bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18398: Malignant Ventricular Arrhythmias in Lamin A/C Cardiomyopathies: Prevalence, Clinical Course and Outcome
Authors: Wijchers Sip , Akca Ferdi , Caliskan Kadir , Constantinescu Alina , Manintveld Olivier , Szili-Torok Tamas
Published: July 2021

Introduction:
Genetic mutations in the Lamin A/C (LMNA) genes have been recognized as a possible cause of familial cardiomyopathies (CMP). Ventricular Tachycardias (VT) are frequently associated with LMNA cardiomyopathy, but data is limited on time of occurrence, prevalence of and used

treatment options and their efficacy of these VTs.

The aim of this study is to describe ventricular arrhythmias in LMNA cardiomyopathy

Methods:
This was a retrospective cohort study including data from all patients diagnosed with LMNA CMP within the Erasmus MC department of cardiology, a tertiary referral centre. Follow up continued until the patient either got a heart transplantation (HTX) or died.

Results:
Twenty patients were identified with LMNA CMP. The follow up time ranged between 14 and 208 months with a median of 67. Malignant VTs were documented in 14 out of 20 (70%) patients. Five patients (25%) had documented non sustained (NS) VT before a diagnosis was made using genetic testing, whereas the remaining VTs occurred 45 ± 54 months during follow up. All patients with documented VT or frequent premature ventricular complexes showed at least 2 or more morphologies with variable coupling intervals. Pharmacological therapy was beta blockade for 80 % of the cohort. Amiodarone was used in 45% of the patients and was discontinued in another 20%. An ICD was implanted in 95% of the patients. Twelve of the 19 (63%) received appropriate therapy. Three patients (15%) underwent radio frequent catheter ablation (RFCA) for a recurrent VT. Two of whom had multiple morphologies. All three patients had VT recurrence showing different and multiple morphologies after 0, 2 and 33 months. Two of these patients died of electrical storm at 0 and 27 months after RFCA and the third received a HTX after 98 months. All patients of the total cohort that showed VT during monitoring had documented recurrences despite different treatment strategies. Five patients (25%) died after a mean of 9 ± 7 years. Three patients (15%) received a HTX.

Conclusions:
Patients with LMNA CMP have an increased risk for malignant VT with very limited treatment options. Both medical regimes as well as the few ablations had 100% recurrences. Because the VTs are multiform in nature we would advise taking a reticent stand towards RFCA
Abstract 18440: Cardiac Output Reserve Predicts Exercise Capacity and Need for Surgery in Aortic Stenosis
Authors: Lumley Matthew , Williams Rupert , Navales Michelle , Parkin Denise , Rimington Helen , Marber Michael , Rajani Ronak , Chambers John , Perera Divaka
Published: July 2021

Background:
The development of symptoms in patients with aortic stenosis (AS) relates inconsistently with echocardiographic measures of stenosis severity. This is a reflection of the dynamic interaction between the valve and ventricle on exercise, which is not captured by any single parameter. We hypothesised that cardiac output reserve (COR), the ratio of cardiac output at peak exercise to cardiac output at rest, would predict exercise capacity (EC) and the need for aortic valve surgery.

Methods:
40 patients with moderate-severe AS, were prospectively recruited. All patients underwent resting transthoracic echocardiography, modified Bruce exercise treadmill testing (ETT), B-type natriuretic peptide measurement and bicycle exercise stress echocardiography. EC was defined by exercise duration during the ETT. The decision to refer the patient for surgery was made by the specialist valve team who had access to all data but were blinded to COR results. Regression analysis was performed using independent variables shown to correlate with each outcome measure on univariate analysis.

Results:
The mean±SD of the EC was 645±294s, aortic valve area (AVA) 0.92±0.28cm
2
and COR 1.86±0.39. 22 of the 40 patients were referred for surgery.

Exercise Capacity:
On univariate analysis, resting AVA or mean/peak pressure gradient (AVG) did not correlate with EC. EC significantly correlated with COR (r = 0.71, p < 0.000001), age (r = -0.63, p < 0.00005), BNP (r = -0.49, p = 0.03), peak AVG at maximal exercise (peak AVG

ex

) (r = 0.32, p = 0.04) and tissue Doppler lateral mitral valve annulus systolic velocity, Sa (r = 0.32, p = 0.05). By multiple linear regression, only COR (β = 0.5, p = 0.0004) and peak AVG

ex

(β = 0.3, p = 0.09) were predictive of EC.

Referral for Surgery:
By ROC analysis, a COR of 1.8 (AUC 0.87, 95% CI 0.77-0.98) best predicted the need for surgery. Energy loss index at maximal exercise, meanAVG at rest and AVA at maximal exercise were also predictors of need for surgery. By binary logistic regression, only COR was predictive of the need for surgery (OR 0.02, 95% CI 0.00001-0.53, p = 0.03)

Conclusion:
Cardiac Output Reserve is a novel index that predicts exercise capacity and the need for surgery in moderate to severe AS.
Abstract 18446: Identification of a Novel Cellular Actor Participating in Vascular Remodeling During Pulmonary Arterial Hypertension : the PW1+ Progenitor Cells
Authors: Dierick France
Published: July 2021

AIM:
PW1+ progenitors were identified in various adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis is that PW1+ progenitors are recruited to participate in the vascular remodeling during pulmonary arterial hypertension (PAH).

METHODS:
PW1IRESnLacZ+/- mice express the β-galactosidase as a reporter gene for PW1 expression allowing to follow the lineage of PW1+ cells during a few days. These mice were exposed to chronic hypoxia (CH) to induce PAH, lung vessels neomuscularisation and SMC proliferation. PW1+ and β-Gal+ cells were studied by FACS and by immunofluorescence.

RESULTS:
PW1+ cells are localized in the lung parenchyma and in the perivascular zone in rodent and human lung. Two PW1+ populations were identified by flow cytometry in the mouse lung 1/ a Sca-1high/CD34high/PDGFR-α+ population which differentiates into calponin+ or α-SMA+ SMC and into vWF+ endothelial cell and 2/ a CD34-/CD146+ population expressing pericyte markers.

