Term Follow-Up Substudy
Authors: Thomas Sabu , Moss Arthur J , Zareba Wojciech , McNitt Scott , Barsheshet Alon , Klein Helmut , Goldenberg Illan , Huang David T , Kutyifa Valentina
Published: July 2021

Background:
Among patients with heart failure (HF), cardiac resynchronization therapy (CRT) combined with a defibrillator (CRT-D) reduces HF events and mortality compared with a defibrillator (ICD) alone. Whether these benefits extend to all age-groups during long-term follow-up is unclear.

Hypothesis:
We hypothesized that CRT-D would benefit all age groups with respect to reductions in HF events and all-cause mortality.

Methods:
We assessed the effect of age on HF events and death among patients in the MADIT-CRT long-term follow up study. 1281 patients with class I or II heart failure and left-bundle branch block (LBBB) were randomized to CRT-D or ICD alone. Patients were divided into 3 age groups: <60, 60-74 or ≥75 years and evaluated over 7 years for mortality and HF events. We compared cumulative events using the log-rank test and adjustments were made using a multivariate logistic regression model with various pre-specified covariates.

Results:
Overall 761 patients received CRT-D and 520 received ICD alone. The median age was 65 years. Among the three age groups, <60, 60-74 and ≥75 there were 399, 651 and 231 patients respectively. Multivariate analysis (Table) revealed that CRT-D compared to ICD alone significantly reduced the composite outcome of HF or death across all age groups: <60 years relative risk reduction (RRR)=39%, p=0.0236; 60-74 years RRR=59%, p<0.001; ≥75 years RRR=55%, p<0.001. CRT-D also significantly reduced HF events in all age groups <60 years RRR=52%, p=0.003; 60-74 years RRR=61%, p<0.001; ≥75 years RRR=73%, p<0.001. CRT-D was associated with significant mortality reduction only in the 60-74 year age group RRR 58%, p<0.001.

Conclusion:
Among patients with asymptomatic or mild heart failure, reduced LVEF and LBBB, CRT-D results in significant reduction of HF events and in the composite of all-cause mortality and HF events during long-term follow-up. All-cause mortality was significantly reduced with CRT-D only in the 60-74 year age group.
Abstract 13269: Reduced Expression of scaRNAs Disrupts Spliceosome Function and Heart Development in Zebrafish and Infants with Tetralogy of Fallot
Authors: Bittel Douglas C , Patil Prakash , Uechi Tamayo , Kibiryeva Nataliya , Marshall Jennifer , Artman Mike , O’Brien James E , Kenmochi Naoya
Published: July 2021

The splicing of messenger RNA plays a fundamental role in regulating vertebrate development and differentiation. Although it is well established that alternative splicing (AS) plays an important role in regulating mammalian heart development, a clear link between misregulated splicing and congenital heart defects has not been shown. We recently reported that more than 50% of genes associated with heart development had significant changes in splice forms in the right ventricle of infants with tetralogy of Fallot (TOF; 14M/7F; all less than 1 yr old). Moreover, there was a significant decrease (30-50%, p<0.05) in the level of 12 scaRNAs. scaRNAs are members of the large family of noncoding small RNAs that are responsible for biochemical modification of specific nucleotides in spliceosomal and ribosomal RNAs. These 12 scaRNAs target two spliceosomal RNAs, U2 and U6. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several key genes regulating human heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and 2). In addition, using available RNA-Seq data, we provide evidence that during zebrafish development, there are dynamic oscillations in scaRNAs and splice isoforms of genes that regulate heart development. We knocked down the expression of two scaRNAs; ACA35 (Scarna1) and U94 (Snord94), in zebrafish and saw a corresponding disruption of heart development. Importantly, there was an accompanying alteration in the ratios of splice isoforms of key cardiac regulatory genes. Based on these combined results, we propose that scaRNAs directly regulate the proficiency of the spliceosome by controlling spliceosomal RNA maturation. This in turn contributes to splice isoform dynamic equilibrium and ultimately heart development. These results are consistent with a failure of normal temporal and spatial splicing patterns during early embryonic development, leading to a breakdown in communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for understanding congenital cardiac malformations.
Abstract 13293: Acyl-coa Binding Protein is Marker of Myocardial Ischemia
Authors: Shi Xu , Lewis Gregory , Keyes Michelle , Farrell Laurie , Carr Steven , Keshishian Hasmik , O’Donoghue Michelle , Sabatine Marc , Gerszten Robert
Published: July 2021

