bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11800: Whole Exome Sequencing in a Large Pedigree With DCM Identifies a Novel Mutation in RBM20
Authors: Robyns Tomas , Van Cleemput Johan , Willems Rik , Jhangiani Shalini , Muzny Donna , Gibbs Richard , Lupski James R , Breckpot Jeroen , Devriendt Koenraad , Matthijs Gert , Corveleyn Anniek
Published: July 2021

Background and hypothesis:
Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 30 different genes. None of these genes have an expected diagnostic yield of more than 10% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We performed WES in a large family with autosomal dominant DCM complicated by end stage heart failure and ventricular arrhythmias. The index of this family was evaluated previously by means of targeted gene panel analysis including 28 genes, but no causal mutation was found.

Methods and results:
WES was applied on 2 affected cousins. First, shared heterozygous variants (single nucleotide variants, small insertions and deletions) located inside the exon or at the exon/intron boundary were selected. Synonymous variants were excluded, except if they were located at the exon/intron boundaries. Variants with a minor allele frequency of >0.1% in publically available exome databases (1000 Genomes and ESP) were excluded. Furthermore, variants that were present in an in-house exome cohort performed for other disease entities were also excluded since these probably represent local SNV’s. The remaining 19 variants were evaluated using a comprehensive scoring system that includes different in-silico analysis tools, orthologous and paralogous conservation and population frequencies. Subsequently Sanger sequencing was performed for 10 variants that were classified as likely pathogenic (N=1) or variants of unknown significance (N=9) according to the scoring system in order to confirm the presence of the variant and to evaluate co-segregation. Only one variant in exon 9 of the RBM20 gene (c.2714T>A, p.Met950Lys, NM_001334363) showed full co-segregation in the 7 affected family members resulting in a maximum 2-point LOD score of 2.1 and suggesting this as the pathogenic mutation responsible for the phenotype. Recently mutations in RBM20 have been linked to dilated cardiomyopathy caused by defective splicing of the giant sarcomeric protein titin.

Conclusions:
We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.
Abstract 11919: Dementia and Stroke Rates Were Lower Among Patients Receiving Long-term Anticoagulation Therapy With Novel Oral Anticoagulants Compared to Warfarin
Authors: Jacobs Victoria , May Heidi T , Bair Tami L , Anderson Jeffrey L , Crandall Brian G , Cutler Michael , Day John D , Mallender Charles D , Osborn Jeffrey S , Stevens Scott M , Weiss J P , Woller Scott C , Bunch T J
Published: July 2021

Introduction:
Patients with atrial fibrillation (AF) are at an increased risk of developing dementia, and this risk appears sensitive to quality of warfarin control. Longstanding warfarin use predisposes AF patients to the development of microbleeds if they are over-anticoagulated and microemboli if they are under-anticoagulated. The novel oral anticoagulants (NOACs) offer an alternative to warfarin with a predictable anticoagulant effect, and comparatively favorable intracranial bleeding and thrombosis rates which may lower the risk of dementia.

Hypothesis:
The use of NOACs will be associated with a lower risk of stroke, TIA, and dementia compared to warfarin.

Methods:
Patients receiving long-term anticoagulation therapy with either warfarin or a single NOAC for thromboembolism prevention were studied (June 2010-December 2014). NOAC and warfarin patients were matched 1:1 by index date (± 6 months) and propensity score (±0.01). Multivariable Cox hazard regression was performed to evaluate the association of NOAC compared to warfarin use for the composite outcome of dementia, stroke, and TIA.

Results:
A total of 5,254 (2,627 per group) patients were studied, and those receiving NOACs included: apixaban= 590 (22.5%), dabigatran=583 (22.2%), and rivaroxaban=1,454 (55.3%). Average age was 72.4±10.9 and 59.0% were male. The majority of patients were receiving long-term anticoagulation for AF (warfarin: 96.5% vs. NOAC: 92.7%, p<0.0001). History of a prior stroke/TIA were similar between the groups (warfarin: 10.7% vs. NOAC: 10.8%, p=0.89). Dementia incidence alone was lower in the NOAC group compared to the warfarin group (0.3% vs. 1.6%, p<0.0001). The composite outcome of dementia, stroke, and TIA occurred in 4.7% of warfarin patients and 1.8% of NOAC patients (p<0.0001). After adjustment, patients taking NOACs had a 51% decreased risk of dementia incidence or subsequent stroke or TIA compared to patients taking warfarin (HR=0.49 (0.35, 0.69), p<0.0001).

Conclusions:
This study shows the use of NOACs in a community setting to be superior to that of warfarin for the composite outcome of dementia, stroke, and TIA among patients receiving long-term oral anticoagulation.
Abstract 12239: Efficacy and Safety of the Non-vitamin K Antagonist Oral Anticoagulants (NOACs) in Japan: A Retrospective Cohort Study Using the National Database of Health Insurance Claim
Authors: Inoue Masahiro , Miyamoto Yoshinori , Yasuda Kotaro , Ikeda Shunya , Nishigaki Masakazu , Takamatsu Kazuhiro , Sato Michiyoshi , Kuriyama Masaru , Yagita Yoshiki
Published: July 2021

Objective:
Examine efficacy and safety of anticoagulation (AC) treatment in Japanese Acute hospitals

Methods:
Insurance claim data of 66, 693 patients who received anticoagulant treatment were extracted from 352 (20%) of hospitals of all 1580 hospitals enrolled in national database of health insurance, Diagnosis Procedure Combination (DPC) database. All the patients received anticoagulant treatment using warfarin and/or non-vitamin K antagonist oral anticoagulants (NOAC) during 10/1/2012 and 9/30/2014. NOACs in this study are: dabigatran, rivaroxaban, and apixaban. We observed incidence of ischemic stroke as efficacy related outcome. We also observed following unfavorable events: intracranial hemorrhage, gastrointestinal hemorrhage, and all-cause death. Outcomes were compared between group of warfarin-treated patients and NOACs-treated patients.