After 2-4 days of CH, the number of lung PW1+ cells is increased (x3.5, p<0.01) and, in small pulmonary vessels media, the proportion of β-Gal+ SMC derived from PW1+ cells is increased (64±6% vs 35±3%, p<0.05) suggesting a recruitment and differentiation of PW1+ cells into lung vascular SMC. Moreover WT mice irradiated and engrafted with GFP+/β-Gal+ bone marrow cells do not show any increase in GFP+ SMC in lung vessels and do not show any β-Gal+ cells in the lung indicating that the lung PW1+ progenitors are not derived from bone marrow .

Moreover, in the human PAH lung, PW1+ cells were observed in remodeled vascular structures: in the media of remodeled vessel and in plexiform lesions.

CONCLUSION:
These results suggest that lung resident PW1+ progenitors are recruited to participate in the vascular remodeling of small pulmonary vessels in experimental and human PAH. These progenitors show characteristics of pericytes and of vascular progenitors.
Abstract 18449: Genetic Variants for Katp Channels as Protective Factors in Ischemic Heart Disease Susceptibility: Gender Differences
Authors: Severino Paolo , Cinque Alessandra , Calabrese Giorgio , Salvi Nicolò , Bruno Pasqualina , Pucci Maria Teresa , De Marchis Maria Laura , Palmirotta Raffaele , Mancone Massimo , Fedele Francesco
Published: July 2021

Background:
Coronary artery disease has been widely considered a “man’s disease” and not a major concern for women. However, scientists have been trying to unlock the female physiology of ischemic heart disease (IHD). In fact, women are more prone than men to microvascular coronary dysfunction. Recently, we proposed that genetic polymorphisms (SNP) of coronary ion channels may be involved in IHD susceptibility. Our published data showed that the genotype distribution of SNP rs5215 for Kir6.2 subunit of ATP-dependent potassium (KATP) channels moderately deviated from the HW equilibrium and that rs5215_GG is correlated with IHD susceptibility. In particular, we described that rs5215_GG genotype of Kir6.2 might have a ‘‘protective’’ role in IHD genesis.

Aim and methods:
In order to better describe the role of SNP rs5215_GG in IHD susceptibility in woman, we conducted a gender difference in term of prevalence of rs5215_GG on our previous population, i.e. 242 patients with acute coronary syndrome or stable angina, of which 155 with CAD, 46 with microvascular dysfunction and 41 with anatomically and functionally normal coronary arteries.

Results:
Among 242 patients, rs5215_GG was found to be more frequent in women (16/82; 19.51%; p=0.0450) compared to men. In particular, rs5215_GG was more frequent in female patients with anatomically and functionally normal coronary arteries (8/24; 33.3%; p=0.0428) compared with women with CAD, whereas there was no difference between men in normal and CAD groups.

Discussion and conclusion:
The polymorphism rs5215_GG is a missense SNP (ATC-GTC) that results in the substitution of isoleucine (I) residue with valine (V) in the Kir6.2 subunit of KATP channels. Our data validate the hypothesis that rs5215_GG could reduce susceptibility to IHD. In fact, rs5215_GG was confirmed to be present more frequently in woman presenting anatomically and functionally normal coronary arteries. Our results suggest that coronary KATP channels expressing rs5215_GG play a protective key role against IHD. Our data endorse the prospect of associations between SNP encoding coronary ion channels and IHD, validating the idea that ion channels play in coronary homeostasis and that their polymorphisms act in IHD genesis.
Abstract 18491: Metformin Lowers Circulating Adiponectin Levels in Patients with Myocardial Infarction
Authors: Cannon Megan V , Lexis Chris P , Rogier van der Velde A , van der Horst Iwan C , Lipsic Erik , Dokter Martin M , van Veldhuisen Dirk J , van der Harst Pim , de Boer Rudolf A
Published: July 2021

Introduction:
Adiponectin is an adipokine and its levels are reduced in obesity, diabetes, and prevalent heart disease. However, the association of adiponectin and CV disease is complex, and studies have reported contradictory results with respect to the relation between adiponectin and CV disease. Furthermore, the oral antidiabetic agent, metformin, has multiple effects on metabolic parameters and is associated with better clinical outcomes compared to other antidiabetic agents. This study sought to determine the effects of metformin on adiponectin levels in patients with myocardial infarction (MI).

Methods:
The GIPS-III trial was a randomized, double-blind, placebo-controlled study conducted in 380 patients who underwent primary percutaneous coronary intervention (PCI) for a first time MI. The aim was to evaluate the efficacy of 4 months metformin treatment on preserving left ventricular function post-MI in non-diabetic patients. From 308 patients (mean age 58 ± 11 years, 78.9% male), both baseline and 4 month samples were available for plasma adiponectin measurement.

Results:
Placebo and metformin groups were well-matched, and metformin treatment had no effect on plasma glucose levels. Median baseline adiponectin level was 5057 ng/ml (IQR: 3325-7596) and median adiponectin level after 4 months was 4643 (IQR: 2768-6867). We observed a significant lowering of adiponectin levels following 4 months of metformin treatment compared to placebo (-629 versus -166, respectively; P=0.026). Baseline adiponectin levels were further assessed and divided into quartiles (Q1: 67 - 3297; Q2: 3352 - 5051; Q3: 5064 - 7549; Q4: 7643 -20118). Increasing adiponectin levels were associated with increased age (P=0.02), gender (higher in females, P<0.001), lower BMI (P=0.01), elevated heart rate (P=0.03), as well as higher N-terminal pro-B-type natriuretic peptide levels both at baseline (P<0.001) and at 4 months (P<0.001).

Conclusions:
In this study, we show that treatment with metformin lowers circulating adiponectin levels. Metformin has been associated with improved CV outcomes, and the lowering of adiponectin may explain, at least in part, the cardioprotective effects of metformin.
Abstract 18498: Description of Aortic Root Growth and Outcomes in a Cohort of Pediatric Patients with Loeys-Dietz Syndrome
Authors: Viswanathan Nitya , Morris Shaine A
Published: July 2021

Background:
Loeys Dietz Syndrome (LDS) is associated with rapid aortic dilation and aortic dissection, but data on children with LDS are limited. The goal of this study is to describe aortic root growth and outcomes in children with LDS.