Background:
We recently applied a liquid chromatography tandem mass spectrometry (LC-MS/MS) based proteomics platform to plasma samples from individuals undergoing a “planned” myocardial infarction (PMI; alcohol ablation for hypertrophic cardiomyopathy) and identified acyl-CoA binding protein (ACBP) as a potential circulating biomarker of myocardial injury. ACBP is a 10 kDa intracellular protein that is highly expressed in cells with a high turn-over of fatty acids such as cardiomyocytes. We sought to determine the site of ACBP release and whether ischemia alone is sufficient to trigger an increment in plasma levels in humans.

Methods:
Coronary sinus (CS) and peripheral venous samples were obtained simultaneously from PMI patients; peripheral venous samples were obtained from derivation/validation cohorts of subjects undergoing cardiac stress testing. Plasma ACBP levels were measured by immunoassay.

Results:
In PMI patients (n=11), pre-injury levels of ACBP were comparable in the CS and peripheral samples. As early as 10 min after PMI, ACBP levels were 27% higher in the CS than in the periphery (P = 0.01), and remained 30% higher at 60 minutes (P = 0.02). Next, we studied 105 patients undergoing cardiac stress testing, 52 of whom demonstrated inducible ischemia (cases) and 53 of whom did not (controls). Baseline ACBP levels were comparable in cases and controls. Changes in median ACBP levels after the exercise stress challenge were significantly greater in the ischemic patients (cases) than in the controls (22% increase in cases; 1% decrease in controls; P = 0.0001), findings which were validated in a second cohort of 101 patients subjects (P = 0.002). These findings remained significant in a multivariable model adjusting for age, male sex, diabetes, BMI, smoking, creatinine, hypercholesterolemia, and total minutes of exercise. By contrast, the effects of exercise on established biomarkers (cTnI, NT-proBNP and FABP) did not differ betwen cases and controls.

Conclusions:
We provide initial verification that ACBP is rapidly released from the injured heart and increases in response not only to infarction but also ischemia. These findings motivate additional clinical studies of this novel biomarker in heterogeneous patient cohorts.
Abstract 13324: Single Ascending Dose Pharmacokinetics and Pharmacodynamics of MDCO-216 (ApoA-I Milano/POPC) in Healthy Volunteers
Authors: Bellibas S. Eralp , Kallend David , Bobillier Alain , Kempen Herman , Wijngaard Peter L
Published: July 2021

Introduction:
MDCO-216, a complex of dimeric recombinant apolipoprotein A-I Milano (apoA-I M) and a phospholipid (POPC), is currently under development to improve cardiovascular outcomes by reducing plaque burden in patients with atherosclerotic disease. An earlier version of MDCO-216 has been shown to reduce atherosclerotic plaque burden in animal models and in patients with ACS. The purpose of this study was to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of newly manufactured MDCO-216 first time in healthy volunteers.

Methods:
24 healthy volunteers received a single dose of MDCO-216 (5, 10, 20, 30 or 40 mg/kg) or placebo (in 2:1 ratio) as a 2 hour IV infusion in a double-blind, randomised design. Serial blood samples were collected for PK and anti-drug Ab (ADA) analysis. An ex-vivo cholesterol efflux assay was used as one of several exploratory PD biomarkers for MDCO-216 activity.

Results:
No ADA was detected with any dose at any time point. Plasma mean T
1/2
of MDCO-216 ranged from 48 to 61 hours (56 hr. in average) and median T
max
ranged between 2 to 4 hours. No obvious difference in CL was observed with increases in dose and ranged from 0.62 to 0.98 mL/hr/kg. Exposure parameters increased with dose in a slightly less than dose-proportional manner with a range of 138 to 794 μg/mL for C
max
and 3391 to 20788 μg.hr/mL for AUC
0-48
. Dose-dependent increases in ABCA1-mediated efflux capacity of up to 4-fold above baseline and smaller increases of SRB1-mediated efflux capacity occurred rapidly after infusion at all doses. The dose-response analysis for ABCA1-mediated efflux best fitted into a sigmoid E
max
(maximum effect) PD model and predicts an E
max
of 15.6% which saturates around a 30 mg/kg dose of MDCO-216.

