bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18840: Left Ventricular Enlargement Detected by Cardiac Magnetic Resonance Imaging Predicts Atrial Fibrillation Recurrence Following Pulmonary Vein Isolation
Authors: Pu Daniel K , Weinsaft Jonathan W , Lin Frank S , Chanin Jake M , Ip James E , Markowitz Steven M , Liu Christopher F , Thomas George , Lerman Bruce B , Cheung Jim W
Published: July 2021

Introduction:
Recurrence rates of atrial fibrillation (AF) following catheter ablation remain substantial. Studies on cardiac magnetic resonance imaging (cMRI) assessment of predictors of AF recurrence following pulmonary vein (PV) isolation have centered on left atrial volume and fibrosis. We sought to identify other anatomic predictors of recurrent AF following PV isolation by cMRI.

Methods:
Eighty-seven consecutive patients (72 [83%] male; age 61 ± 10 yrs) who underwent PV isolation for symptomatic AF (63% paroxysmal) and baseline cMRI were evaluated. Baseline left ventricular (LV) mass, LV end-diastolic and end-systolic volumes, LV size, LV ejection fraction, left atrial diameter and area, right atrial sizes, right ventricular size and function and presence of left common PV and right middle PV were assessed by cMRI. Recurrent AF (defined as AT/AF ≥ 30 seconds) during follow up was noted.

Results:
Over mean follow-up of 372 ± 109 days, a total of 30 (35%) patients had evidence of recurrent AF. Patients with LV enlargement (≥ mild) by cMRI had significantly reduced AF-free survival (53% vs. 73% at 1 year; p = 0.012) and patients with LV mass index ≥ 74.5 g/m
2
had significantly reduced AF-free survival (54% vs. 72% at 1 year; p = 0.031). There was no difference in AF-free survival among patients with and without left atrial, right atrial, and right ventricular enlargement. Patients with and without recurrent AF had similar right ventricular function and LV ejection fractions. In a multivariate analysis of cMRI parameters of cardiac anatomy, LV enlargement was the only significant independent predictor of recurrent AF (HR 2.78; 95% CI 1.26-6.11; p=0.011).

Conclusion:
Left ventricular enlargement assessed by cMRI is a significant independent predictor of recurrent AF following PV isolation. In addition to abnormal left atrial substrate, negative LV remodeling may also be an important marker of increased susceptibility to AF after ablation.
Abstract 18845: Left Ventricular Assist Device Normalizes Multiple Pathogenic Pathways in Both the Left and Right Ventricle in Patients With Dilated Cardiomyopathy
Authors: Parajuli Nirmal , Basu Ratnadeep , Famulski Konrad S , Nagendran Jayan , Kim Daniel H , Mullen John C , Buchholz Holger , Halloran Philip F , Oudit Gavin Y
Published: July 2021

Introduction:
Heart failure (HF) continues to be a common cause of morbidity and mortality and dilated cardiomyopathy (DCM) is a common cause of adverse ventricular remodeling and HF. Left ventricular assist device (LVAD) has emerged as an important mode of therapy for advanced HF by unloading the LV and maintaining systemic perfusion. The extent to which LVAD mediates beneficial remodeling in the right ventricle (RV) is incompletely understood.

Hypothesis:
Differential mRNA expression in a chamber-specific manner may elucidate LVAD mediated functional reverse remodeling in end-stage HF.

Methods and Results:
Right (RV) and left (LV) ventricle tissue from explanted failing and non-failing control (NFC) human hearts were collected within 20 mins of explantation. Global mRNA expression profiling in DCM patients without (n=8; 7M/1F; age 42-54 years; ejection fraction (EF): 17.5% (15-26%) and with (n= 8; 7M/1F; age 44-58 yrs; EF 15% (12.5-25.0%) LVAD (HeartMate II) was compared to NFC (n=6; age 39-56 yrs; 4M/2F). mRNA microarray was performed using Affymetrix PrimeView gene chips and evaluated using the
Ingenuity Pathway Analysis (
IPA) program. LVAD use was associated with marked reduction of myocardial hypertrophy, interstitial fibrosis and apoptosis in both the LV and RV. The cleaved caspase-3 and Tunnel-positive cardiomyocytes were reduced in both RV and LV with LVAD. Total gene entities of 991 in the LV and 860 in the RV were differentially expressed in hearts with DCM without LVAD. LVAD use was independently associated with the altered regulation of 280 genes in the LV and 380 genes in the RV. The total up/down regulated genes involved in cardiac hypertrophy ranged from 20-60% and myocardial fibrosis ranged from 10-80% and were altered in both the RV and LV in response to LVAD therapy. In addition, 14-30% of the total apoptotic-related genes and 6-20 % of the cytokine-related genes were changed in both ventricles.

Conclusions:
LVAD reduced pathological hypertrophy and fibrosis in both LV and RV and is correlated with altered gene expression controlling adverse myocardial remodeling and fibrosis, apoptotic and inflammatory pathways. LVAD therapy represents a viable long-term therapy for HF patients and is associated with improved RV remodeling.
Abstract 18855: Outcomes after Coronary Artery Bypass Graft Surgery in Patients Treated with Thoracic Radiotherapy for Cancer
Authors: Liang Jackson J , Sio Terence T , Stulak John M , Lennon Ryan J , Prasad Abhiram , Miller Robert C , Sandhu Gurpreet S
Published: July 2021

Introduction:
Thoracic external beam radiation therapy (XRT) for cancer is associated with a multitude of long-term cardiotoxic side effects. Previous studies have suggested worse outcomes in XRT-treated cancer survivors who undergo revascularization with CABG, but sample sizes have been small. In addition, XRT after CABG is thought to portend decreased patency and survival. We aimed to examine outcomes after CABG in patients with XRT compared with to those without XRT.