Methods:
Patients with LDS were identified from an institutional database. Data regarding genetic mutation, medications, aortic root dimensions by transthoracic echocardiography (TTE), aortic dissection and surgical intervention were collected. For those with >2 TTEs 1 year apart, rate of change in z-score was calculated using linear regression. TTEs performed after aortic surgery were excluded. We examined if variables were associated with rate of aortic root growth.

Results:
Of 16 patients, 8 were female. Five had a TGFBR1 and 9 had a TGFBR2 mutation; 2 patients did not have genetic data available. Median aortic root Z-score at diagnosis was 3.5 (range 0.5-25.4). Fifteen patients were on medication (2 beta-blocker (BB), 5 angiotensin receptor blocker (ARB), 5 BB+ARB, and 3 with past use of both). Four patients underwent prophylactic root replacement at ages 3.3, 6.7, 8.7, and 9.4 years at root dimensions 3.2, 6.5, 4.0, and 4.1 cm respectively. One patient had a Type A dissection at age 15y after prior root replacement and underwent repeat surgery. Another underwent heart transplant at 6.9 years old after prior root replacement. Ten patients had serial TTE data. Median change in aortic root diameter and Z-score was 0.11cm/year and 0.1/year respectively. Mean change in z-score per year for those on on BB was -0.1± (range -1.2 to 0.7), ARB 0.5 (range 0.1 to 1.1) and both 0.0 (range -0.2 to 0.2, p=NS). No variables studied were associated with faster aortic growth.

Conclusions:
Degree of aortic root dilation and rate of aortic root growth is highly variable in children with LDS, although factors associated more aggressive disease are unclear. The high proportion of patients with adverse outcomes including aortic dissection and surgery is concerning.
Abstract 18506: Relief of Myocardial Edema in Advanced Decompensated Heart Failure is Associated with Improved Left Ventricular Systolic and Diastolic Function
Authors: Verbrugge Frederik H , Willems Endry , Bertrand Philippe B , Gielen Ellen , Mullens Wilfried , Giri Shivraman , Raman Subha V , Verhaert David
Published: July 2021

Introduction:
Cardiac magnetic resonance (CMR) imaging with quantitative T2-mapping allows identi[[Unable to Display Character: ﬁ]]cation of myocardial edema, improving risk-stratification in acute coronary syndromes and myocarditis.

Hypothesis:
Global myocardial edema contributes to left ventricular (LV) dysfunction in advanced decompensated heart failure (ADHF).

Methods:
CMR with quantitative T2-mapping was performed in consecutive ADHF patients (n=17) undergoing right heart catheterization for worsening dyspnea and volume overload. Patients received vasodilators and diuretics to achieve pulmonary capillary wedge pressure (PCWP) ≤18 mmHg and central venous pressure (CVP) ≤10 mmHg, while maintaining mean arterial pressure ≥65 mmHg. After reaching hemodynamic targets, the pulmonary arterial catheter was removed and CMR imaging repeated. Changes in LV T2-values, hemodynamics, and CMR volumetric measurements were compared.

Results:
Study patients (64±11 years, male 88%, LV ejection fraction 23±8%, ischemic cardiomyopathy 50%) received decongestive treatment during 5±2 days. PCWP and CVP decreased from 25±7 to 17±4 mmHg and 13±6 to 7±3 mmHg, respectively (p<0.001 for both), while cardiac index increased from 2.14±0.60 to 2.58±0.49 L/min/m
2
(p=0.012). LV T2-values dropped consistently from 59.6±4.9 ms to 56.3±5.2 ms after decongestion (p=0.002; Figure). Decreasing LV T2-values correlated well to both decreasing PCWP (r=0.75; p=0.001) and increasing cardiac index (r=0.58; p=0.023). Although LV end-diastolic volume index (142±31 to 135±34 mL/m
2
; p=0.033) and end-systolic volume index (110±29 to 99±33 mL/m
2
; p=0.001) both decreased significantly, the extent of these changes were not correlated to changing T2-values (r=0 and 0.11, respectively; p=ns).

Conclusions:
Global LV myocardial edema is observed in ADHF and reversible with successful decongestive therapy. Relief of myocardial edema strongly correlates with improvements in systolic and diastolic function.
Abstract 18538: The ATRIA Stroke Risk Score Predicts Ischemic Stroke Better than CHADS2 and CHA2DS2-VASc in a large Swedish Cohort of Patients with Atrial Fibrillation
Authors: Aspberg Sara , Chang Yuchiao , Singer Daniel
Published: July 2021

Introduction:
Atrial fibrillation (AF) is a major risk factor for acute ischemic stroke (AIS). Anticoagulation therapy (OAC) effectively prevents AIS, but increases bleeding risk. There is a need for better AIS risk prediction to optimize the anticoagulation decision in AF. The ATRIA stroke risk score (ATRIA) (table) was superior to CHADS2 and CHA2DS2-VASc in two large California community AF cohorts. We now report the performance of the 3 scores in a very large Swedish AF cohort.

Methods:
The cohort consisted of all Swedish patients hospitalized with a diagnosis of AF from July 1, 2005 to December 31, 2008. Predictor variables and the outcome, AIS, were obtained from inpatient ICD-10 codes. Warfarin use was determined from National Pharmacy Database. Risk scores were assessed via c-index (C) and net reclassification index (NRI).