Findings:
Of 66,693 patients treated with anticoagulants, 50,523(77.3%) were treated with Warfarin, 16,170(24.8%) were with NOACs. Among 66,693 patients, 1,378 patients (2.1%) who were treated with both drugs were excluded for the analysis. The event rate of ischemic stroke was similar between warfarin-treated group and NOACs-treated group 849 (1.68%) vs 245 (1.52%), respectively (p=0.16). On the other hands, unfavorable events were observed significantly more frequently in warfarin-treated group than NOACs-treated group: all-cause death, 4,875(9.6%) vs 724(4.5%), respectively (p<0.001); intracranial hemorrhage, 685(1.4%) vs 94(0.6%), respectively (p<0.001); gastrointestinal hemorrhage, 883 (1.74%) vs 157 (0.97%), p<0.001).

Conclusions:
This retrospective study based on large-scale national database revealed that efficacy of warfarin and NOACs were equivalent. However, risk of all-cause death and unfavorable bleeding events was higher in warfarin-treated patients than NOACs-treated patients. This study demonstrates that NOACs contribute a beneficial effect on anticoagulation treatment for the patients with atrial fibrillation in the real world.
Abstract 12418: Fish Consumption and Adipose Tissue Content of Marine n-3 PUFA is Inversely Associated With Myocardial Infarction: A Danish Prospective Cohort Study
Authors: Gammelmark Anders , Nielsen Michael S , Bork Christian S , Lundbye-Christensen Søren , Overvad Kim , Schmidt Erik B
Published: July 2021

Introduction:
Several studies have investigated the potential benefits from marine n-3 polyunsaturated fatty acids (PUFA) on cardiovascular disease, generally suggesting a lower risk of coronary heart disease. However, recent trials have questioned these results and clinical guidelines are currently at debate.

Hypothesis:
This study investigated the association of fish consumption, intake of marine n-3 PUFA and adipose tissue content of marine n-3 PUFA with incident myocardial infarction (MI), expecting to find an inverse relationship.

Methods:
In a Danish prospective cohort study 57,053 subjects between the age of 50-64 years were enrolled from 1993-97. From national registries we identified all cases of incident MI. Dietary intake of total, fatty and lean fish was assessed using a semi-quantitative food questionnaire, and analyzed in a traditional cohort design. Adipose tissue biopsies were analyzed for all MI-cases and a randomly selected sub-cohort (n=3409). Associations between adipose tissue content of major marine n-3 PUFA and MI were examined using a nested case-cohort design.

Results:
During a mean follow-up time of 15.9 years, we identified 3,089 cases of incident MI. In both men and women, a high intake of fatty fish (>28 g/day) was inversely related to incident MI. Comparing the highest and lowest quintile, we found a 12 % lower relative risk in men (HR=0.88; 95% CI: 0.77;1.00) and a 24% lower relative risk in women (HR=0.76; 95% CI: 0.61;0.95). Total and lean fish was neutrally associated with MI. Furthermore, high content of EPA and DHA in adipose tissue was negatively associated with incident MI. However, only EPA remained statistically significant after multivariate adjustments with a HR of 0.76 (CI: 0.59;0.98) for men and HR of 0.65 (CI: 0.45;0.94) for women.

Conclusions:
Incident MI was inversely associated with fatty fish intake and content of EPA in adipose tissue. This study supports the view that consumption of fatty fish may protect against MI.
Abstract 12428: Efficacy of a Risk Reduction Program to Improve Cardiovascular Outcomes in Patients With Peripheral Arterial Disease: A Propensity Score-Matched Study
Authors: Hussain Mohamad A , Al-Omran Mohammed , Mamdani Muhammad , Wang Xuesong , Verma Subodh , Lindsay Thomas
Published: July 2021

Introduction:
Patients with peripheral arterial disease (PAD) are often undertreated for cardiovascular (CV) risk factors, and they are at high risk for CV events.

Hypothesis:
A program that focuses on guideline-based risk factor management reduces adverse CV and limb events in PAD patients.

Methods:
A propensity-score matched observational cohort study with up to 7 years of follow-up was conducted using administrative databases in Ontario, Canada. Symptomatic PAD patients that were enrolled in the Systematic Assessment of Vascular Risk (SAVR) program between July 2004 and April 2007 were matched with up to 2 (control) patients with PAD from other Ontario tertiary vascular centers not enrolled in the program. The primary outcome was a composite of death, stroke or myocardial infarction (MI). Secondary outcomes included lower limb amputation and revascularization procedures. Cox proportional hazards regression analysis was used to compare outcomes between the groups.

Results:
A total of 791 patients were studied. During follow-up, the SAVR group (n=290) experienced the primary outcome at a significantly lower rate than the control group (adjusted HR, 0.64 [95% CI, 0.52 to 0.78]; P<0.001) (Figure). SAVR patients were also less likely to undergo major amputation (adjusted HR, 0.47 [95% CI, 0.29 to 0.77]; P=0.002), minor amputation (adjusted HR, 0.26 [95% CI, 0.13 to 0.54]; P<0.001), arterial bypass surgery (adjusted HR, 0.47 [95% CI, 0.30 to 0.73]; P<0.001), and less likely to have a hospitalization due to heart failure (adjusted HR, 0.73 [95% CI, 0.53 to 0.998]; P=0.048). The rate of peripheral angioplasty was higher among the SAVR group (adjusted HR, 3.0 [95% CI, 2.2 to 4.1]; P<0.001).

Conclusions:
A multifactor risk reduction program targeted to patients with PAD is associated with fewer adverse CV and limb events over the long-term. Greater focus is needed on developing structured programs for risk factor control in these high-risk patients.
Abstract 12442: Hypercholesterolemia and Angiotensin II Induces Spontaneous Atherothrombotic Occlusion of balloon-injured Rabbit Iliac Arteries; Effects of Lipid-Lowering Therapies
Authors: Honda Katsuya
Published: July 2021

Background:
Atherothrombotic occlusion of a coronary artery with an intact fibrous cap is a major cause of acute coronary syndrome that is attributed to plaque erosion. We developed an animal model of spontaneous atherothrombotic occlusion of fibrous cap-intact arteries in rabbits.

