bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13500: Association Between Breast Cancer and Cardiac Autonomic Function as Measured by Heart Rate Variability in the Women’s Health Initiative
Authors: Branch Mary , Schaich Christopher L , Beavers Daniel , Soliman Elsayed Z , Reding Kerryn , Shadyab Aladdin , OKWUOSA Tochi M , Wells Gretchen L , Valencia Celina , Barac Ana , Vitolins Mara
Published: May 2021

Background:
Autonomic dysfunction (AD) as measured by heart rate variability (HRV) is associated with increased risk of cardiovascular disease (CVD) and breast cancer. No study has utilized a large prospective multi-center cohort of diverse women to assess differences in HRV associated with incident breast cancer.

Objectives:
To identify heart rate variability changes in women with breast cancer compared to controls in the Women’s Health Initiative (WHI).

Methods:
In a retrospective cohort study, we utilized 5,031 women in the WHI CT cohort who were breast cancer free at baseline and compared 1) those with incident breast cancer v. 2) those who were breast cancer free during the ECG follow-up period as controls. HRV was calculated utilizing 10-second ECG with two measures of two-domain HRV: standard deviation of all normal-to-normal RR intervals (SDNN) and the root mean square of successive differences in normal-to-normal RR intervals (rMSSD). HRV was measured from ECGs collected at baseline, years 3, 6, and 9 in the comparison groups. An adjusted mixed linear model was used to evaluate the differences in SDNN and rMSSD comparing women with incident breast cancer to controls. Cardiovascular risk factors utilized in the adjusted model were determined via questionnaire at baseline.

Results:
At baseline, women with incident breast cancer diagnosed by years 3, 6, or 9 were significantly older (median age 63 vs. 61, P<0.0001) and had a higher prevalence of hypertension (35% vs. 32%, P=0.02). SDNN at years 3 and 6 in women with breast cancer compared to controls was significantly lower (P=0.0002, P=0.03 respectively). As well, rMSSD was significantly lower at year 3 compared to controls (P<0.0001) (
Figure 1
).

Conclusions:
HRV as a measure of AD is significantly lower in women with incident breast cancer compared to women without breast cancer. Reduction in HRV is associated with CVD outcomes in the literature. Our study suggests HRV may predict CVD in breast cancer patients.
Abstract 13508: Left Ventricular Contractile and Kinetic Changes in Failing Human Myocardium Due to Anthracycline Toxicity
Authors: Mashali Mohammed , Saad Nancy , Kiduko Salome , Peczkowski Kyra , Huang Amanda , Fazlollahi Farbod , Hare Austin , Torres Matias Gina , Whitson Bryan , Mokadam Nahush , Campbell Courtney , Janssen Paul
Published: May 2021

Introduction:
Anthracyclines are used effectively to treat many cancers. However, cumulative and irreversible cardiotoxicity can limit anthracyclines’ clinical benefit. Mechanisms of cardiotoxicity have been assessed in murine models, but no studies directly assess human heart contractility. Our objective was to assess left ventricular contractile force, kinetics of contraction and relaxation, and frequency-dependent activation in anthracycline-induced failing human myocardium.

Methods:
From 2009-2019, we assessed live tissue-level contractile forces and kinetics in isolated left ventricular intact trabeculae from failing and non-failing human hearts. After the trabeculae were transferred to and stabilized in a custom setup, baseline contractile force and kinetic parameters were assessed at 1 Hz (normal resting
in vivo
heart rate), followed by frequency-dependent activation (0.5-3.0 Hz) under near-physiological conditions. Retrospectively, we analyzed muscles from three cohorts of individuals: (1) with non-ischemic cardiomyopathy due to anthracycline toxicity (NICM-AC;
n
=14), (2) with NICM and history of cancer without anthracycline or known cardiotoxic treatments (NICM;
n
=14), and (3) with non-failing myocardium and no history of cancer (NF;
n
=14).