Results:
The cohort included 158,370 AF patients off warfarin who contributed 340,332 person-years of follow-up, and 11,823 incident AIS, for an overall AIS rate of 3.47%/yr, higher than the 2%/yr seen in the California cohorts. Using the entire point score, ATRIA had a good C of 0.712 (0.708-0.716), significantly better than CHADS2, 0.694 (0.689-0.698), or CHA2DS2-VASc, 0.697 (0.693-0.702). Using published cut-points for Low/Moderate/High AIS risk, C deteriorated for all scores but ATRIA and CHADS2 were superior to CHA2DS2-VASc. NRI favored ATRIA; 0.16 (0.15-0.18) versus CHADS2; 0.22 (0.21-0.24) versus CHA2DS2-VASc. However, NRI decreased to near-zero when cut-points were altered to better fit the cohort’s stroke rates.

Conclusion:
Findings in this large Swedish AF cohort validate those in the California AF cohorts, with the ATRIA score predicting stroke risk better than CHADS2 or CHA2DS2-VASc. However, relative performance of the categorical scores varied by population stroke risk. Knowledge about this population risk may be needed to optimize cut-points on the multipoint scores to achieve better net clinical benefit from OAC.
Abstract 18569: Inhibition of Prolyl Hydroxylase Stimulates Hif-mediated Sdf-1 Expression and CXCR4+ Cell Recruitment for Myocardial Repair
Authors: Ghadge Santhosh Kumar , Pham Thi Van , Messner Moritz , Doppelhammer Maximilian , Franz Wolfgang-Michael , Zaruba Marc-Michael
Published: July 2021

Objective:
Data from our lab indicate that stabilization of the cardiac SDF-1/CXCR4 axis preserves myocardial function and attenuates ischemic cardiomyopathy. However, HIF-1α dependent SDF-1 upregulation lasts only for 48-72 hours after MI limiting the targeting of stem cells to ischemic myocardium. To overcome this caveat, we aimed to activate SDF-1 expression by stabilization of HIF-1α through inhibition of prolyl hydroxylase with the ratio to augment CXCR4+ stem cell recruitment and stimulate myocardial repair.

Methods:
To evaluate the effects on HIF-1α mediated SDF-1 expression, genetically taggedSDF1-EGFP mice were subjected to optimal doses (80mg/kg i.p.) of the prolyl hydroxylase Inhibitor dimethyloxalylglycine (DMOG). To track the fate of CXCR4+ cells, genetically tagged CXCR4-EGFP BAC reporter mice were utilized. FACS and immunhistochemical analyses of CXCR4+ bone marrowm(BM), peripheral blood, and heart cells as well as infarct sizes were analyzed under normoxaemic and ischemic conditions with and without DMOG treatment.

Results:
SDF1-EGFP mice treated with DMOG showed robust induction of SDF-1 in the heart. SDF-1 upregulation after DMOG treatment was further confirmed by SDF-1 ELISA of heart lysates. FACS of transgenic CXCR4-EGFP BM and hearts revealed that CXCR4+ was most frequently expressed on CD11b+ monocytes, and to a less amount on angiogenic CD31+ , CD34+, c-kit+, and Flk1+ cells, as well as stem cell populations like ACC133+ and Lin-/c-kit+/Sca-1+. After myocardial ischemia these cell populations were highly upregulated. A subpopulation of CXCR4-EGFP+ cells co-expressed CD31 in capillaries. Treatment with DMOG revealed a robust upregulation of CXCR4+ cell populations in the ischemic heart, predominantly of angiogenic CXCR4+/CD11b+ monocytes. Further analysis showed that DMOG Treatment after 7 days leads particularly to upregulation of CD206+ subpopulation in infarcted hearts in favor of repair mechanisms characterized by reduced infarct sizes.

Summary and Conclusion:
Our data suggest that inhibition of prolyl hydroxylase may be a promising target for HIF-1a mediated SDF-1 activation to increase stem cell homing and myocardial repair.
Abstract 18575: The Transcriptional Cofactor Eyes Absent 4 is a Critical Regulator for Maintaining Normal Cardiac Function
Authors: Williams Tatjana , Hundertmark Moritz , Nordbeck Peter , Voll Sabine , Arias-Loza Anahi Paula , Elsner Ines , Oppelt Daniel , Olivares Silvana , Schoenberger Jost , Ritter Oliver
Published: July 2021

Introduction:
E193, a human mutation in the transcription cofactor Eyes absent 4 (EYA4) causes hearing impairment followed by terminal heart failure, defining an important role for Eya4 in maintaining normal cardiac function.

METHODS AND RESULTS:
First, in-vitro experiments show that overexpression of Eya4 and the mutant isoform alter the expression of p27kip1 on both, transcript and protein levels. Next, we generated transgenic mice with cardiomyocyte-specific Eya4 or E193 overexpression to elucidate the in vivo function of Eya4 upon cardiac physiology. Luciferase and CHIP assays revealed that Eya4 and E193 bind to and regulate p27 expression in a contradictory manner, as already seen in vitro. Activity and phoshorylation of the downstream molecules CK2α and HDAC2 were significantly elevated in Eya4 mice, whereas they were significantly reduced in E193 animals compared to WT littermates. MRI and hemodynamic analysis indicate that a constitutive overexpression of Eya4 results in the age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 overexpressing animals develop onset of dilative cardiomyopathy as seen in human patients carrying the E193 mutation. Morphometric analysis proved ventricular hypertrophy or dilation of the LV associated with a thinning of the myocardial wall, interstitial fibrosis of myocardial tissue and alterations in cell size. Re-activation of fetal genes also occured in both TG models, characteristic for cardiac disease. Both cardiac phenotypes were aggravated upon pressure overload.

Finally, we identified a new human heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein.

Conclusion:
Our results implicate that Eya4 plays a critical role in regulating normal cardiac physiology and function via Six1/p27/CK2α/HDAC2 and that an imbalance within the Eya4/Six1 transcriptional complex leads to an age dependent onset of cardiomyopthy and heart failure.
Abstract 18592: Anti-arrhythmic Effect of a Novel Rycal, S44121 / Arm036, in a Post-myocardial Infarction Mouse Model of Heart Failure
Authors: Thireau Jerome , Farah Charlotte , Bouly Muriel , Roussel Jerome , Lacampagne Alain , Richard Sylvain
Published: July 2021

Introduction:
Targeting leaky cardiac ryanodine receptors (RyR2) to prevent diastolic Ca2+ release from the sarcoplasmic reticulum (SR) is a promising pharmacological approach, to rescue the impaired cardiac contraction and prevent Ca2+-dependent arrhythmias in heart failure (HF) and disease.