Methods:
We identified all patients who were treated with both CABG (between 1999 and 2013) and curative thoracic XRT for cancer (between 1971 and 2013) (>30 Gray). Baseline clinical characteristics and comorbidities at time of CABG, as well as long-term outcomes after CABG and XRT were compared with propensity matched control cohorts.

Results:
A total of 38 patients underwent CABG following XRT [Group 1] (mean age 67.9, 63% female) and 43 patients underwent XRT after CABG [Group 2] (mean age 69.3, 63% female). Compared with propensity-matched controls (Group 1: n=141; Group 2: n=167), baseline clinical and demographic characteristics between cases and controls were similar in both groups, except a lower incidence of triple vessel disease in XRT cases in Group 2 (64 vs 80%, p=0.02). For Group 1, there was no significant difference in all-cause survival in long-term follow-up after CABG (Fig. 1, p=0.72). Meanwhile, Group 2 cases had significantly higher all-cause mortality following XRT (Fig. 2, p<0.001).

Conclusions:
Patients previously treated with thoracic XRT who subsequently undergo CABG for coronary artery disease have a similar overall mortality rate compared to patients without prior XRT. This suggests that CABG is an effective method of revascularization in these patients. The higher mortality rates in CABG patients who subsequently develop disease requiring thoracic XRT is likely due to oncologic rather than cardiovascular causes, but more data are necessary to evaluate this finding.
Abstract 18874: A microRNA Signature of Tobacco Exposure
Authors: Willinger Christine , Rong Jian , Huan Tianxiao , Tanriverdi Kahraman , Courchesne Paul , Dupuis Josée , O’Connor George , Freedman Jane , Larson Martin G , Levy Daniel
Published: July 2021

BACKGROUND:
Smoking is a cardinal risk factor for cardiovascular disease, and microRNAs (miRNAs) are key regulators of gene expression that may be involved in the development of smoking-related diseases. We sought to unravel the relationship between miRNAs and smoking by describing a miRNA signature of tobacco exposure and relating these results to the expression of smoking-associated genes.

METHODS:
Expression profiling of 333 miRNAs was conducted on whole blood RNA from 5,728 Framingham Heart Study participant samples using TaqMan assays and high-throughput qRT-PCR. Smoking status was classified as current, former, or never. The association of miRNA expression with smoking status was tested using general linear models, and significant miRNAs were analyzed in pairwise comparisons. Smoking-related mRNA expression associations were identified from gene expression profiling of the same RNA samples with the Affymetrix Human Exon Array ST v1.0. MiRNA-mRNA coexpression was analyzed using linear mixed effects models.

RESULTS:
Seven miRNAs were associated with smoking status: miR-1180, miR-181a2-3p, miR-423-5p, miR-25-5p, miR-1285-3p, miR-342-5p, and miR-744-3p (Table 1). 1,626 gene transcripts were coexpressed with one or more smoking-related miRNAs. Gene ontology enrichment analysis implicated the coexpressed genes in multiple biological processes, e.g., the ubiquitin cycle, intracellular transport, and DNA metabolism. Four genes were coexpressed with all seven smoking-associated miRNAs; most notable were
TMEM56
, reported to be associated with coronary heart disease, and
DOCK8
, which has been linked to lung cancer
in vitro
.

CONCLUSIONS:
We identified a novel miRNA signature of tobacco exposure featuring decreased expression of miRNAs in smokers. Our coexpression results implicate these miRNAs in smoking-related diseases and suggest broad regulatory effects on protein synthesis and turnover.

TABLE 1.
miRNA Associations with Smoking Status
Abstract 18884: Proteomic Profiling Reveals Reduction in Electron Transport Chain Proteins in the Hearts of Hibernating Arctic Ground Squirrels Compared with Rats after Surgical Ischemia and Reperfusion: A Convergence of Mammalian Cardio-protective Strategies
Authors: Quinones Quintin J , Ma Qing , Zhang Zhiquan , Henao Ricardo , Soderblom Erik , Moseley Martin A , Newgard Christopher , Drew Kelly , Barnes Brian M , Podgoreanu Mihai V
Published: July 2021

Introduction:
Mammalian hibernation is a natural molecular adaptation to extreme environmental conditions with important applications for perioperative organ protection. We conducted an integrated proteomic analysis to identify species and season-specific correlates of the cardioprotective phenotype.

Methods:
Quantitative 2D-LC/LC-MS/MS was used in the myocardium of summer active arctic ground squirrels (AGS), winter hibernating AGS, and rats subjected to deep hypothermic cardiac arrest and reperfusion.

Results:
Hibernating AGS display robust cardioprotection in our model of I/R compared with rats using both biomarker (Fig 1) and echocardiographic assessment of cardiac injury. Proteomic analysis revealed significant reduction in subunits of all five electron transport chain (ETC) complexes in hibernating AGS compared with rats, only complex 5 showed increased expression of some subunits after I/R.Fig 2

Conclusions:
Proteomic profiling revealed dichotomy in the cardioprotective adaptations employed by hibernating AGS and rat. The proteomic profile of hibernating AGS resembles that of myocardial hibernation in other mammals, with significant downregulation of mitochondrial ETC complexes. However, unlike myocardial hibernation in non-hibernators, AGS demonstrated downregulation of glycolytic and other myocardial energetic pathways with the exception of fatty acid oxidation. Sirtuin 3 - a key regulator of mitochondrial bioenergetics - was robustly upregulated in AGS, suggesting that preventing hyperacetylation of key metabolic enzymes may be a cardioprotective strategy employed by hibernators.
Abstract 18974: Rhythm Control with Catheter Ablation Improves Cardiomyopathy and Heart Failure Compared with Rate Control
Authors: Lakshmanadoss Umashankar , Deshmukh Amrish , Choudhary Gunjan , Deshmukh Pramod
Published: July 2021

Introduction:
Role of rhythm control in addition to rate control, in patients with atrial fibrillation and heart failure reduced EF (HFrEF) is unknown.