Methods and Results:
We performed balloon injury in bilateral iliofemoral arteries in male Japanese white rabbits fed with high (2 %) cholesterol diet and infused with angiotensin II (50 ng/kg/min). Animals were divided into 3 groups; 1. no treatment, 2. Ezetimibe 0.6 mg/kg/day, and 3. Rosuvastatin 1.0 mg/kg/day. We examined the occurrence of atherothrombosis by high-resolution ultrasonograpy (Vevo2100) 3 times/week. (Fig. A) After the occurrence of acute thrombotic occlusion, the presence of thrombosis was confirmed by angiographic and histopathologic examination. Histochemical analysis in the atherothrombotic sites revealed; 1) no severe stenosis (% stenosis: 49±7), 2) no plaque rupture or lipid core, and 3) no PECAM1-positive endothelial layer. Interestingly, there were smooth muscle-like cells (αSMA+/SM1, SM2, SMemb and calponin-) with tissue factor expression at the neointima-thrombus interface.

Oral treatment with Ezetimibe but not Rosuvastatin significantly reduced the incidence of atherothrombotic occlusion (Fig. B). Serum from the model rabbits induced TF in cultured rat smooth muscle cells. TF induction by serum from Ezetimibe-treated rabbits was significantly less compared with those from animals without treatment or with Rosuvastatin treatment (Fig. C).

Conclusions:
We established for the first time an appropriate animal model of spontaneous atherothromobotic occlusion in rabbits, which mimicked the pathological features of plaque erosion observed in human coronary arteries. This model may provide a clue to a mechanistic understanding and potential therapeutic approaches for plaque erosion.
Abstract 12449: The Electrocardiogram Left Ventricular Hypertrophy With Strain Pattern Predicts Recurrence in Paroxysmal Atrial Fibrillation Patients After Radiofrequency Catheter Ablation
Authors: Wang Lu , Li Song-Nan , Salim Mohamed , Wang Zhe , Yang Wang-Yang , Ning Man , Tang Ri-Bo , Sang Cai-Hua , Jiang Chen-Xi , Yu Rong-Hui , Long De-Yong , Liu Nian , Bai Rong , Du Xin , Dong Jian-Zeng , Ma Chang-Sheng
Published: July 2021

Introduction:
The present of left ventricular hypertrophy (LVH) or LVH with strain pattern on electrocardiogram (ECG) are independently predictors of new-onset atrial fibrillation (AF).

Hypothesis:
We assessed the hypothesis that LVH with or without strain can predict recurrence after radiofrequency catheter ablation (RFCA) of AF in paroxysmal atrial fibrillation (PAF) patients.

Methods:
436 PAF patients undergoing RFCA were enrolled and clustered into 3 subgroups: Non-LVH (218 patients), LVH (182 patients), LVH with strain (36 patients). LVH was characterized by the Romhilt-Estes point system and ECG strain was defined as ST-segment depression≥1-mm and T-wave inversion≥1 mm in the lateral leads.

Results:
After 42 (interquartile range, 18.0 to 60.0 months) months follow-up period with a median of 1 (1 to 3) RFCA procedure, sinus rhythm was maintained in 248 patients (60.2%) without antiarrhythmic drugs. Patients with LVH (79, 43.6%) and LVH with strain (22, 62.9%) tended to experience much higher AF episodes recurrence ratio compared to those with non-LVH (71, 33.3%; P=0.000). In multivariate analysis after adjustment for age, sex, CHA2SDVAS score and left atrial diameter (LAD), the present of LVH with strain was the only independent risk factor of AF recurrence (95%CI: 1.242 to 5.808, P=0.012).

Conclusions:
That present of LVH with strain but not LVH alone is a strong and independent predictor of AF recurrence in PAF patients following RFCA.
Abstract 12903: The Myocardial Contraction Fraction Calculated From Two-dimensional Echocardiography is Associated With Lower Incidence of Heart Failure, Cardiovascular Disease and Mortality: The Cardiovascular Health Study
Authors: Maurer Mathew S , Jen Hoe Koh William , Bartz Traci M , Vullaganti Sirish , Barasch Eddy , Gardin Julius M , Gottdiener John S , Psaty Bruce M , Kizer Jorge R
Published: July 2021

Introduction:
The myocardial contraction fraction (MCF), the ratio of LV stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening. With 3D-echocardiography and MRI, MCF distinguished pathologic from physiologic hypertrophy and predicted incident CV events. However, the association between 2D echo-determined MCF and adverse CV outcomes is not known, nor has the premise that this ratio adequately captures the predictive information of its components, SV and MV, been tested.

Methods:
Using CHS data, we calculated MCF from 2-D guided M-mode echo dimensions to estimate LV volumes and SV. MV was estimated from the measurements of LV mass divided by myocardial density. Among individuals with a normal EF, Cox regression was used to examine the associations between MCF with incident heart failure (HF), cardiovascular disease (CVD), and all-cause mortality adjusting for clinical and echo parameters. We further examined the validity of the premise that log(SV) and log(MV) contribute in the expected ratio of 1: -1 with our outcomes of interest.

Results:
1556 participants were identified with an EF ≥ 55% (age 72±5) that had baseline echo data and available covariate information. MCF averaged 58% (Range: 21-104%). After controlling for CV, clinical risk factors, echo variables and NT-proBNP, a 10% relative increase in MCF was significantly associated with reduced risk of HF, CVD and death. When included separately in the models, both MV and SV showed significant associations with CVD and death, however, only MV was significant for HF and the coefficients violated the 1:-1 ratio suggesting MCF is not the best way to model this relationship.