Hypothesis:
Based on prior work from the Marks group, the Rycal S44121 (also known as ARM036) is an experimental small molecule stabilizer of RyR. We investigated the effects of S44121 in a post-myocardial infarction (PMI) mouse model of HF.

Methods and results:
Mice were randomly assigned to 3 groups: Sham, PMI (subjected to left coronary artery ligation), and PMI-S (treated for 3 weeks with S44121 by subcutaneous osmotic pumps on day 7 post-MI, 10 mg/kg/day). Intracellular Ca2+ was measured on single left ventricular myocytes. PMI mice exhibited a 4-fold increase in the frequency of spontaneous Ca2+ release events, Ca2+ sparks, as measured in quiescent cells using the fluorescent Ca2+ indicator Fluo-4. PMI mice also exhibited higher global diastolic Ca2+, measured with the ratiometric fluorescent probe, Indo-1 AM, and increased the occurrence of ectopic diastolic Ca2+ waves. Acute application of S44121 (10 μM for 15 min) reduced Ca2+ sparks frequency. Chronic treatment of mice with S44121 also normalized the frequency of Ca2+ sparks and of ectopic Ca2+ waves, and corrected diastolic cellular Ca2+ overload. Effects were maximal at 20 mg/kg/day. Furthermore, treatment with S44121 abolished Ca2+ waves promoted by β-adrenergic challenge (acute application of isoproterenol, 10 nM). The potential anti-arrhythmic benefit of S44121 was assessed in vivo using telemetric surface electrocardiograms. S44121 had no effect on ECG intervals and did not alter the heart rate. However, anti-arrhythmic effects were confirmed by observation of a dose-dependent reduction of spontaneous ventricular extrasystoles and ventricular tachycardia. Near maximum benefits were observed at 10 mg/kg/day, both in basal conditions or following a challenge with acute treatment of isoproterenol (0.5 mg/kg, dosed ip).

Conclusion:
In mice with post-ischemic HF, treatment with S44121 prevented the abnormal diastolic SR Ca2+ leak and ectopic Ca2+ waves, and reduced ventricular arrhythmias.
Abstract 18607: Intra-ventricular Papillary Muscle Banding vs. Undersized Mitral Annuloplasty to Treat Ischemic Mitral Regurgitation in a Chronic Swine Model
Authors: Padala Muralidhar , Kalra Kanika , Shi Weiwei , Wang Qian , Guyton Robert A , Sun Wei , Thourani Vinod H , Sarin Eric L
Published: July 2021

Introduction:
Intra-ventricular papillary muscle banding (PMB), is a new mitral repair technique for ischemic mitral regurgitation (IMR), which reduces lateral distance between the two muscles to relieve leaflet tethering (Fig A). In this study, we compared the hemodynamic efficacy of PMB against undersized mitral annuloplasty (UMA) and the combination of PMB and UMA, in a chronic swine IMR model.

Methods:
Six swine were induced with chronic IMR via percutaneous infarction of the postero-lateral wall of the left ventricle(LV), and followed to 6 weeks to develop >3+ IMR. At 6 weeks, via a left atriotomy an adjustable PMB externalized through the LV wall, and an adjustable UMA suture externalized through the anterior annulus were implanted (Fig B1,B2). The animals were weaned from bypass, and physiological swine hemodynamics of 90/65 mm Hg were achieved at 75 bpm. PMB was done such that 50% reduction in the lateral distance between the muscles was achieved, and UMA reduced septal-lateral annular dimension to 24mm. Epicardial echocardiography was performed to assess mitral valve function, with IMR severity and tenting area recorded. Computational valve modeling was performed to quantify leaflet stresses and chordal forces, to assess and compare repair durability.

Results:
Table 1 summarizes valve function after each repair, with PMB reducing MR grade from 3.67±0.52 to 0.33±0.52 (p<0.05), which was significantly better than the persistent MR grade of 1.5±0.55 after UMA (p<0.05). PMB+UMA achieved the best results overall. Similar trends in tenting area were seen, with PMB reducing the tenting area better than UMA, but the combination demonstrating the best results. Table 2 summarizes the valve and chordal stresses, with PMB alone or with UMA reducing the overall leaflet peak stress and chordal peak forces.

Conclusions:
PMB alone or concomitant with UMA is an effective technique to repair IMR in this model, with good hemodynamic efficacy and better mechanics compared to UMA.
Abstract 18667: Impact of Direct Contact Force Measurement on Electrical Reconnections after Circumferential Pulmonary Vein Isolation for Atrial Fibrillation Using a Contact Force-Sensing Catheter
Authors: Nakamura Kohki , Naito Shigeto , Sasaki Takehito , Minami Kentaro , Nakano Masahiro , Kumagai Koji , Funabashi Nobusada , Kobayashi Yoshio , Oshima Shigeru
Published: July 2021

Purpose:
To prospectively evaluate the incidence of pulmonary vein (PV) reconnections (PVRs) and identify predictors of PVRs after circumferential PV isolation (CPVI) using a contact force (CF)-sensing ablation catheter.

Methods:
Sixty-five patients (51-males; 61±10 years) undergoing an initial CPVI were studied. Both the right and left CPVI lines were divided into 12 segments and multiple regression models were used to predict PVRs in the four regions (each including 6 segments), the anterior and posterior RPVs and LPVs (A-RPVs, P-RPVs, A-LPVs, and P-LPVs). Each radiofrequency application was delivered with 15-30W for <30s along the P-LPVs and 30-40W for 40-60s along the others.