Conclusions:
This data demonstrate that MDCO-216 can profoundly stimulate the first step of reverse cholesterol transport at clinically achievable doses with a predictable PK/PD profile.
Abstract 13333: Imatinib Attenuates LPS-induced Inflammation and Vascular Leakage in Clinically Relevant Murine Models of Acute Lung Injury
Authors: Rizzo Alicia N , Letsiou Eleftheria , Sammani Saad , Esquinca Adeline , Garcia Joe G , Dudek Steven M
Published: July 2021

Introduction:
Acute lung injury (ALI) is characterized by inflammation-induced disruption of the endothelial cell (EC) barrier lining the pulmonary vasculature, which causes leakage of fluid and inflammatory cells into the airspaces. The mechanisms underlying ALI are critically dependent on EC cytoskeletal regulation of vascular permeability. The Abl family kinases Abl and Abl Related Gene (Arg) are key mediators of the endothelial cytoskeleton. The pharmaceutical agent imatinib inhibits these kinases and is used clinically for the treatment of multiple different malignancies.

Hypothesis:
Imatinib attenuates LPS-induced inflammation and vascular leakage in murine ALI and retains its protective properties when combined with high tidal volume (Tv) mechanical ventilation (MV).

Methods:
As a clinically relevant combination model of ALI stimuli, animals were given intratracheal (i.t) LPS (0.5mg/kg) (vs. PBS), allowed to recover for 20 hours, and then intubated for MV (Tv 30ml/kg, RR 75/min, PEEP 0 cm H2O, 4hrs). Imatinib (75mg/kg) (vs. vehicle) was given i.p. 30 min before LPS and 30 min before MV. For post-injury experiments, imatinib (75mg/kg) (vs. vehicle) was given 4 hours after LPS (1mg/kg) and animals were harvested after 18 hrs. Bronchoalveolar lavage fluid (BAL) was analyzed for total cell counts, neutrophil number, total protein, albumin content, and cytokine levels. Lung tissues were used for MPO activity, albumin content, histology, and Evans Blue dye extravasation.

Results:
Imatinib attenuated inflammation in both combination model studies and post-LPS treatment studies as measured by BAL cell count, PMN number, MPO activity, TNFα levels, and H&E staining. Additionally, in both models, imatinib decreased vascular leakage as measured by total protein, BAL and lung tissue albumin, and Evans Blue dye extravasation.

Conclusions:
Imatinib attenuates LPS-induced inflammation and vascular leak in mice. Additionally, imatinib is protective in a clinically relevant murine model of combined LPS and mechanical ventilation injury. Imatinib may have potential for translational use in ALI patients.
Abstract 13349: Long Term (4 Years) Clinical and Echocardiographic Results of Transcatheter Self-expanding Medtronic Corevalve Device in Patients With Aortic Stenosis
Authors: Voudris Vassilis , Thomopoulou Sofia , Vavuranakis Manolis , Kariori Maria , Stefopoulos Christos , Karavolias George , Moldovan Carmen , Sbarouni Efthychia , Balanika Marina , Khouri Mazen , Stefanadis Christodoulos
Published: July 2021

Introduction:
Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for patients (pts) with severe aortic stenosis considered inoperable or at high operative risk. However, little is known about long-term outcomes following TAVI. In this study we assessed the 4-year clinical and echocardiographic outcomes of pts undergoing TAVI with the self expanding Medtronic CoreValve prosthesis.

Methods:
The 4-year outcomes following successful TAVI with the self-expanding aortic valve device (Medtronic CoreValve) were evaluated in 60 pts (mean age 79+6 years, male 47 %, Logistic Euroscore 28.43+10.93%). Principal outcome measures were death from any cause. An echocardiograpic examination was performed at prespecified intervals of 6 and 12 months, and every year afterwards. Categorical variables were compared using X2 test, and continuous variables using t test. Survival curves were also constructed.