Conclusions:
Among older adults with normal EF, 2D-echo MCF was associated with a lower risk of adverse CV outcomes after adjustment for clinical factors, echo parameters, and NT-proBNP. However, MCF compared to its component measures might be inadequate for risk prediction in HF.
Abstract 12966: Combination of Urine Sodium Concentration and Plasma Brain Natriuretic Peptide Level Best Predicted the Clinical and Hemodynamic Effects of Tolvaptan Therapy in Patients With Heart Failure
Authors: Sato Yuichi , Dohi Kaoru , Takeuchi Tetsushiro , Tanimura Muneyoshi , Sugiura Emiyo , Kumagai Naoto , Nakamori Shiro , Fujimoto Naoki , Yamada Norikazu , Ito Masaaki
Published: July 2021

Purpose:
We identified the best predictors of clinical response to simple add-on tolvaptan (TLV) therapy in patients with heart failure (HF).

Methods:
We retrospectively enrolled 60 HF patients with excess fluid retention despite receiving adequate medical therapy including oral diuretics. All patients received simple add-on TLV (median of 7.5mg/day). They underwent right heart catheterization at baseline and after 7-day treatment.

Results:
Although the majority of patients were successfully treated with simple add-on TLV therapy (Group 1), but 22% (Group 2) were defined as being unsuccessfully treated because 1) HF symptom score worsened or 2) HF symptom score >6, and mean pulmonary capillary wedge pressure (PCWP) >18 mmHg and mean right atrial pressure (RAP) >10 mmHg after TLV therapy. Although the degrees of body weight reduction and increment of urine volume were similar between the two groups, HF symptom score and mean PCWP and RAP improved, and plasma BNP level decreased only in the group 1 after TLV therapy. The group 2 had lower urine sodium/creatinine ratio (UNa/UCr) and higher plasma BNP level than responders at baseline, and they were identified as the independent predictors of unsuccessful TLV therapy by multivariate logistic regression analysis. Receiver operating characteristic curve analysis showed that UNa/UCr was the strongest predictor of unsuccessful TLV therapy with cut-off point of 46.5 mEq/gCr (AUC 0.847, 95% CI; 0.718-0.976, sensitivity 77%, specificity 81%, P<0.001). Furthermore, combination with UNa/UCr 778 pg/ml best predicted unsuccessful TLV therapy with sensitivity of 54%, specificity of 100%, positive predictive value of 100%, negative predictive value of 89%, and accuracy of 90%.

Conclusion:
Simple add-on tolvaptan therapy ameliorated HF symptoms and provided hemodynamic improvement in majority of patients with HF, and the measurements of UNa/UCr and BNP level can help clinicians tailor HF treatment.
Abstract 13194: The Effects of Methotrexate Therapy on Myocardial Infarction With ST-Segment Elevation (TETHYS Trial)
Authors: Moreira Daniel M , da Silva Roberto L , Lueneberg Maria E , Fattah Tammuz , Gottschall Carlos A
Published: July 2021

Introduction:
Acute myocardial infarction provokes inflammatory activation. Methotrexate is one drug that has been shown to have anti-ischemic effects in experimental studies.

Hypothesis:
Methotrexate could reduce inflammation and the ischemia area in acute myocardial infarction

Methods:
We randomly assigned patients with myocardial infarction with ST-segment elevation to receive either methotrexate (0.05 mg/kg bolus followed by 0.05 mg/kg/h for 6 h) or matching placebo (riboflavin sodium phosphate 0.1%, in order to preserve double-blinding) at a ratio of 1:1. Patients in both groups were given a 5mg single dose of folic acid. The primary endpoint was infarct size, determined by the area under the curve (AUC) for creatine kinase (CK) release. Secondary endpoints were AUC of CK-MB and AUC of troponin I; peak CK, peak CK-MB and troponin I; B-type natriuretic peptide (BNP) level, high-sensitivity C-reactive protein (hsCRP) result and erythrocyte sedimentation rate (ESR); left ventricular ejection fraction (LVEF); TIMI frame count; Killip score; mortality and reinfarction incidence. The safety endpoint was the incidence of adverse reactions.

Results:
We included 84 patients. The AUC of CK was 78,861.00 in the methotrexate group and 68,088.00 in the placebo group (P=0.10). Patients given methotrexate and placebo exhibited, respectively, AUC for CK-MB of 9,803.40 and 8,037.00 (P=0.42); AUC for troponin I of 3,691.11 and 2,132.63 (P=0.09); peak CK of 2,806.00 and 2,147.00 (P=0.05), peak CK-MB of 516.00 and 462.25 (P=0.25) and peak troponin I of 121.00 and 85.05 (P=0,06). At 3 months, LVEF was lower in patients who received methotrexate (48.97±14.09%) than in patients given placebo (56.37±9.97%) (P=0.01). There were no differences in hsCRP, ESR, BNP, Killip scores or TIMI frame count. There were also no differences in reinfarction or mortality rates or in incidence of side effects, with the exception of higher median serum glutamic-pyruvic transaminase (SGPT) levels in the methotrexate group.

Conclusions:
Methotrexate did not reduce infarction size and worsened LVEF at 3 months.
Abstract 13242: What is the Optimal Blood Pressure in Patients With Asymptomatic Aortic Valve Stenosis: The SEAS Study
Authors: Nielsen Olav W , Sajadieh Ahmad , Sabbah Muhammad , Greve Anders M , Olsen Michael H , Boman Kurt , Nienaber Christoph A , Kesäniemi Antero , Pedersen Terje , Willenheimer Ronnie , Wachtell Kristian
Published: July 2021

Introduction:
Very limited data regarding blood pressure and antihypertensive treatment in asymptomatic aortic valve stenosis (AS) have been published, and no announced consensus statement has provided recommendations for optimal blood pressure targets in this patient population.

Hypothesis:
Our research question was to use the best available observational data from the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) trial to identify what blood pressure (BP) would be optimal in terms of mortality in asymptomatic AS.