Objective:
We sought to compare catheter ablation with rate control in patients with AF and HFrEF.

Methods:
Ninety patients with AF and LVEF < 40 % underwent pulmonary vein isolation with or without substrate modification. Follow-up included Holter monitoring and echocardiography at baseline, 3 months and at 6 months. A propensity-matched group of 80 patients with AF and LVEF <40% treated with rate control was used for comparison. Post-matching weighted linear regression analysis was used to compare outcomes.

Results:
At 6 months, 64% of patients who underwent ablation remained in sinus rhythm. Average heart rate (HR) was similar between groups at baseline and follow up. (79 ± 14.5 to 76 ± 7.7 in ablation group and 82.4 ±8.9 to 78.3 ± 8.8 in rate control group). LVEF significantly improved in patients who underwent ablation (30.9 ± 8.6 to 43.4 ±10.9) compared with no change in patients who were rate controlled (to 25.8 ±19.3 to 25.2 ±6.64) (p=2E-16). NHYA class improved from 2.26 ±0.44 to 1.62 ±0.64 with ablation compared to 2.4 ±0.5 to 2.24 ±0.44 with rate control but did not reach statistical significance. Patients who remained in AF after ablation had minimal change in LVEF and NHYA class. No procedural complications noted.

Conclusions:
In patients with AF, HFrEF, and adequate HR control, rhythm control by catheter ablation improved LVEF compared with a propensity matched group of patients treated with rate control. Rhythm control with catheter ablation may be considered in patients with AF and HF who are adequately rate controlled
Abstract 18984: Discrepancy Between Originally Assigned and Adjudicated Causes of Out-of-Hospital-Cardiac-Arrest of “No Obvious Cause” in Young Patients
Authors: Allan Katherine S , Morrison Laurie J , Tu Jack V , Pinter Arnold , Common Matthew R , Patel Dhanisha , Nguyen Brian , Landry Cameron , Dorian David , Dorian Paul
Published: July 2021

Background:
Death due to out-of-hospital cardiac arrest (OHCA) is most commonly attributed to “no obvious cause” after review of the prehospital and in-hospital documentation. To establish cause of death in younger patients, autopsy and toxicology data are important, especially in younger patients. We examined the probable cause of death in a large urban cohort of younger OHCA patients.

Methods:
A prospective population-based registry of all OHCAs attended by Emergency Medical Services (EMS) in the Toronto area was used to identify cases from 2009-2012. Identified OHCAs were cases aged 2-45 who died and assigned ‘no obvious cause’ based on abstracted data from ambulance call reports and in-hospital chart review, including narrative review and contributing factors compliant with the Resuscitation Outcomes Consortium Epistry Manual of Operations.

Cases with inadequate information (coroners and/or EMS), or with expected death (e.g. DNR or long term care) or homicide were then excluded. The remaining cases were adjudicated by 3 reviewers using additional data from coroner investigative statements, autopsy, toxicology and police reports, and classified as primary cardiac or another non-cardiac etiology.

Results:
A total of 2048 OHCA cases with no obvious cause were identified; of these, 547 were excluded. Of the remaining 1501 cases with complete information, 48.2% were treated by EMS. Of the treated cases, 41.3 % (299/724) of those assigned to ‘no obvious cause’ had an adjudicated cardiac etiology. Of the untreated group, 21.2% (165/777) had an adjudicated cardiac etiology. The majority consisted of drug overdoses (214/425; 50.3%) and other non-cardiac causes (49.7%) including trauma (Figure 1).

Conclusions:
In younger OHCA patients who die, the category "OHCA of no obvious cause”, on detailed review, is most often due to a non-cardiac cause. This observation may contribute to a better understanding of the etiology of sudden cardiac death in younger patients.
Abstract 18986: Low Density Lipoprotein Cholesterol Response and Statin Persistence among Patients with High Coronary Heart Disease Risk Initiating Treatment
Authors: Vupputuri Suma , Joski Peter J , Kilpatrick Ryan , Woolley Michael , Robinson Brandi E , Farkouh Michael E , Yun Huifeng , Safford Monika M , Muntner Paul
Published: July 2021

The 2013 American College of Cardiology/American Heart Association cholesterol treatment guideline recommends monitoring percent reduction in low density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. We examined LDL-C reduction and statin persistence among high risk patients initiating statins in a real-world setting. This retrospective cohort study included 1,066 Kaiser Permanente Georgia members with a history of coronary heart disease or risk equivalent(s) initiating statins in 2011. Percent change in LDL-C was defined using measurements before and 60-450 days after statin initiation. Statin persistence was defined by proportion of days covered and categorized as high (≥80%), intermediate (50-79%), and low (<50%). Overall, 58.4% of patients failed to achieve a ≥30% LDL-C reduction after statin initiation. The prevalence of high, intermediate and low statin persistence was 41.3%, 23.2%, and 35.6%, respectively. Of patients with high persistence, 42.3% did not achieve a ≥30% reduction in LDL-C compared with 54.7%, and 79.7% of those with intermediate and low statin persistence, respectively. After multivariable adjustment and compared to high persistence, the risk ratio for a low LDL-C reduction was 1.31 (95%CI: 1.13,1.52) for intermediate persistence and 1.88 (95%CI: 1.67,2.11), for low persistence. Women and African-Americans were less likely to have high persistence while having cardiologist follow-up visits was associated with high persistence. Also, after multivariable adjustment, patients with an LDL-C ≥ 100 mg/dL versus < 100 mg/dL were less likely, while those initiating therapy with pravastatin were more likely to have a ≥30% reduction in LDL-C. In a real-world setting, many patients initiating statins did not achieve a 30% or larger LDL-C reduction. These data support the ACC/AHA recommendation to monitor LDL-C response among patients initiating statins.
Abstract 18987: Time of Hospital Admission and Its Effect on Treatment and Outcome in Patients After Cardiac Arrest
Authors: Uray Thomas , Mayr Florian B , Spiel Alexander , Stratil Peter , Sterz Fritz
Published: July 2021

Introduction and Hypothesis:
Previous studies suggest worse outcomes after out-of-hospital cardiac arrest (OHCA) at night. We analyzed whether patients admitted after OHCA receive induced hypothermia at equal rates and equally prompt during day- and night, as well as potential differences in neurologic outcomes.