Results:
All cause mortality at 1, 2, 3, and 4 years was 16.7%, 28.3%, 30%, and 40% respectively. Mean aortic valve gradient decreased from 50.96+18.6 mm Hg pre to 9.22+ 4.6 mm Hg after TAVI (P<0.001) and remained at 15.69+6.3 mm Hg at 4 years (p for post-TAVI trend <0.01). Mean aortic valve area increased from 0.66+ 0.14 cm2 pre to 1.87+0.33 cm2 after TAVI (p<0.001) and remained at 1.23+ 0.25 cm2 at 4 years (p for post-TAVI trend <0.01). Paravalvular leak (minimal to moderate) was observed in 61% of pts post-TAVI; however, there was no case of progression to severe regurgitation at 4 years follow-up.

Conclusions:
TAVI with the Medtronic CoreValve prosthesis is associated with sustained clinical and functional cardiovascular benefits in inoperable or high-risk patients with symptomatic aortic stenosis up to 4-year follow-up.
Abstract 13370: Long-term Outcomes of Patients with Pseudoaneurysms and a History of Prior Cardiovascular Surgery
Authors: Chenier Michael , Patel Krishna , Pettersson Gosta , Lytle Bruce , Navia Jose , Sabik Joseph , Rodriguez Leonardo , Grimm Richard , Griffin Brian , Desai Milind
Published: July 2021

Background:
Data regarding long-term outcomes in patients with cardiovascular (CV) pseudoaneurysms (PSA) is sparse. In patients with prior CV surgery, we sought to assess outcomes in patients with PSAs (defined as paravalvular, aortic root, or ascending aorta PSAs) & compare them with matched controls.

Methods:
As part of a cohort study (total n=342), we included 114 patients with prior CV surgery who presented with paravalvular (n=71, 59 at the aortic valve & 12 at the mitral valve) & ascending aortic (n=43) PSAs. A control group of patients (n=228) with prior CV surgery, matched in a 2:1 fashion based on age, gender, type & time of CV surgery, were also included. Standard clinical, echocardiographic & surgical data was collected & Euroscore was calculated. A composite endpoint of death & stroke during follow-up were recorded.

Results:
Baseline data are shown in Figure A. 80% of patients in each group underwent redo CV surgery during follow-up. Over a follow-up of 6.7±4 years, there were 78 (23%) events (32 or 28% in PSA group & 46 or 20% in control group). 30-day events occurred in 7% of the PSA group & 1% of controls. Kaplan-Meier survival curves for the 2 groups are shown in Figure B. In the multivariate Cox Survival Analysis, Euroscore (HR 1.18 [1.10-1.27]) & the presence of PSA (HR 2.83 [1.66-4.85]) predicted a higher rate of events, while subsequent CV surgery (as a time-dependent covariate HR 0.38 [0.22-0.67])) & antibiotic use (HR 0.29 [0.27-0.31]) predicted improved freedom from events (all p<0.01).

Conclusion:
In patients with prior CV surgery, the presence of a cardiac PSA was associated with increased long-term adverse events, while redo CV surgery and antibiotic use improved outcomes.
Abstract 13389: Early Matrix Metalloproteinase-9 Inhibition Stimulates Neutrophil Infiltration and Delays Neutrophil Apoptosis Post-Myocardial Infarction in Mice
Authors: Iyer Rugmani P , Patterson Nicolle L , Fields Gregg B , Lindsey Merry L
Published: July 2021