Methods:
We evaluated 1798 patients with asymptomatic AS enrolled in the SEAS trial. Average follow-up BP was examined. Primary outcome was all-cause mortality, and secondary outcomes were cardiovascular death, heart failure, stroke and aortic valve replacement (AVR).

Results:
Average blood pressure was 144/82 mmHg and half the patients had a history of hypertension. In multivariate analysis, all-cause mortality was increased for systolic BP < 120 (HR=5, p<0.001), systolic 120-139 (HR=1.5, p=0.031) and diastolic BP >= 90 mmHg (HR=1.9, p=0.015). Adjusting for time dependent in-between events such as aortic valve replacement, heart failure and non-fatal myocardial infarction did not significantly modify the risk. Patients at 75 years of age or more with history of hypertension had increased mortality risk with diastolic BP >= 90 mmHg (HR= 3.3, p=0.004). Patients below 75 years of age with a history of hypertension had an increased risk with systolic BP >= 160 mmHg (HR=2.1, p=0.049).

Conclusions:
In asymptomatic aortic valve stenosis all-cause mortality is lowest at a systolic BP between 140 to 159 mmHg and at a diastolic between 70 to 89 mmHg. Patients with low systolic blood pressure, in general, had increased mortality risk, and should undertake individual clinical assessment.
Abstract 13540: Peritoneal Dialysis vs. Furosemide for the Treatment of Oliguria in Infants After Cardiopulmonary Bypass
Authors: Kwiatkowski David M , Goldstein Stuart L , Cooper David S , Nelson David P , Morales David L , Krawczeski Catherine D
Published: July 2021

Objectives:
Acute kidney injury (AKI) is a frequent and serious complication in infants after cardiac surgery with cardiopulmonary bypass (CPB). Often the earliest sign is oliguria, which can lead to fluid overload, prolonged mechanical ventilation and ICU stay, abnormal electrolytes and increased mortality. We hypothesized that the use of peritoneal dialysis (PD) compared to furosemide use would mitigate these complications.

Methods:
This is a single-center, surgical complexity-stratified, randomized controlled trial performed within a cohort of patients younger than 6mo undergoing cardiac surgery with a preoperative plan of PD catheter placement due to risk of post-CPB kidney injury. If enrolled patients had urine output < 1mL/kg/hour for 4 hours during the first postoperative day, the patient was randomized to either a standardized regimen of furosemide or PD. If the patient demonstrated poor response to furosemide, PD could be initiated on postoperative day 2.

Results:
A total of 73 patients were randomized and completed the trial, including 2 patients who were randomized to furosemide and subsequently received PD. Using intention-to-treat analysis, the PD group was less likely to have fluid overload, had a lower delayed-extubation rate and fewer electrolyte replacements. There were no differences in mortality or ICU/hospital stay. No serious PD related complications were observed. PD was discontinued early in 9 patients due to pleural-peritoneal communication.

Conclusions:
Our study demonstrates that the use of PD in neonates with oliguria after CPB is associated with reduced morbidity but not differences in mortality or ICU/hospital stay. A multi-center study is necessary to further support these findings as well as determine association with mortality.
Abstract 13686: Implementing a Regionalized Integrated Network for ST-segment-Elevation Myocardial Infarction (STEMI) Care is Associated With Higher Use of Evidence-Based Medication and Better Survival Among STEMI Patients: Long-Term Results From the RESISST Registry
Authors: Filgueiras Filho Nivaldo M , Solla Davi J , Argolo Felipe C , Braghiroli Oddone F , Paiva-Filho Ivan M , Lima Marina B , Costa Fernanda F , Feitosa-Filho Gilson S , Newby Lauren K , Lopes Renato D
Published: July 2021

Introduction:
We have shown that implementing a Regional Network in developing countries is feasible.

Purpose:
Describe temporal trends in 30-Day mortality among STEMI patients enrolled in a prospective registry in Brazil.

Methods:
From Jan 2011 to Aug 2013, 520 patients received primary STEMI care at 23 non-specialized public health units (7 general hospitals; 16 community-based emergency units) with the option to be transferred to one of two public cardiology reference centers (CRC). These patients were identified through a Regional STEMI Network supported by telemedicine and the local prehospital emergency medical service.

Results:
Mean age was 62.0 ± 12.2y, and most patients were men (55.6%). Mean GRACE score was 145 ± 34. Overall mortality at 30 days was 15.0%. The median pain-to-admission time was 180 (IQR 66-430) min and admission-to-ECG, 159 (IQR 70-379) min. We analyzed the differences of results over 2.5 year period, separating the patients in 5 6-month periods from 1/2011 to 1/2013. There were no differences in pain-to-admission or admission-to-ECG times and no difference in GRACE score over time. Use of several acute medical treatments increased significantly from baseline to period 5: dual antiplatelet therapy (1/2011, 61.8%; 1/2013, 93.6%; p<0.001) and statin (1/2011, 60.4%; 1/2013, 79.7%; p<0.001). Rates of primary reperfusion also increased (1/2011, 29.1%; 1/2013, 53.8%; p<0.001) and more patients were transferred to CRC (1/2011, 44.7%; 1/2013, 76.3%; p=0.001). 30-day mortality rates decreased from 20.4% in 1/2011 compared with 7.5% in 1/2013 (p<0.001) (Figure).

Conclusion:
Implementation of a regional STEMI system was associated with lower mortality rates at 30 days and higher use of evidence-based treatment. Our findings highlight opportunities to improve the care of STEMI patients in developing countries.
Abstract 13875: Torsade de Pointes Arrhythmias Arise at the Site of Maximal Heterogeneity of Repolarization in the Chronic Complete AV-block Dog
Authors: Dunnink A , Stams TRG , Beekman HDM , Bossu A , Wijers SC , Meijborg VMF , de Bakker JMT , Vos MA
Published: July 2021

Introduction:
The chronic complete atrioventricular block (CAVB) dog model is highly sensitive for drug-induced Torsade de Pointes (TdP) arrhythmias. Focal mechanisms have been considered as trigger for the onset of TdP, however, its exact mechanism remains unclear. In this study, detailed mapping of the heart was performed to assess intraventricular heterogeneity of repolarization in relation to the initation of TdP.