Results:
In 63 reconnected gaps, the right-PVs had more gaps in the anterior and posterior carina, while the left-PVs had more in the posterior carina than elsewhere, respectively (P<0.05). The P-RPVs and P-LPVs had significantly more gaps than the A-LPVs (17 A-RPVs, 21 P-RPVs, 6 A-LPVs, and 19 P-LPVs; P<0.05). The mean CF in the A-RPVs and P-RPVs (odds ratios (ORs), 0.916 and 0.854; P=0.014 and <0.001, respectively) and Force-Power-Time Index (FPTI) in the A-LPVs (OR, 0.99; P=0.012) were significant negative predictors of PVRs. According to the receiver operating characteristics analysis, at optimal cutoffs of mean CFs of 18g (A-RPVs) and 12g (P-RPVs), and FPTI of 36,737g.W.s (A-LPVs), the sensitivity and specificity for predicting PVRs were 81.3% and 61.9%, 71.3% and 52.9%, and 58.6% and 100%, respectively.

Conclusions:
The carina regions can be common sites for PVRs despite a higher CF and FPTI. An optimal CF and FPTI may be needed to prevent PVRs during an initial CPVI, especially in the RPVs and A-LPVs.
Abstract 18699: Negative Predictive Value of Transthoracic Echocardiography for Infective Endocarditis in the Modern Era
Authors: Sivak Joseph A , Vora Amit N , Navar-Boggan Ann Marie , Crowley Anna L , Kisslo Joseph , Velazquez Eric J , Samad Zainab
Published: July 2021

BACKGROUND:
Transesophageal echocardiography (TEE) is often recommended to exclude infective endocarditis (IE) in patients presenting with bacteremia despite a negative transthoracic echocardiogram (TTE). Previous studies showing inadequate sensitivity of TTE for native valve endocarditis are dated, and do not reflect modern advances in ultrasound image optimization technology. We hypothesized that with current generation echocardiography technology, a TTE absent mobile echo targets and without significant valvular abnormalities would have sufficient negative predictive value to exclude IE.

METHODS:
The Duke Echocardiographic Database was queried from 1/1/2007 [[Unable to Display Character: –]] 2/28/2014 for TTEs performed within 7 days prior to a TEE ordered for bacteremia/endocarditis. The dominant imaging platform used for both TTE and TEE during this era was the Philips IE33, with frequent use of fundamental frequencies to enhance spatial resolution beyond that of harmonic imaging alone. TTE studies identified as having poor sound transmission were excluded. A normal TTE was defined by the demonstration of normal cardiac anatomy, at most trivial valvular regurgitation, and absence of valvular stenosis, mobile/oscillating echo targets on valves, and hardware including catheters. The demonstration of an oscillating target on TEE along with clinical criteria based on chart review defined IE.

RESULTS:
A total of 974 unique patients had a TTE followed by a TEE within a week. IE was suggested in 209 of these patients by TEE. Among 107 patients meeting the a priori normal criteria on TTE, 3 patients had an abnormal TEE consistent with IE. These results correspond to a negative predictive value (NPV) of 97.2% (95% C.I. 91.4% - 99.3%) for a normal TTE to exclude IE.

CONCLUSIONS:
In this retrospective analysis from an academic medical center echocardiography laboratory, we demonstrated that an adequate quality TTE alone in a patient with a structurally normal heart without indwelling hardware has a high NPV for IE. Current TTE image optimization approaches may obviate the need to pursue TEE in patients after a recent preceding normal TTE.
Abstract 18701: Frequency and Contributing Factors to Diaphragm Paresis Following Pediatric Cardiac Surgery
Authors: Zafurallah Intikhab , Honjo Osami , Laussen Peter , MacDonald Cathy , Floh Alejandro
Published: July 2021

Introduction:
Diaphragm paresis can occur as a complication of pediatric cardiac surgery that can prolong ventilation and length of ICU stay. Diaphragm plication (DP) may be necessary to improve respiratory mechanics and decrease duration of ventilation support. Early identification of patients who are likely to benefit from DP has not been studied.

Methods:
Patients at our institution diagnosed with diaphragm paresis between 2002 - 2012 were identified. Mode of diagnosis, demographics, operative procedures during index admission, and intervals of care were evaluated. Associations between predictors and DP were assessed by univariable and multivariable logistic regressions.

Results:
Diaphragm paresis was diagnosed in 161 patients following 6448 index surgeries, of whom 31 (19%) underwent DP (DP+). Paresis was diagnosed by ultrasound in 160 (99%) subjects at a median (IQR) time from surgery of 7 (3, 11) days in DP+ vs 10 (6, 19) days in DP- (p=0.02). DP was completed after a median (IQR) of 4 (1, 17) days after diagnosis. DP+ were younger in age [median (IQR) days DP+ 42 (14, 84) vs DP- 168 (28, 784); p<0.001], underwent surgery of higher RACHS-1 score [DP+ 3 (3, 4) vs DP- 3 (2, 4); p=0.02], and had a higher rate of hypothermic circulatory arrest [DP+ 14 (45%) vs DP- 23 (18%); p=0.001]. DP+ subjects had a rate of single ventricle physiology (32%), median sternotomy (94%), and bypass (87%) similar to DP- subjects. Only younger age (OR 1.003 per day, p=0.02) and use of hypothermic circulatory arrest (OR 3.06, p=0.01) remained significant on multivariable modeling. DP+ subjects had longer duration of ventilator support [DP+ 15 (9, 30) vs DP- 6.5 (3, 12.5) days; p<0.001] and ICU admission [DP+ 23 (18, 42) vs DP- 8 (5, 17) days; p<0.001]. However, ventilation was discontinued after a median of 1 (1,2) day after plication. The time interval from index surgery to diagnosis (EST 0.91, p<0.0001) and interval from diagnosis to DP (EST 0.94, p<0.0001; r2=0.91) were associated with a longer ICU stay even after adjusting for age and bypass time.