Matrix metalloproteinase-9 (MMP-9) increases in the first week post-MI, and targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-myocardial infarction (MI), but whether MMP-9 inhibition early post-MI is effective therapeutic strategy has not been evaluated. Adult male C57BL/6J mice (3-6 months old, n=80) were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03 μg/day) was delivered at 3 h post-MI, and the mice were sacrificed at days 1 or 7 post-MI. Infarct area was similar in the saline (57±1%) and MMP-9i (55±1%) groups (p=0.22), indicating equal initial injury. The 7 day post-MI survival rates showed no significant difference between saline and MMP-9i groups (p=0.54). MMP-9 inhibition resulted in a 31±1% reduction in MMP-9 activity at day 1 post-MI (p<0.05 vs. saline). Surprisingly, MMP-9 inhibition worsened LV function at day 7 post-MI, as shown by ejection fractions of 13±1% for saline vs. 8±1% for MMP-9i (p<0.05). Of 84 inflammatory genes examined in the day 7 infarct, 15 pro-inflammatory genes were increased and one decreased in the MMP-9i group (all p<0.05 vs. saline). Because MMP-9i showed increased inflammation at day 7, we measured neutrophil numbers. The saline group showed increased neutrophils at day 1, with numbers declining by day 7 due to induction of apoptosis. In MMP-9i, neutrophils were 2-fold higher at day 1 and persisted at day 7 for an 18-fold difference from saline, indicating prolonged neutrophil presence. Isolated blood neutrophils stimulated with active MMP-9 showed increased levels of pro-apoptotic markers Bcl and Bax compared to unstimulated control (both p<0.05). Interestingly, neutrophils stimulated with active MMP-9 and treated with MMP-9i showed increased levels of anti-apoptotic markers Mcl and Xiap (both p<0.05) compared to MMP-9 treated cells. This suggests that prolonged neutrophil presence with the MMP-9 inhibition was due to a dramatic reduction in neutrophil apoptosis. In conclusion, MMP-9 inhibition starting immediately post-MI decreased neutrophil apoptosis leading to increased inflammation and resulting in exacerbated LV dysfunction.

Cat: 515 - Apoptosis and Necrosis
Abstract 13392: Deficiency of Microrna-378 Contributes to the Development of Cardiac Fibrosis Involving a Tgfβ1-dependent Paracrine Mechanism
Authors: Nagalingam Raghu S , Noor Mariam , Gupta Mahesh P , Solaro R.John , Gupta Madhu
Published: July 2021

Understanding the regulation of cardiac fibrosis is critical for controlling adverse cardiac remodeling during the development of heart failure. Previous studies implicated that microRNA-378 is primarily expressed in cardiomyocytes, and it is down-regulated during heart failure. To understand the consequence of miR-378 depletion during cardiac remodeling, the present study employed a LNA-modified-antimiR to target miR-378 in vivo. Results showed that loss of miR-378 function in mouse hearts led to the development of cardiomyocyte hypertrophy and fibrosis. Upon evaluation of the mechanism of profibrotic response of miR-378 inhibition, we found that antimiR treatment induced TGFβ1 expression in mouse hearts as well as in cultured cardiomyocytes, whereas its expression in cardiomyocytes abolished AngII-stimulated induction of TGFβ1 mRNA. Among various secreted cytokines, only TGFβ1 levels were found to be increased in the conditioned-media of miR-378 depleted cardiomyocytes. Treatment of cardiac fibroblasts with the conditioned-media of miR-378 depleted myocytes activated pSMAD2/3, a critical step in TGFβ-signaling, and induced fibrotic gene expression. This effect of miR-378 depletion was counteracted by including a TGFβ1-neutralizing antibody in the conditioned-medium. In cardiomyocytes, antimiR-mediated stimulation of TGFβ1 mRNA was correlated with the increased expression of c-fos and c-jun. Adenovirus expressing dominant negative N-Ras or c-Jun prevented antimiR-mediated induction of TGFβ1 mRNA, documenting the importance of Ras and AP-1 signaling in this response. These results demonstrate that reduction in miR-378 levels during pathological conditions participate in the process of cardiac remodeling through paracrine release of a profibrotic cytokine, TGFβ1, from cardiomyocytes. Our data imply that the presence of miR-378 in cardiomyocytes plays a critical role in the protection of neighboring fibroblasts from activation by pro-fibrotic stimuli.
Abstract 13407: A Mouse Model of Heart Failure with Preserved Ejection Fraction (HFpEF) due to Chronic Infusion of a Low Subpressor Dose of Angiotensin II
Authors: Toldo Stefano , Marchetti Carlo , Al Husseini Aysar , Carbone Salvatore , Regan Jessica , Mauro Alfonso G , Nordio Andrea , Sonnino Chiara , Mezzaroma Eleonora , Van Tassell Benjamin W , Abbate Antonio
Published: July 2021

Introduction:
Heart failure with preserved ejection fracture (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of all patients with HF, the mechanisms of disease are poorly understood, animal models of HFpEF not due pressure overload are lacking, and therapies for HFpEF are generally ineffective.