Methods:
In 6 animals, 48 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500ms) local unipolar electrograms were recorded before and after administration of dofetilide. Activation- and repolarization times (RT) were measured at baseline and before occurrence of the first TdP or at 5 minutes after start of dofetilide infusion in inducible and non-inducible dogs. Maximal RT differences were calculated in the left ventricle 1) within adjacent electrodes in different planes (transmural, apex-base, anterior-posterior) and 2) within a square of 4 needles (3D dispersion).

Results:
TdP could be induced in 3 out of 6 animals. No difference in mean RT was observed between inducible and non-inducible dogs both at baseline (343±30 vs. 345±17ms) and after dofetilide administration (582±73 vs. 508±15ms). Maximal dispersion of RT was not different between both groups at baseline: 36±32 vs. 32±7ms (transmural), 50±20 vs. 42±9ms (apex-base), 71±28 vs. 47±13ms (anterior-posterior), 83±19 vs. 70±6ms (3D dispersion). After dofetilide infusion anterior-posterior (203±28 vs. 142±34ms, p=0.04) and 3D dispersion (268±41 vs. 176±48ms, p=0.03) showed a higher RT difference in the inducible animals. No differences were observed for transmural (124±14 vs. 116±18ms, p=0.557) and apex-base dispersion (142±12 vs. 121±23ms, p=0.229). The initiating beat of the TdP arose consistently from the region with the largest local spatial dispersion of repolarization moments.

Conclusion:
TdP arises from a region with maximal heterogeneity of repolarization and animals susceptible for TdP demonstrate higher RT differences. These results suggest that a certain gradient of repolarization moments is required in order to initiate TdP in CAVB dogs.
Abstract 14035: Parathyroid Hormone and Subclinical Cerebrovascular Disease: Findings From the Atherosclerosis Risk in Communities (ARIC) Brain MRI Study
Authors: Michos Erin D , Zhao Di , Guallar Eliseo , Lutsey Pamela L , Alonso Alvaro , Sharrett A. R , Post Wendy S , Reis Jared P , Mosley Thomas H , Gottesman Rebecca F
Published: July 2021

Background:
Elevated parathyroid hormone (PTH) levels have been associated with incident hypertension, insulin resistance, endothelial dysfunction, and increased cardiovascular disease events. We hypothesized that elevated PTH would also be associated with subclinical cerebrovascular disease. White matter hyperintensities (WMH) and subclinical infarcts measured on brain MRI are associated with reduced cognitive performance. We examined the relationship of elevated PTH levels with cerebrovascular pathology among white and black participants aged 55-72 in the ARIC Brain MRI study.

Methods:
We measured PTH from stored serum at visit 3 (1993-1994) among participants free of prior clinical stroke who underwent a brain MRI at visit 3 (n=1703) and a second brain MRI ~10 years later (n=948). PTH levels ≥65 pg/ml were considered elevated (n=204). Participants who did not return for a follow-up MRI had higher PTH levels and increased prevalence of cardiovascular risk factors at visit 3 (p<0.05 for all); therefore multiple imputation methods were used. The cross-sectional and prospective associations of PTH levels with WMH and MRI defined infarcts (and their progression) were investigated using multivariable regression models.

Results:
At visit 3, mean age of participants was 62 yrs, 60% female and 49% black. In models adjusted for demographic/lifestyle factors, elevated PTH was cross-sectionally associated with higher WMH score and prevalent infarcts (
Table
). Results were attenuated after adjustment for potential cardiovascular risk factor mediators. However, no prospective associations were found between PTH and incident infarcts or change in estimated WMH volume, although estimates were imprecise.

Conclusions:
Contrary to our hypothesis, we did not confirm any associations of elevated PTH with progression of cerebrovascular changes on serial brain MRIs ~10 years apart. The relationship of PTH with subclinical brain disease warrants further study.
Abstract 14315: New Insights Into the Mechanisms of Sepsis: The Role of Proprotein Convertase Subtilisin/kexin Type 9 as a Key Regulator of Pathogen Toxin Clearance
Authors: Topchiy Elena , Wang Yingjin , Boyd John , Walley Keith R
Published: July 2021

Background:
To prevent severe inflammation during infection, the patient must quickly clear bacterial endotoxins from the circulation before they accumulate and are able to interact with immune cells and vascular endothelium, and induce inflammatory organ failure. Bacterial endotoxins are carried within lipoprotein particles. Thus, one mechanism of action for sepsis treatments could be acceleration of lipoprotein clearance by adipocytes and hepatocytes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases the rate of lipoprotein clearance. We have recently reported that reduced function of PCSK9 improves outcome and prevents cardiovascular complications associated with sepsis.

Hypothesis:
PCSK9 inhibits LDL associated LPS clearance through hepatic LDLR and VLDL associated LPS clearance through adipose VLDLR.

Methods and Results:
Using siRNA against the LDLR in HepG2 hepatocytes decreased uptake of fluorescently labeled LPS (fLPS) after 48 hours by 1.50±0.10 fold (n=3, p<0.05). Addition of recombinant PCSK9 in the absence of LDLR did not alter uptake of LPS. We confirmed that hepatic uptake of LPS is exclusively via the LDLR by fluorescent microscopy of
ex vivo
LPS treated primary hepatocytes isolated from LDLR
-/-
mice. To address the importance of the LDLR upon clearance of LPS from plasma, we injected fLPS into the portal vein of LDLR-/-, PCSK9-/- and wild type mice (WT). Compared to WT, LDLR-/- mice had 36±13% (n=9, p<0.001) increase in plasma LPS after 1 hour, whereas PCSK9-/- show a significant decrease (28±4%, n=9, p<0.001) in plasma LPS. LDLR-/-, but not PCSK9-/- mice showed 46±7% decrease (n=10, p<0.05) in hepatic uptake. On the other hand, compared to the WT PCSK9-/- mice had 200±35% (n=8, p<0.001) increase in LPS uptake by visceral adipose tissue whereas LDLR-/- had no effect compared to WT mice. To further investigate LPS uptake by adipose tissue we injected flLPS into the tail vein of VLDLR-/- and WT mice. VLDLR-/- mice had 33±6% (n=10, p<0.001) decrease in visceral adipose tissue uptake, with no significant change in hepatic uptake.