Results:
At stimulation of 1 Hz, active developed force (Fdev) of NICM-AC trabeculae was significantly lower than NF and NICM trabeculae. NICM-AC trabeculae exhibited prolonged 90% relaxation time (RT90), significantly slower maximal rate of force decay (-dF/dt), and slower maximal kinetic rate of relaxation (-dF/dt/Fdev). In addition, frequency-dependent activation and relaxation were markedly impaired in both failing groups.

Conclusions:
Human myocardium failing due to anthracycline toxicity had significantly decreased force and slower relaxation kinetics compared to non-ischemic failing myocardium. With increase in stimulation frequency, anthracycline treated myocardium exhibited impaired activation and relaxation kinetics. These findings suggest that cardio-protection strategies should aim to improve not only contractile force, but also kinetics of relaxation.
Abstract 13529: Percutaneous Coronary Intervention in Ambulatory Surgery Centers: Is It Safe?
Authors: Li Kevin , Kalwani Neil M , Heidenreich Paul A , Fearon William F
Published: May 2021

Introduction:
In January 2020, Medicare began reimbursing for percutaneous coronary intervention (PCI) performed in ambulatory surgery centers (ASCs), but little is known about characteristics and outcomes of patients who have undergone ASC PCI previously.

Methods:
Using commercial insurance claims from the MarketScan® Databases, we characterized patients 18 years or older who underwent hospital outpatient department (HOPD) or ASC PCI for stable ischemic heart disease between April 1, 2007, and December 1, 2016. We used propensity score matching of HOPD and ASC PCI cohorts to measure the association between treatment setting and 30-day outcomes (myocardial infarction, bleeding complications, and all-cause admission).

Results:
The unmatched sample consisted of 95,492 HOPD and 849 ASC PCI patients. Patients were more likely to undergo ASC PCI if they were younger than 65 (OR 1.72, 95% CI 1.43-2.06), lived in the southern U.S., or were covered by managed (OR 2.31, 95% CI 1.73-3.08) or consumer-driven (OR 2.57, 95% CI 1.73-3.82) compared to comprehensive health plans. ASC PCI was less likely in patients with a history of stroke (OR 0.45, 95% CI 0.28-0.72). Intravascular imaging and physiology testing were more frequently performed in HOPD than in ASC PCI (18.3% vs. 12.5%, respectively; p < 0.001). After propensity-score matching, ASC PCI was associated with increased odds of bleeding complications (OR 2.43, 95% CI 1.22-4.84, p = 0.011). Differences in other outcomes were not statistically significant.

Conclusions:
Patients undergoing outpatient elective PCI in ASCs were younger and more likely to live in the southern U.S or have managed or consumer-driven health insurance plans. Intravascular imaging and physiology testing were performed more frequently in HOPD than in ASC PCI. PCI in the ASC setting was also associated with an increased risk of bleeding complications. Further study of this population is warranted as ASC PCI volume increases under Medicare.
Abstract 13559: Engineered Three-dimensional Cardiac Tissues Maturated by Dynamic Culture in a Rotating Wall Vessel Bioreactor Remodel the Diseased Heart in the Rat Infarction Model
Authors: Nakazato Taro , Miyagawa Shigeru , Uemura Toshimasa , Liu Li , Li Junjun , Sasai Masao , Harada Akima , Toda Koichi , Sawa Yoshiki
Published: May 2021

Introduction:
To completely repair the distressed heart with few myocytes it may be crucial how to construct massive engineered three-dimensional cardiac tissues (E3DCTs) and integrate them to myocardium after transplant. We hypothesized that E3DCTs maturated by dynamic culture could enhance to remodel diseased left ventricle (LV) in the distressed rat heart.

Methods:
We made E3DCT by seeding 2.0 х 10
6
human induced pluripotent stem cell derived cardiomyocytes on the 6mm х 6mm PLGA fiber sheet. It was cultured in a rotating wall vessel bioreactor for seven days (RWV group) or culture dishes for the control. After in vitro assessment, these tissues were transplanted to myocardial infarction model nude rats, and 4 weeks after transplantation, we evaluated functional recovery and histology.