Methods:
We retrospectively analyzed data of non-traumatic OHCA patients who regained restoration of spontaneous circulation (ROSC) and were admitted to our emergency department with an integrated intensive care unit (resuscitation center) at a tertiary care university hospital between 01/01/2006 and 10/31/2012. Data reported include admission time (day defined from 8am to 4pm based on staffing), first blood gas, use of induced hypothermia (IH) and time from admission to initiation of hypothermia. A good neurologic outcome after 6 months was reported as CPC 1 or 2.

Results:
Of 1172 OHCA patients admitted during the study period, 970 patients (73.8% male, n= 716) with a median age of 60 (IQR 49-70) were included. Times from arrest to ROSC, and ROSC to admission were similar in day- and night-admissions [19 (IQR 10-29) min vs. 18 (IQR 8-29) min; p= 0.69 and 36 (IQR 24-51) vs. 38 (IQR 24-52) min; p=0.58, respectively]. Similarly, there was no difference between day and night in first measured pH (7.17 vs. 7.16; p=0.9) and lactate (7.3 vs. 7.9 mmol/l; p=0.54) after admission. Induced hypothermia was applied to 338 (75.6%) of 447 day-admissions and to 410 (78.4%) of 523 night-admissions (p =0.30). For the patients whose cooling was initiated after admission, time from admission to cooling start did not differ between day and night (mean time 52 ± 5 minutes during day vs. 58 ± 8 minutes at night, p=0.54). At 6 months, a good neurologic outcome was achieved in 202 patients (45.2%) after day admission and 231 patients (44.2%) after night admission (p= 0.75).

Conclusion:
Patients admitted to our facility after OHCA were equally likely to receive timely high-quality post-resuscitation care irrespective of time of day. Similarly, favorable neurologic outcomes did not differ between day and nighttime admissions. Reported circadian differences in OHCA outcomes may be due to differences in the quality of post-resuscitation care provided at non-specialized centers.
Abstract 19018: Variation in Treatment and Outcomes in ACS: Insights from the Alberta Contemporary Acute Coronary Syndrome Patients Invasive Treatment Strategy (COAPT) Study
Authors: Bainey Kevin R , Kaul Padma , Liu Wei , Norris Collen , Traboulsi Mouhieddin , Brass Neil , Ali Imtiaz , Nagendran Jayan , Knutdson Merril L , Armstrong Paul W , Welsh Robert C
Published: July 2021

Background:
In a universal health care system, we examined variations in treatment strategies and clinical outcomes in a contemporary cohort of acute coronary syndrome (ACS) patients.

Methods:
Hospitalization claims of 15,264 patients with ACS between April 1, 2010 and March 2012 were deterministically linked to the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) angiographic database. We compared baseline characteristics and use of diagnostic and therapeutic procedures across 3 invasive sites. For patients who underwent an invasive strategy, we examined 1-year rates of death and repeat revascularization.

Results:
Of the study cohort, 14.3% were medically treated at 91 non-invasive hospitals without transfer to an invasive site and had a 9.3% rate of in-hospital death. The remaining patients were admitted or transferred to one of the three invasive sites (A 5935 pts [40.4% transfer]; B 3910 pts [47.1% transfer]; C 3243 pts [57.4% transfer]). The majority were treated with an invasive strategy: A 87.4%, B 88.9%, C 90.1%, p<0.001). Patient characteristics according to invasive site are reported below (Table). Most notable are the dissimilar rates of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) along with the different use of drug-eluting stents (DES). Mortality rates were similar (in-hospital and 1-year). However, significant differences in one-year repeat revascularization were observed.

Conclusion:
Results from this large contemporary Canadian study suggest variation in revascularization strategies exist resulting in differences in clinical outcome at one year. Further investigations are warranted to allow alignment of best practice and patient outcomes for patients with ACS.
Abstract 19037: Exercise Reduces 24-hr Blood Pressure and Albuminuria in Patients with Moderate Diabetic Kidney Disease
Authors: Bronas Ulf G , Weber Marc , Drawz Paul , Bantle John , Duprez Daniel , Rosenberg Mark
Published: July 2021

Introduction:
Observational studies have shown an inverse association between physical function and CVD mortality in patients with chronic kidney disease (CKD) through unknown mechanisms. We have previously reported a significant exercise-induced reduction in resting blood pressure (BP) in 85 patients with stage 2-4 type 2 diabetes related CKD (DKD). The efficacy of exercise to reduce 24-hour ambulatory blood pressure (ABP) and albumin-creatinine ratio (ACR) is unclear. The purpose of this study was to test the hypothesis that 12wks of exercise would reduce 24-hr ABP and ACR in patients with stage 3-4 DKD and hypertension, compared to the control group.