Conclusions:
Expression of hepatic LDLR and adipose VLDLR is mainly regulated by PCSK9 and both play important role in clearing LPS from circulation.
Abstract 14332: Factors Associated With Quality of Life in Atrial Fibrillation: Results From the ORBIT-AF Registry
Authors: Randolph Tiffany C , Simon DaJuanicia N , Fonarow Gregg C , Gersh Bernard J , Kowey Peter R , Reiffel James A , Naccarelli Gerald V , Chan Paul S , Spertus John A , Peterson Eric D , Piccini Jonathan P
Published: July 2021

Background:
With increasing options for treating atrial fibrillation (AF), it is important to understand and quantify patient symptoms and quality of life (QoL), as improving symptoms and maximizing QoL are primary treatment goals. However, little is known about the factors associated with QoL.

Methods:
The Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) is a disease-specific QoL tool for AF, with domain and summary scores ranging from 0 (the worst health status) to 100. Using hierarchical pseudo-binomial regression, we evaluated factors associated with baseline AFEQT Summary and Subscale scores in the ORBIT AF registry. Adjusted associations were reported as odds ratios (OR) and 95% confidence intervals (CI).

Results:
AFEQT was assessed in 2,007 AF outpatients from 99 sites. Median age and interquartile range (IQR) was 76 (67-82); 43% were female; and the median CHA2DS2-VASC score was 4 (3-5). Median AFEQT summary score was 82 (67, 94). Median symptom score was 92 (78-100) and daily activity score was 77 (52-94). Female sex, younger age, new onset AF, higher heart rate, obstructive sleep apnea, and CAD were all associated with reduced QoL. (Table) Similar trends were seen for the symptoms subscale: female sex [OR 0.57 CI (0.48, 0.68)], younger age [OR 1.10 CI (1.06, 1.15)], and new onset AF [OR 0.55 CI (0.43, 0.70)] were associated with worse symptoms. Likewise, for the daily activities subscale, Other race [OR 0.54 CI (0.36-0.80)] and higher BMI [OR 0.98 CI (0.98-0.99)] were associated with decreased activity.

Conclusions:
In the largest community-based assessment of QoL in patients with AF, we found several patient factors to be associated with low QoL, including female sex, new onset AF, younger age, higher heart rate, and certain cardiopulmonary comorbidities. Understanding patient characteristics associated with worse QoL can be a foundation for eradicating disparities and tailoring treatment.
Abstract 14384: Scar Homogeneization Ablation in Patients With Ischemic Cardiomyopathy: Comparison Between Remote Magnetic Navigation and Manual Ablation
Authors: Di Biase Luigi , Tung Roderick , Burkhardt J. David , Romero Jorge , Trivedi Chintan , Mohanty Sanghamitra , Gianni Carola , Santangeli Pasquale , Bai Rong , Horton Rodney , Sanchez Javier , Gallinghouse G. Joseph , Hranitzky Patrick , Al-Ahmad Amin , Lakkireddy Dhanujaya , Lakkireddy Dhanujaya , Reddy Madhu , Beheiry Salwa , Hongo Richard , Shivkumar Kalyanam , Natale Andrea
Published: July 2021

Introduction:
Remote magnetic navigation (RMN) and ablation with the magnetic irrigated tip catheter has been reported as a feasible and safe technique for the treatment of ventricular arrhythmias (VA). We compared the procedural benefit and the outcomes of patients with ischemic cardiomyopathy (IC) undergoing VAs ablation with the RMN versus the manual approach.

Methods:
Consecutive pts with IC undergoing VAs ablation both with RMN and with manual ablation at different Institutions were enrolled. Substrate mapping and ablation technique with scar homogenization were utilized for ablation with the end point of elimination of all abnormal electrograms within and or around the scar area. Procedural data and outcomes were analyzed. Post-ablation pacing maneuvers and isoproterenol were used to verify Vas inducibility.

Results:
A total of 218 consecutive pts (85.3% male, 69.2±7.7 years, LVEF 30.6±8.2) with IC were included with 80 pts undergoing manual ablation while 138 pts underwent RMN ablation. Patients with a scar size < 60 cm2 at the 3D voltage mapping system were excluded. The mean scar size was 140 ± 61 cm2. VT was inducible in 83% pts with a cycle length of 352.1±70.7 msec. The density of the substrate map was higher in the RMN group when compared to the manual ablation group (553±118 vs 347±97, p<0.001). Acute ablation success was achieved in 217 (99.5%) of pts. The mean procedural duration and fluoroscopy time was 255.8±116.6 min and 34.8±22.9 min respectively. The mean mapping time was lower in the RMN group (80.3 ± 13.8 min) compared to the manual ablation group (96.1 ± 20.3 minutes, p < 0.001), while the radiofrequency time was lower in the manual ablation group(66.1 ± 27.3 min vs. 74.4 ± 20.7 min, p=0.02).

At 15.4±6.8 months follow-up the success rate in the RMN group was 81.2% (112) while in the manual ablation group 55 (69%) pts were recurrence free (p=0.037).

There was one pericardial tamponade which required pericardiocentesis in the manual ablation group.