Results:
In the RWV group, thickness of E3DCTs were around 400μm, and cardiomyocytes showed mature phenotype evidenced by significantly higher expression of Troponin T (TnT), sarcomeric α actinin (SAA), connexin 43 (Cx43) and myosin heavy chain 7 (MYH7) with upregulation of mammalian target of rapamycin by Western blots (TnT; 2.1±0.2 vs. 1.0±0.2, SAA; 2.0±0.2 vs. 1.0±0.2, Cx 43; 2.0±0.3 vs. 1.0±0.1, MYH7; 2.0±0.2 vs. 1.0±0.2, p<0.05, respectively) (Figure 1A). Moreover, the concentration of angiogenic cytokines was significantly higher in the RWV group. Four weeks after transplantation, the LV ejection fraction was significantly improved in the RWV group than in the control (47±4.9 vs. 38±6.9%, p<0.01). On histological analysis, transplanted E3DCT reached a thickness of 1mm and vascular-like structures were partially observed inside (Figure 1B). In the RWV group, LV remodeling was significantly attenuated and neovascularization was significantly noted (Figure 1C, 1D).

Conclusions:
E3DCTs maturated by dynamic culture in a RWV bioreactor could remodel the diseased LV in rat infarction model, proposing potent armamentarium for cardiomyogenesis therapy in failed heart.
Abstract 13567: Variability in Reported Post-percutaneous Coronary Intervention Mortality Among Physicians Practicing at Multiple Sites in New York State
Authors: Yang Nancy , Groeneveld Peter W , Khatana Sameed Ahmed M , Giri Jay S , Fanaroff Alexander C , Nathan Ashwin
Published: May 2021

Introduction:
New York State (NYS) publicly reports physician-level post-percutaneous coronary intervention (PCI) mortality at each individual site they practice, to empower patients to make informed decisions. Given that mortality is a rare event and some sites have low case volumes, we hypothesized that the reported data at each site for physicians practicing at multiple sites is highly unstable and thus misleading for patients. In this study, we examined variation in site-specific risk-adjusted mortality rates (RAMR) for physicians practicing at multiple sites in NYS.

Methods:
This study uses publicly reported 30-day physician-level RAMR for all PCI performed in NYS between 2014 and 2016. We obtained the site-specific RAMR (ssRAMR) at each hospital where the physician performed PCI, and overall mean RAMR (mRAMR) for the physician. We excluded physicians who performed PCI at only one hospital. We identified outliers for mRAMR and maximum ssRAMR if values were greater than the 95
th
percentile for each measure and plotted the outliers.

Results:
Between 2014 and 2016, 142,853 PCI procedures were performed by 373 physicians at 61 hospitals. Among 207 (55.5%) physicians practicing at multiple sites who performed 82,075 PCI (57.5%), the median mRAMR was 1.11% (IQR 0.66-1.60%, range 0-5.33%) and the median ssRAMR was 0.52% (IQR 0-1.53%, range 0-47.69%). Among the 11 physicians classified as ssRAMR outliers, only 3 (27.2%) physicians were also classified as an mRAMR outlier.

Conclusion:
We found that the individual ssRAMRs reported for a physician practicing at multiple hospitals is highly variable, and that mRAMR and ssRAMR outlier status are not consistent with each other. Thus, we believe public reporting of ssRAMR in NYS does not adequately reflect the quality of care delivered by physicians performing PCI.

Figure:
mRAMR and ssRAMR among maximum ssRAMR outliers. Each letter (A-K) represents a separate outlier physician.
Abstract 13577: Human Induced Pluripotent Stem Cell-derived Cardiomyocyte Patches Ameliorate Right Ventricular Diastolic Dysfunction in a Rat Pressure-overloaded Right Heart Model
Authors: Watanabe Takuji , Miyagawa Shigeru , Harada Akima , Kawamura Ai , Kawamura Takuji , Ueno Takayoshi , Toda Koichi , Kuratani Toru , Sawa Yoshiki
Published: May 2021

Introduction:
Right ventricular (RV) failure following definitive repair of congenital heart diseases (CHD) have great impact on survival after surgical intervention. Recently, human induced pluripotent stem cell-derived cardiomyocyte (hiPS-CM) sheet transplantation ameliorated left ventricular dysfunction in preclinical study, associating possible efficacy in RV failure of CHD.