Hypothesis:
A continuous infusion of low dose of angiotensin II (ATII) may be sufficient to induce changes in left ventricular (LV) diastolic function without increasing blood pressure nor induce LV hypertrophy.

Methods:
Osmotic pumps were implanted subcutaneously in 8 week-old CD1 male mice randomly assigned to the ATII (200 ng/kg/day) or vehicle (N=8/group). Transthoracic echocardiography was performed at baseline and 4 weeks to measure LV dimensions, systolic and diastolic function. Aortic systolic and diastolic pressures (AoP), LV peak systolic and end-diastolic pressures (LVPSP, LVEDP) were measured at LV catheterization. Fibrosis was measured using Masson’s trichrome stain. The expression of Interleukin (IL)-18 mRNA levels, a cytokine associated with impaired cardiomyocyte relaxation, was measured at 4 weeks.

Results:
When compared to the baseline values or vehicle group, ATII infusion had no effects on AoP, LVPSP and HR, and had no effects on LV dimensions or mass, nor on LVEF (all P>0.2). ATII induced a significant impairment in LV diastolic function as measured by an increase (worsening) of the myocardial performance index (MPI), the LV isovolumetric relaxation time (IVRT) and of LVEDP (Figure). Cardiac expression of IL-18 mRNA was significantly increased 7-fold after ATII infusion (P<0.001), suggesting a potential mechanistic role of IL-18.

Conclusion:
Chronic infusion of low dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing blood pressure. The use of this mouse model may help understanding the mechanisms leading to HFpEF syndrome in patients.
Abstract 13408: Successful Prediction of MACE by not Occurrence of Non Sustained Ventricular Tachycardia but Presence of Myocardial Fibrosis on CT in HCM Cases without Obstructed Coronary Arteries. a Long Follow-Up Study with a Median of 69 Months
Authors: Funabashi Nobusada , Takaoka Hiroyuki , Ozawa Koya , Kobayashi Yoshio
Published: July 2021

Introduction:
Hypertrophic cardiomyopathy (HCM) presents several risk factors for sudden cardiac death and the presence of myocardial fibrosis (MF) on CT is a novel candidate to predict prognosis in HCM patients.

Aim:
To compare the value of non sustained ventricular tachycardia (NSVT) and MF in risk stratification for major adverse cardiac events (MACE) in HCM patients without obstructed coronary arteries.

Methods:
We selected 48 consecutive HCM patients (33 males, 61±14 y) who underwent cardiac CT and 24 h of ECG monitoring within 12 mo between 2002 and 2009. Patients had no significant luminal coronary artery stenosis (>50%) on CT or previous myocardial infarction. On CT, if a contrast defect was observed in the early phase and abnormal late enhancement was observed at a corresponding site, we diagnosed MF. NSVT was defined as ≥3 consecutive premature ventricular beats. Follow-up after CT for MACE was a median of 69 mo. MACE included cardiac death, cardiac arrest, 2 or more hospitalizations for heart failure, sustained ventricular tachycardia (VT) (continued >30 s), ventricular fibrillation and appropriate discharge of Implantable cardioverter defibrillators.

Result:
NSVT was detected in 24 patients. There was no significant difference in MACE between patients with and without NSVT (13% and 8%; P=1.00, respectively). No significant differences between HCM patients with and without NSVT, were seen at each time point and when the entire follow-up period was compared with Kaplan-Meier and log rank tests (P=0.60). MF was detected by CT in 29 patients. Patients with MF had a higher risk of MACE (17%) than those without (0%; P=0.07, n.s.). Significant differences between HCM patients with and without MF were seen at each time point and when the entire follow-up period was compared with Kaplan-Meier and log rank tests (P=0.04).

Conclusions:
MF is a stronger predictor of MACE than NSVT in HCM patients without obstructed coronary arteries following a median of 69 mo.