Conclusion:
This study shows that VAs ablation using RMN in pts with IC and a scar size greater than 60 cm2 increases success rate at follow up when compared to manual ablation. The better outcome might be due to the higher amount of time dedicated to RF applications to achieve scar homogenization rather than mapping
Abstract 14759: Aggressive Risk factor REduction STudy: Implications for the Substrate for Atrial Fibrillation (ARREST-AF Substrate Study)
Authors: Pathak Rajeev K , Middeldorp Melissa E , Stolcman Simon , Willoughby Scott , Mahajan Rajiv , Lau Dennis H , Sanders Prashanthan
Published: July 2021

Introduction:
Cardiac risk factors (RF) such as hypertension, diabetes mellitus, obesity and sleep apnoea have been associated with structural and electrical remodeling of the atria that forms the substrate leading to the development and progression of atrial fibrillation (AF). We evaluated the impact of aggressive management of RFs on the AF substrate.

Methods:
50 consecutive AF pts with BMI ≥ 27 kg/m2 and ≥1 cardiac risk factor were randomized to either RF management (RFM) or usual care (Control). The RFM group were managed in a physician-led clinic directed at RF control in accordance with AHA/ACC guidelines. Both the groups were studied with electrophysiological (EP) study, echocardiography, cardiac MRI, serum fibrosis and endothelial function markers at baseline and repeated at > 6 mths later. Subjects in RFM group had >10% weight loss at repeat study.

Results:
There were no differences in baseline characteristics or follow-up duration (15±3 mths) between the groups (p=NS). RFM resulted in greater reduction in weight (p<0.001), systolic blood pressure (p=0.004), better glycaemic control (p=0.003) and lipid profile (p=0.04), reduced LA size (p=0.003) and total pericardial fat volume (p=0.001). The table presents the data showing that RFM resulted in marked reversal in atrial electrical parameters, reduced pro-inflammatory/fibrotic markers and improved endothelial/platelet function.

Conclusion:
Aggressive risk factor management reverses electrical and structural remodeling and results in a significant improvement in endothelial and platelet function underscoring its importance in AF management. (Trial registration: ACTRN12613000444785)
Abstract 14921: Right Ventricular Extracellular Volume Fraction by Magnetic Resonance T1 Mapping in Pulmonary Hypertension and Heart Failure
Authors: Bilchick Kenneth C , Mehta Bhairav B , Workman Virginia , Auger Daniel , Chen Xiao , Kennedy Jamie , Gay Elizabeth , Epstein Frederick H
Published: July 2021

Introduction:
Current cardiac magnetic resonance (CMR) T1 mapping techniques such as Modified Look-Locker inversion recovery (MOLLI) imaging have limited resolution, but the Accelerated and Navigator-Gated Look-Locker Imaging for Cardiac T1 Estimation (ANGIE) is a novel CMR sequence with spatial resolution suitable for T1 mapping of the thin-walled RV.

Hypothesis:
In pulmonary hypertension (PH) and heart failure (HF), RV extracellular volume (ECV) fraction (as a surrogate measure for RV fibrosis) is a unique parameter describing RV structure that tends to increase with increasing RV size and declining RV function.

Methods:
Patients with either World Health Organization group 1 or group 4 pulmonary hypertension (PH) or heart failure with reduced ejection fraction (HFrEF) were recruited to undergo contrast-enhanced CMR. RV and LV ECV fractions were determined using pre-contrast and post-contrast T1 mapping using ANGIE (RV and LV) and MOLLI (LV).

Results:
22 patients (41% female, median age 61 years old, IQR 51-70 years old) were enrolled, including n=12 with PH and n=10 with HFrEF. ANGIE ECV imaging was of high quality (Figure). A multivariable linear model with RVEF and RVEDVI as independent variables and RVECV as the outcome variable showed independent associations for RVEF and RVEDVI with RVECV (R
2
=0.553) (Table), consistent with a complex relationship involving RV function, dilation, and fibrosis.

Conclusions:
Pre- and post-contrast ANGIE imaging provides high-resolution ECV determination for the thin-walled RV. RV fibrosis increases with increasing RV size and decreasing overall RV function. Further studies of RVECV in PH and HFrEF are indicated.
Abstract 14922: Prognostic Value of Baseline BNP and NT-ProBNP and its Interaction With Spironolactone in Patients With Heart Failure and Preserved Ejection Fraction in the TOPCAT Trial
Authors: Anand Inder S , Solomon Scott D , Claggett Brian , Shah Sanjiv J , O’Meara Eileen , Boineau Robin , Fleg Jerome L , Pfeffer Marc A , Pitt Bertram
Published: July 2021

Background:
Plasma natriuretic peptides (NP) are helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) and predict adverse outcomes. Levels of NP beyond a certain cut-off level are often used as inclusion criteria in clinical trials to ensure that the patients have HF, and to select patients at higher risk. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. In the I-Preserve trial a benefit of irbesartan on all outcomes was only seen in HFpEF patients with low but not high NP levels. We hypothesized that in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, spironolactone might have a greater benefit in patients with lower NP levels.

Methods and Results:
BNP (n=468) or NT-proBNP (n=400) levels were available at baseline in 868 patients with HFpEF enrolled in the natriuretic peptide stratum (BNP ≥100 pg/mL or an NT- proBNP ≥360 pg/mL) of the TOPCAT trial. In a multi-variable Cox regression model, that included age, gender, region (Americas vs. Russia/Georgia), atrial fibrillation, diabetes, eGFR, BMI and heart rate, higher BNP or NT-proBNP as a continuous, standardized log-transformed variable or grouped by terciles (see Figure for BNP & NT-proBNP tercile values) was independently associated with an increased risk of the primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for heart failure (Figure-1). There was a significant interaction between the effect of spironolactone and baseline BNP or NT-proBNP terciles for the primary outcome (P=0.02, Figure-2), with greater benefit of the drug in the lower compared to higher NP terciles.

Conclusions:
The benefit of spironolactone in lower risk HFpEF patients may indicate effects of the drug on early, but not late higher-risk stage of the disease. These findings question the strategy of using elevated NP as a patient selection criterion in HFpEF trials.