Conclusion:
Diaphragm paresis is common after congenital heart surgery. Earlier diagnosis and plication may shorten length of ventilation support and ICU stay, particularly in younger patients. Long-term outcome studies following DP are required.
Abstract 18703: Impact of the 2014 Atrial Fibrillation Guideline on the Proportion of Patients Recommended for Oral Anticoagulation
Authors: O’Brien Emily C , Kim Sunghee , Hess Paul L , Freeman James V , Thomas Laine , Fonarow Gregg C , Ansell Jack E , Kowey Peter R , Hylek Elaine M , Mahaffey Kenneth W , Chang Paul , Piccini Jonathan P , Peterson Eric D
Published: July 2021

Introduction:
In 2014, the AHA/ACC/HRS published new atrial fibrillation (AF) treatment guidelines recommending use of a refined stroke risk score and revised threshold for oral anticoagulation (OAC) initiation.

Methods:
Using data from ORBIT-AF, an ongoing, national, outpatient AF registry conducted at 176 sites, we examined changes in the number of patients qualifying for OAC based on clinical stroke risk scores under 2011 ACCF/AHA/HRS versus 2014 AHA/ACC/HRS guidelines. Patients were considered recommended for OAC under the 2011 guideline with a CHADS2 score >=2 and under the 2014 guideline with a CHA2DS2-VASC score >=2. We reported the fraction of patients treated with OAC (warfarin or dabigatran) among patients qualifying for OAC under each guideline.

Results:
From 2009 - 2010, 10132 patients were enrolled in ORBIT-AF (median age [IQR] = 75 years [67 - 82]; 42.3% female). The proportion of patients qualifying for OAC increased from 71.8% under the 2011 guideline to 90.8% under the 2014 guideline (Figure). For patients under the age of 65, the proportion qualifying for treatment with OAC increased from 43.1% to 60.6%. Similar increases were observed for patients over the age of 65: 79.1% indicated for OAC under the 2011 guideline, compared with 98.5% under the 2014 guideline. There were 97.7% of women who qualified for OAC under the 2014 guideline, compared with 76.7% under the 2011 guideline. The fraction of indicated patients who were not receiving OAC increased under the 2014 guideline (21.9% vs. 19.9% under the 2011 guideline), with the highest undertreatment rates for patients younger than 65 (25.4%).

Conclusions:
The 2014 AF treatment guideline substantially increased the proportion of patients who qualified for OAC, with near-universal indication for women and for patients older than 65. Under the 2014 guideline, approximately 22% of the indicated patients in our community-based cohort did not receive OAC.
Abstract 18767: Association of Protein-Coding Genetic Variants with Coronary Arterial Calcification in 21,000 Individuals of European and African Ancestries
Authors: Natarajan Pradeep , Bielak Lawrence F , Bis Joshua C , Bowden Donald , Feitosa Mary F , Guðnason Vilmundur , Hwang Shih-Jen , Kathiresan Sekar , Kavousi Maryam , Lyytikäinen Leo-Pekka , Tada Hayato , Van Setten Jessica , Yanek Lisa R , Yao Jie , Yerges-Armstrong Laura M , O’Donnell Christopher J ,   Cohorts for Heart and Aging Rsch in Genomic Epidemiology (CHARGE) Consortium
Published: July 2021

Introduction:
Coronary arterial calcification (CAC) is a marker of subclinical atherosclerosis in asymptomatic individuals, and is a heritable risk factor that correlates with the risk of coronary artery disease (CAD) development. Genotyping protein-coding regions of the genome with an array is a scalable approach to potentially discover causal low-frequency and rare protein-coding mutations with large phenotypic effects.

Methods:
Using the Illumina HumanExome BeadChip, we genotyped 247,870 variants (of which 231,539 are in exons) in each of 17,953 participants of European ancestry and 3,078 participants of African ancestry without clinical CAD from the Diabetes Heart Study, Framingham Heart Study, Family Heart Study, Cardiovascular Health Study, Rotterdam Study, Age Gene/Environment Susceptibility Study, Multi-Ethnic Study of Atherosclerosis, Dutch & Belgian Lung Cancer Screening Trial, Young Finns Study, Gene Study of Atherosclerosis Risk in Families, High Risk Plaque Bioimage Study, Old Order Amish Study, and Jackson Heart Study. We tested whether protein-coding variants, individually or aggregated within a gene, were associated with CAC, both as a continuous and binary variable.

Results:
We first robustly replicated prior CAC genomic non-coding association signals at 9p21 (p=9.85 x 10-29) and PHACTR1 (p=4.10 x 10-23) identified in GWAS based on HapMap imputation. A rare nonsynonymous variant in APOB (rs5742904) was associated with increased CAC (p=1.01 x 10-10) although this signal was driven by the Old Order Amish where it is a known founder mutation. The nonsynonymous APOE rs7412 variant (maf=0.078), the APOE epsilon2 allele, was associated with reduced CAC (p=2.61 x 10-9). Additionally, there was evidence of association for the nonsynonymous SSTR3 rs4988466 variant (maf=0.046) (p=7.77 x 10-8). SSTR3 is involved in cell proliferation, among other functions. Gene-based burden approaches did not yield statistically significant associations.

Conclusions:
We discovered nonsynonymous coding variants in APOB, APOE, and SSTR3 associated with CAC in a meta-analysis approach of 21,000 individuals using an exon-enriched genotyping array.
Abstract 18787: Hypertension Treatment and Control Rates in United States Adults by Risk Group
Authors: Karmali Kunal N , Ning Hongyan , Lloyd-Jones Donald M
Published: July 2021

Introduction:
Ten-year cardiovascular disease (CVD) risk and absolute benefit from antihypertensive therapy vary at any given BP based on associated risk factor levels. Thus, implications of treatment and control rates at a particular BP vary substantially in different risk groups.

Objectives:
We examined the prevalence, treatment, and control of hypertension (HTN) by risk group in US adults without prevalent CVD.

Methods:
We used data from the National Health and Nutrition Examination Survey 2005 to 2010 for adults age 40-79 years without prevalent CVD (n=4,066). We estimated 10-year risk for an atherosclerotic CVD (ASCVD) event using the ACC/AHA 2013 Pooled Cohort risk equations. We examined HTN treatment and control rates according to current guidelines in middle-aged (40-59 years) and older (60-79 years) adults with: 10-year ASCVD risk <7.5% (no diabetes/kidney disease); 10-year ASCVD risk ≥7.5% (no diabetes/kidney disease); and either diabetes or kidney disease.