Methods:
We randomly assigned 28 participants (21 male, age 62.9 yrs, BMI 34.8 kg/m2) with stage 3-4 DKD and hypertension (141(17)/75 (10) mmHg) to either 12-wks of moderate-intensity exercise training, 4x/wk for 45 minutes (n=15) or a usual medical care control group (n=13). The primary endpoint was change in 24-hr ABP at 12-wks.

Results:
There were no significant differences between groups in baseline demographic or medical variables. There were no changes in pharmacological variables at 12-week follow-up; group comparisons were analyzed by ANCOVA using baseline and exercise performed as covariates. Systolic BP levels and ACR were significantly reduced in the exercise-intervention group compared to the control group (Table 1). Reductions in diastolic BP levels were not significant between groups. Heart rate variables did not differ between groups. There was a strong inverse association between change in aerobic capacity and change in systolic and diastolic BP levels in the exercise group only (r=-.56, p=.039, and -.66, p=.011).

Conclusion:
This study suggests that exercise training imparts a favorable modulation of BP levels and ACR in patients with stage 3-4 DKD, potentially providing insight into the cardioprotective effect of exercise in this population.
Abstract 19072: Cardiac Autonomic Dysfunction in Mice Lacking Methyl CpG Binding Protein 2
Authors: Herrera Jose A , Ward Christopher S , Neul Jeffrey L
Published: July 2021

Background:
Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder primarily caused by mutations in
Methyl-CpG-binding protein
(
MECP2
), a transcriptional regulator. Twenty-five percent of all deaths in RTT are sudden and unexpected, and autonomic nervous system (ANS) dysfunction is hypothesized to be the cause of sudden deaths in RTT. However, the role of
MeCP2
in cardiac autonomic function has not been investigated in depth.

Design/Methods:
Male (2 months) and female (9 months)
Mecp2
deficient and wildtype mice were implanted with ETA-F10 telemeters and 24h recordings were taken to calculate heart rate, heart rate variability, and incidence of arrhythmic events. Effects of pharmacological stimulants or inhibitors on heart rate were normalized to saline injection response.

Results:
Male
Mecp2
deficient mice (NULL) have a decreased heart rate (WT = 634 ±3, NULL = 518 ±8, p<0.001), while female deficient mice (NULL/+) do not present with a decreased heart rate. Interestingly, NULL and NULL/+ mice both have a high incidence of sinus pauses and AV block (WT 1/5, NULL 6/6, NULL /+ 4/4, p<0.05). Additionally, both NULL and NULL/+ mice have increased bradycardia events defined as a heart rate below 200 bpm, (WT = 17 ±6, NULL = 307 ±94, NULL/+ = 198 ±67, p<0.05) and an increased heart rate variability. The normalized heart rate response to atropine, a parasympathetic blocker, of NULL mice was above wildtype levels (p<0.05) Chemical denervation by combined antagonism of parasympathetic (atropine) and sympathetic (propranolol) resulted in NULL mice having an increased normalized heart rate response compared to wildtype (p<0.05). Finally, the incidence of AVB/sinus pauses counts per 30 minutes post-acute treatment with atropine and chemical denervation (NULL saline 49 ±10, NULL atropine 8 ±5, NULL atropine/propranolol 0.5 ±0.5 p<0.05) decreased the severity of the cardiac phenotype in NULL mice.

Conclusions:
In summary,
Mecp2
is required for a normal heart rhythm. Loss of
Mecp2
causes bradycardia, sinus pauses, AV block, and increased heart rate variability that may be attributed by aberrant innervation. Acute atropine and chemical denervation was therapeutic and ameliorated the cardiac phenotype observed in
Mecp2
deficient mice.
Abstract 19074: Relationship Between Hospital Procedure Volume and Complications Following Congenital Cardiac Catheterization: a Report from the IMPACT® Registry
Authors: Glatz Andrew C , Jayaram Natalie M , O’Byrne Michael L , Li Yan , Chan Paul S , Sharma Praneet K , Bergersen Lisa , Spertus John A
Published: July 2021

Background:
The association between institutional procedural volume and outcomes has been demonstrated for many procedures within the field of cardiology, but whether this relationship pertains to congenital cardiac catheterization is unknown.

Methods:
Using the IMPACT® (Improving Pediatric and Adult Congenital Treatment) Registry, we identified all catheterizations between 2011 and 2013 at 64 U.S. centers. Programs were categorized as small (<150 cases/year), medium (150 to 300 cases/year), large (300-500 cases/ year), and very large (>500 cases/ year). Hierarchical logistic regression, adjusted for patient and procedural characteristics, was used to determine the association between annual procedural volume and occurrence of a major adverse event (cardiac arrest; arrhythmia requiring permanent pacemaker; tamponade; air embolus; embolic stroke; device malposition, thrombus, or embolization; new requirement for dialysis; event requiring extracorporeal membrane oxygenation or left ventricular assist device; unplanned cardiac, vascular, or other surgery; or subsequent cardiac catheterization).

Results:
Among 64 hospitals, there were 19 small, 15 medium, 19 large, and 11 very large programs. Among 33,825 catheterizations, a major adverse event occurred in 711 (2.1%). In unadjusted analysis, major adverse events differed based upon annual volume, with a major adverse event occurring in 79 (2.8%) cases at small, 145 (2.3%) cases at medium, 234 (2.1%) cases at large, and 253 (1.9%) cases at very-large programs (p=0.01). After adjusting for patient and procedural risk factors, there was no association between annual procedure volume and occurrence of a major adverse event (odds ratio 0.96 [95% Confidence Interval=0.90, 1.04] per increase in annual volume of 100, p=0.32). There was no interaction between procedure-type risk group and volume on outcomes (p=0.49).