Results:
The proportion of adults with treatment-eligible HTN was 39.3% for those with 10-year ASCVD risk <7.5%, 32.2% for those with 10-year ASCVD risk ≥7.5%, and 28.4% for those with either diabetes or kidney disease (see Table 1). Treatment rates across the risk groups varied from 51.5% to 79.0% for middle-aged adults and 81.8% to 90.2% for older adults. HTN control rates were highest (87.7%) in older adults with 10-year ASCVD risk <7.5% but were lowest (29.3%) in middle-aged individuals with 10-year ASCVD risk ≥7.5%.

Conclusions:
US HTN guidelines, based solely on BP thresholds, identify a higher proportion of low-risk adults and a lower proportion of high-risk adults as being eligible for treatment. Control rates remain suboptimal in high-risk individuals, particularly middle-aged adults. Future guidelines should consider pre-treatment risk stratification to identify those at increased pretreatment ASCVD risk who would benefit most from more intensive therapy.
Abstract 18789: A Learning Collaborative Model to Improve Door to Needle Time for Stroke Thrombolysis in Chicago
Authors: Prabhakaran Shyam , O’Neill Kathleen ,   Chicago Primary Stroke Cntrs QUESTS Initiative
Published: July 2021

Background:
Door-to-needle (DTN) times have remained suboptimal despite overall increases in tissue plasminogen activator use (tPA) for stroke in Chicago. The American Heart Association’s (AHA) Quality Enhancement for Speedy Thrombolysis in Stroke (QUESTS) initiative aimed to identify barriers to reduce DTN times at Chicago’s 15 primary stroke centers (PSCs) and increase the proportion of patients treated with tPA within 60 minutes of hospital arrival.

Methods:
Starting in January 2013, we used face-to-face and on-site meetings with each PSC’s stroke team members to share AHA Target Stroke best practices and strategies to reduce DTN time. A survey of current practice was completed at each site to determine opportunities for improvement and repeated at 1 year to assess implementation of new strategies. We used the Get With The Guidelines (GWTG) Stroke registry to aggregate baseline data DTN times and track performance in each quarter of 2013.

Results:
At baseline, 5 strategies were notably under-utilized at Chicago’s 15 PSCs: 1) Direct to CT scanner (baseline: 0 sites; 1 year: 5 sites); 2) pre-mixing tPA (baseline: 1 site; 1 year: 14 sites); 3) tPA prior to laboratory results (baseline: 3 sites; 1 year: 7 sites); 4) stroke code activation at triage (baseline: 4 sites; 1 year: 13 sites); and 5) streamlined consent process (baseline: 0 sites; 1 year: 12 sites. The proportion of patients treated within 60 minutes increased in each quarter of 2013 from 25% in quarter 1 to 60% in quarter 4 (p<0.01). The median DTN time decreased from 89.5 minutes in quarter 1 to 55 minutes in quarter 4 (p<0.01).

Conclusions:
Using a learning collaborative model to implement strategies to reduce DTN times among 15 PSCs in Chicago, we observed major improvements within a few months. Regional collaboration and best practices sharing should be a model for rapid and sustainable system-wide quality improvement.
Abstract 18795: Resting Patient- and Vessel-Specific Myocardial Perfusion Attenuation Patterns Improves Diagnostic Performance of Coronary Computed Tomographic Angiography
Authors: Xiong Guanglei , Cho Iksung , Gransar Heidi , Kola Deeksha , Elmore Kimberly , Heo Ran , Soohoo Hilary , Truong Quynh , Chang Hyuk-Jae , Min James K
Published: July 2021

Introduction:
Coronary CT angiography (CCTA) demonstrates improved performance for diagnosis of high-grade coronary stenoses, but may be affected by artifacts and overestimation of stenosis severity. Whether the addition of resting myocardial perfusion attenuation patterns subtended by stenosis seen on CCTA improves diagnostic performance has not been examined to date.

Methods:
We evaluated 127 patients (mean age 53.0, 54.3% male) who underwent CCTA and ICA. Percentage of coronary stenosis was assessed by quantitative coronary angiography (QCA), which served as the reference comparator to CCTA. CCTA stenosis was categorized as 0%, 1-24%, 25-49%, 50-69%, 70-99%, and 100% luminal diameter reduction. Automated software (SmartHeart, Redwood City, CA) was used to measure resting CT perfusion attenuation patterns in myocardial segments by AHA 17-segment model. Segmental CT attenuation values were assigned to territories subtended by left anterior descending (LAD), left circumflex (LCX), and right coronary arteries (RCA). Per-patient and per-vessel analyses were based on highest severity (maximal stenosis, minimal attenuation). On both per-patient and per-vessel basis, logistic regression was devised for CCTA stenosis alone and for CCTA plus resting myocardial attenuation. Diagnostic accuracy and area under the receiver operating characteristics curve (AUC) were determined.

Results:
Diagnostic accuracy of CCTA alone was 84.0%, 85.5%, 90.4%, and 88.6%, at per-patient, per-LAD, per-LCX and per-RCA level, respectively. In comparison, the accuracy of CCTA plus myocardial attenuation were 89.6%, 91.9%, 95.2%, and 92.7%. The AUCs using CCTA alone to discriminate QCA-confirmed coronary stenoses >70% were 0.823 (95% CI: 0.737-0.909), 0.782 (95% CI: 0.667-0.898), 0.690 (95% CI: 0.503-0.878), and 0.793 (95% CI: 0.640-0.945) for per-patient, per-LAD, per-LCX, and per-RCA analysis, respectively. The AUCs using CCTA plus myocardial attenuation improved to 0.864 (95% CI: 0.765-0.962), 0.881 (95% CI: 0.793-0.968), 0.772 (95% CI: 0.535-1.000), and 0.820 (95% CI: 0.685-0.954).

Conclusions:
The addition of resting CT myocardial perfusion attenuation patterns improves identification and discrimination of high-grade coronary stenosis by CCTA.