Conclusions:
Although the unadjusted risk of adverse events was lower in centers performing more catheterizations for congenital heart disease, this association between center volume and outcomes did not persist after adjustment for patient and procedural case-mix. The hospital sample size and low event rate may have limited our ability to detect significant differences.
Abstract 19094: Antihypertensive Properties of Subcutaneous M-ANP, a Novel Designer Atrial Natriuretic Peptide, in a Canine Model of Chronic Angiotensin-II Induced Hypertension
Authors: Puccia Giuseppe , Sangaralingham Jeson S , Harty Gail J , Cataliotti Alessandro , Ichiki Tomoko , Malatino Lorenzo , Burnett John C
Published: July 2021

Introduction:
Blood pressure (BP) control remains low despite combination therapy in resistant hypertension (RH). Thus, there is an unmet need for novel strategies targeting RH. Recently we have reported that M-ANP, a novel Mayo engineered ANP-based peptide, possesses greater and more sustained biological actions compared to ANP and is more resistant to neprilysin degradation. The current study was designed to investigate for the first time the efficacy of a single daily subcutaneous (SQ) injection of M-ANP using a chronic canine model of hypertension induced by angiotensin II (Ang-II).

Hypothesis:
We hypothesize that a daily SQ M-ANP injection would have potent BP lowering and renal enhancing properties in our chronic hypertensive canine model.

Methods:
We induced hypertension in canines (n=5) by continuous Ang II (80 ng/kg/min) osmotic mini-pump administration for 24 days. Continuous 24 hour mean BP (MBP) was measured by telemetry and a 24 hour urine collection was used to assess urinary volume, sodium (Na) and cGMP, the second messenger for the ANP system. M-ANP was administered SQ for 5 days (10μg/kg/day). Data are mean±SE. ΨP<0.05 Ang II Day 16 vs. baseline; *P<0.05 Ang II Day 16 vs. M-ANP (Table 1).

Results:
Chronic Ang II administration resulted in model of severe hypertension, with an increase in MBP from 112±2 to 157±2 mmHg (day 16). As seen in Table 1, M-ANP significantly reduced MBP, significantly increased plasma cGMP as well as urinary cGMP excretion, urinary volume rate (UV) and urinary Na excretion (UNa), without significant changes in heart rate (HR). Furthermore, there was a trend for plasma ANP to increase and plasma aldosterone to decrease with SQ M-ANP injection.

Conclusions:
This study demonstrates for the first time that chronic SQ administration of M-ANP reduces BP, activates plasma cGMP, and increases UV and UNa, without significant changes in HR in an experimental model of chronic hypertension.
Abstract 19123: Elevated Growth and Differentiation Factor 15 (GDF15) Levels Predict Outcome in Patients With Severe Aortic Stenosis Undergoing Tavi
Authors: Krau Nora , Freitag-Wolf Sandra , Brehm Doreen , Petzina Rainer , Lutter Georg , Frey Norbert , Frank Derk
Published: July 2021

Background:
GDF15 belongs to the transforming growth factor superfamily and has a significant role in regulating inflammatory and apoptotic pathways. GDF15 is an emerging biomarker for risk stratification in cardiovascular disease. Here we analyze its prognostic value in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI).

Methods and Results:
We prospectively enrolled 217 patients undergoing TAVI (using Edwards Sapien XT prostheses) at our institution over a continuous period of 35 month (2/2011-12/2013). All patients were available for complete follow up. Clinical parameters were determined before the procedure, biomarkers (GDF15 & NTproBNP) were measured before, 3 and 7 days after TAVI.

The primary endpoint was survival time, all available prognostic factors were studied by Cox regression analysis with backward selection based on the likelihood ratio criteria.

At median follow-up of 349 d (Q1-Q3 106-660d), a total of n=66 deaths occurred. 30d mortality was 6.9%. Mean age was 81.8 years (± 6.0 y) and 55.8% were females. Mean log. Euroscore (ES) was 25.4% (± 17.2%). Median preprocedural GDF15 values were 2256 pg/ml (Q1-Q3 1585.5-3082.0). In univariate analyses, increased GDF15 levels (upper quartile compared to lower three quartiles) revealed a HR of 2.4 (CI 1.5-3.9, p<0.001) for adverse outcome. In addition, also log. ES (p= 0.001), log. ES II (p=0.018), STS-Score (p=0.019), NTproBNP (p=0.037) and atrial fibrillation (p=0.02) demonstrated statistical significance for negative outcome.

A multivariate Cox regression analysis including these factors and postprocedural aortic regurgitation, demonstrated that elevated GDF15 had a HR of 2.104 (CI 1.3-3.5; p=0.003) for negative outcome in patients undergoing TAVI, while elevated NTproBNP had HR of 1.412 (CI 0.8-2.4; p=0.212). Moreover, this analysis also revealed the log. ES as an independent risk factor (HR of 2.211, CI 1.3-3.7; p= 0.002).

Conclusion:
Increased GDF15 levels are associated with a poor prognosis in patients undergoing TAVI. Furthermore, GDF15 showed to be superior to the established biomarker NTproBNP in risk stratification of patients undergoing TAVI providing additional prognostic information.
Abstract 19227: Results of an Implantable Cardioverter Defibrillator Screening Program Based on Transthoracic Echocardiography at a Tertiary Academic Medical Center
Authors: Dresen William F , Mealor Augustus E , Camnitz Will , Love Samuel , Choubey Neha , Malhotra Rohit , Darby Andrew , Mason Pamela , Dent John , Mangrum J. Michael , DiMarco John P , Ferguson John D , Bilchick Kenneth C
Published: July 2021

Introduction:
There has been interest in quality improvement programs based on screening of LV function in order to increase rates of adherence to guideline-based recommendations for implantable cardioverter defibrillators (ICDs) for primary prevention (PP) of sudden cardiac death.

Methods:
We queried the echocardiography database at a tertiary academic medical center for patients with LVEF ≤ 35% on a transthoracic echocardiogram (TTE) and analyzed clinical data from the electronic medical record. We then determined the proportion receiving ICDs, reasons ICDs were not implanted, mortality rates, and our risk score for death (JACC 2012; 60:1647-55).

Results:
Of the 406 patients reviewed with LVEF 35% or less, 22.9% had an ICD at the time of the TTE and 10.8% had an ICD implanted during a median follow-up of 4.0 years (ICD-DURING-FU). With respect to patients without ICDs, 6.2% (of total group) did not survive the index hospitalization, 16.4% did not meet primary prevention criteria due to life expectancy less than 1 year or other guideline-based criteria, and 23.4% had spontaneous LVEF improvement to above 35% (LVEF-SPONT-IMPROVED), while the remaining 20.0% met guideline-based criteria for a primary prevention ICD (NO-ICD-DESPITE-CRITERIA) (Table). The NO-ICD-DESPITE-CRITERIA group had a greater mortality (35.8%) than the LVEF-SPONT-IMPROVED group (21.1%; p=0.03) and the ICD-DURING-FU group (20.5%; trend with p=0.07). In a multivariable logistic model, LVEF-SPONT-IMPROVED (v. ICD-DURING-FU) patients had OR=0.50 for death (p=0.049) after adjustment for the risk score.

Conclusions:
In a large cross section of patients with TTEs and extended follow-up, 1 in 5 patients did not have ICDs implanted despite meeting standard PP criteria. Another significant group did not have ICDs implanted because they had improvement in LV function during follow-up, and these patients had a similar survival probability to patients who did have ICDs implanted during follow-up.
Abstract 19241: Downregulation of microRNA-494 Facilitates Smooth Muscle Cell Proliferation and Vascular Remodeling
Authors: Donde Katrin , Daniel Jan-Marcus , Dutzmann Jochen , Bauersachs Johann , Sedding Daniel
Published: July 2021

Introduction:
Proliferation of vascular smooth muscle cells (VSMC) plays a crucial role in the development of vascular proliferative diseases such as atherosclerosis and in-stent-restenosis. MicroRNAs (miR) are small noncoding RNAs that modulate gene expression in a posttranscriptional manner.

Hypothesis:
in this project we aimed to determine the functional impact of a micro-RNA which is strongly regulated during vascular remodeling.

Methods and Results:
Neointima formation was induced by a wire-mediated injury of the femoral artery in C57BL/6 mice. Microarray analysis of the developing neointimal lesion showed a strong reduction of miR-494 (0.411±0.04) at 7 days after injury as compared to uninjured controls, which could be confirmed by qPCR. Interestingly, miR-494 was found to be predominantly expressed in SMC as determined by in situ hybridization. The regulation of miR-494 expression was further analyzed in vitro after stimulation of SMC with 10% FCS. Following this mitogenic stimulation, mir-494 expression dropped robustly and significantly in a time-dependent manner at 6, 9, and 24 hours. To investigate the functional impact of miR-494 on SMC proliferation, miR-494 was overexpressed using miR-494-mimics (20μM). Overexpression of miR-494 significantly reduced the FCS-induced proliferation of SMC as assessed by BrdU-incorporation and total cell counts. In silico analyses of potential target genes for miR-494 identified survivin, an important molecule for cell cycle regulation, as potential target of miR-494. Indeed, survivin was found down-regulated on the mRNA and protein level after transfection of SMC with miR-494 mimics and could be confirmed as direct target using luciferase reporter assays.

Conclusions:
Taken together, our results show that mir-494 is strongly down-regulated in proliferating SMC in vitro as well as during neointimal lesion formation in vivo. Moreover, the anti-proliferative effect of miR-494-reconstitution reveals a crucial functional role of miR-494 in the mitogenic response of SMC. Thus, miR-494 might represent a novel and promising SMC-specific target for future therapeutic strategies in the treatment of vascular proliferative diseases.
Abstract 19300: Drug Screening in Human Neutral Lipid Storage Disease iPSCells Identifies Modulators of Intracellular Lipid Metabolism That Reduce Disease Phenotype in vitro
Authors: Kuppusamy Rajarajan , Feistritzer Becca , Engels Marc , Sturzu Anthony , Plonowska Karolina , Li Guang , Sharma Arun , Nakamura Kenta , John Hinson , Huang Xiaojing , Chuang Wenpo , Hirano Ken-ichi , Wu Sean
Published: July 2021

Induced pluripotent stem cells (iPSCs) hold great promise as in vitro disease models for pathway discovery and therapeutic drug screening. Here, we generated an in vitro model of neutral lipid storage disease, myopathy subtype (NLSD-M), a condition characterized by a marked elevation of lipid accumulation in cardiac and skeletal muscle due to the loss of functional adipose triglyceride lipase (ATGL), by reprogramming patient fibroblasts into iPSCs. These hiPSCs were confirmed of carrying mutations in exon 5and exon 7 of the ATGL gene and were shown to recapitulate the disease phenotype by the presence of Oil Red O positive lipid granules in cardiomyocytes. To corroborate this finding, expression of metabolic genes such as Peroxisome proliferator-activated receptors (PPAR-a and PPAR-g) were significantly decreased in diseased cardiomyocytes compared to control. Furthermore, the down-regulation of PPAR-gamma coactivators (PGC-1a and PGC-1b) and PPAR target genes expression were associated with increased lipid accumulation in vitro. Utilizing the previously identified compounds that induces glycolysis and suppresses oxidative respiration, we found that the accumulation of intracellular lipids in cardiomyocytes was reduced in treated cells when compared with un-treated cells (0.041 ± 0.02 vs 0.186 ± 0.05). Strikingly, such a treatment effect was not observed when Wild Type iPSC derived cardiomyocytes was studied instead, suggesting a disease-specific effect of the identified drugs. Our results represent one of the first successful human induced Pluripotent Stem Cell validation of high throughput drug screening hits from murine iPSC lines. Given the increased prevalence of NLSD-Min the Japanese population, our findings raise the prospect that a treatment for this devastating disease using drug hits from in vitro iPSC screening may be feasible in the near future.
Abstract 19428: TRAF3IP2 Mediates Aldosterone-induced Cardiac Hypertrophy and Fibrosis
Authors: Jalahalli Mariswamy Siddesha , Sakamuri Siva Sankara Vara Prasad , Manjunath Yariswamy , Valente Anthony J , Siebenlist Ulrich , Gardner Jason D , Bysani Chandrasekar
Published: July 2021

Background:
Aldosterone (Aldo) is a key regulator of blood pressure and electrolyte balance. Aldo/salt has been shown to induce oxidative stress, inflammation, cardiac hypertrophy and fibrosis. TRAF3 interacting protein 2 (TRAF3IP2) is a cytoplasmic redox-sensitive adaptor molecule and an upstream regulator of NF-κB and AP-1. It plays a critical role in the regulation of various proinflammatory cytokines that exert prohypertrophic and profibrotic effects. Therefore, we hypothesized that TRAF3IP2 is a critical mediator of Aldo/salt-induced cardiac hypertrophy and fibrosis.

Methods:
TRAF3IP2-null and wild type (WT) mice (male, 12-13 weeks) were infused continuously with Aldo for 4 weeks via mini-osmotic pumps (0.2 mg/Kg/day; n = 6-8). Mice were fed 1% NaCl in drinking water. Salt alone served as control. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography, myocardial function by echocardiography, cardiac hypertrophy by heart weight to body weight ratios, cardiac fibrosis by trichrome Gomori, and gene and protein expression by RT-qPCR, immunoblotting and ELISA.

Results:
Aldo/salt elevated SBP to a similar extent in both TRAF3IP2-null and WT mice. Aldo/salt upregulated TRAF3IP2 expression in left ventricular homogenates from WT mice, and TRAF3IP2 gene deletion (vs. WT) blunted cardiac hypertrophy by 54% (p < 0.05), suppressed ANP expression by 3.5 fold (p < 0.05), prevented concentric LV remodeling (decreased LVPWs; 93%; p < 0.01, LVPWd; 95%; p < 0.05, LVAWs; 29.8%; p < 0.05 and LVAWd; 26.2%, and increased LVIDs; 19.2%; p < 0.01 and LVIDd; 8.53%) and markedly reduced both interstitial and perivascular fibrosis. Further, TRAF3IP2 gene deletion inhibited Aldo/salt-induced p65 and c-Jun activation, and expression of inflammatory cytokine (IL-18 and IL-6), matrix metalloproteinase (MMP2) and extracellular matrix proteins (collagen Iα1 and IIIα1). TRAF3IP2 gene deletion also blunted mRNA and protein expression of lysyl oxidase, an enzyme involved in collagen crosslinking.

Conclusions:
TRAF3IP2 gene deletion blunts Aldo/salt-induced cardiac hypertrophy and fibrosis by inhibiting proinflammatory, prohypertrophic, and profibrotic effects, signifying its potential as a therapeutic target in hypertrophic heart diseases.
Abstract 19583: Autonomous and Non-Autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes
Authors: Josowitz Rebecca , Mulero-Navarro Sonia , Falce Christine , Cohen Ninette , Ullian Erik M , Weiss Lauren A , Rauen Katherine A , Sobie Eric A , Gelb Bruce D
Published: July 2021

Hypertrophic cardiomyopathy (HCM) is a pathological disorder predominantly due to mutations in sarcomeric components. Germline mutations in BRAF cause a developmental syndrome called cardio-facio-cutaneous syndrome (CFCS), in which 40% of patients also develop HCM. Since the role of the RAS/MAPK pathway in HCM is still unclear, we generated a human induced pluripotent stem cell model for CFCS from three patients with activating BRAF T599R or Q257R mutations. In order to examine hiPSC-derived cell-type specific phenotypes and cellular interactions underpinning HCM, we generated a method to purify cardiomyocytes and non-cardiomyocytes simultaneously by cell sorting based on SIRPα and CD90 expression. Purified BRAF-mutant SIRPα+/CD90- cells were >95% cardiomyocytes, displayed cellular hypertrophy with pro-hypertrophic gene expression, and dysregulation of the RAS/MAPK pathway. BRAF-mutant cardiomyocytes also displayed intrinsic calcium handling defects, including increased calcium transient irregularity and increased stored calcium within the sarcoplasmic reticulum. In addition, purified BRAF-mutant SIRPα-/CD90+ cells, which were fibroblast-like, displayed activation of the RAS/MAPK pathway and exhibited a pro-fibrotic phenotype. Cross-culture studies revealed that BRAF-mutant fibroblast-like cells critically modulate cardiomyocyte hypertrophy through TGFβ paracrine signaling, as TGFβ inhibition prevented cardiomyocyte hypertrophy induced by BRAF-mutant fibroblast-like cells. Additionally, inhibition of RAS/MAPK signaling was capable of rescuing BRAF-mutant cardiomyocyte hypertrophy and cardiomyocyte-intrinsic calcium handling abnormalities. Thus, we show for the first time that cell autonomous and non-autonomous defects underlie RASopathy-associated HCM. As fibroblast activation has been documented previously in sarcomeric HCM, our findings suggest that cardiac fibroblasts may contribute to pathologic hypertrophy in addition to causing fibrosis in primary forms of HCM. TGFβ inhibition may be a useful therapeutic option for patients with HCM due to RASopathies or other etiologies.