Hypothesis:
We hypothesized whether hiPS-CM patch could improve distressed RV function in rat pressure overload model.

Methods:
F344/NJcl-
rnu/rnu
rat (7-9 weeks old, male, 180-210g) underwent pulmonary artery banding (PAB) via left thoracotomy under general anesthesia. Four weeks after PAB, hiPS-CM patch transplantation to the RV was performed in the hiPS-CM patch transplantation group (n = 10), whereas a sham operation was performed in the sham group (n =10). We evaluated for cardiac catheterization (CATH) data and pathological findings 8 weeks after PAB.

Results:
In CATH, RV end diastolic pressure (sham; 10.0 ± 4.1 vs hiPS-CM; 5.5 ± 2.7 mmHg, P < 0.01), time constant of isovolumic relaxation (sham; 24.9 ± 8.6 vs hiPS-CM; 16.5 ± 6.4 ms, P < 0.01) and end-diastolic pressure volume-relation (sham; 365.6 ± 246.3 vs hiPS-CM; 214.0 ± 147.4 mmHg/mL, P <0.05) were significantly ameliorated in hiPS-CM group compared with sham group. Sirius-red staining showed a significant anti-fibrotic effects in the hiPS-CM group compared with the sham group (13.4 ± 5.3 vs 20.7 ± 4.8 %, P <0.05). Factor VIII stain showed that myocardial capillary vascular density in the hiPS-CM group was significantly higher than in the sham group (640 ± 131 vs 362 ± 31 units/mm
2
, P <0.001). hiPS-CMs were detectable on epicardium 2 weeks after hiPS-CM patch transplantation. The expression levels of vascular endothelial growth factor and hepatocyte growth factor in the hiPS-CM group was significantly higher than in the sham group (P <0.05).

Conclusions:
In a rat model of a pressure-overload RV, hiPS-CM patch transplantation improved the diastolic function with suppressed ventricular fibrosis and increased capillary density, suggesting a promising treatment for RV failure in CHD patients after surgical repair.
Abstract 13583: Secondary Findings of Loss-of-function Variants in
FLNC
Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes in a General Clinical Population
Authors: Haggerty Christopher M , Kelly Melissa , Tichnell Crystal , Murray Brittney ,   Regeneron Genetics Cntr, Sturm Amy C , Fornwalt Brandon , James Cynthia
Published: May 2021

Introduction:
The
FLNC
gene, encoding the Filamin C sarcomere protein, has gained recent attention as a potential cause of severe cardiomyopathy and arrhythmia phenotypes through genetic testing of individuals with known inherited heart disease. We sought to characterize the phenotypes associated with rare, putative loss-of-function variants in
FLNC
ascertained through secondary findings of exome sequencing in a large clinical population.

Methods:
We reviewed exome data from the first 135,878 sequenced participants in the Geisinger MyCode Community Health Initiative with linked electronic health records (EHR; the DiscovEHR cohort) to identify rare frameshift, stop gain, or canonical splice site variants in
FLNC
(FLNC
LOF
). We compared data on diagnoses and cardiac diagnostic testing (i.e., ECG and echocardiography, when available) from the EHR between individuals with and without FLNC
LOF
using SAIGE mixed linear models adjusted for age, sex, and ancestry.

Results:
We observed 46 individuals (0.03%) carrying one of 24 distinct FLNC
LOF
variants. These individuals had significantly increased odds for diagnoses of dilated cardiomyopathy (OR: 49, 95% CI: [4-560]), ventricular tachycardia (OR: 170, [5-6317]), and supraventricular tachycardia (OR: 11, [2-77]). We also observed significantly increased left ventricular (LV) diameter (5.1 ± 0.8 cm vs. 4.6 ± 0.7 cm, p = 0.001) and decreased LV ejection fraction (Figure) by echocardiography (available in 50% of FLNC
LOF
individuals), and a trend toward higher prevalence of inverted T waves in any precordial lead beyond V2 (23% vs. 7%, p = 0.06).

Conclusion:
Loss-of-function variants in
FLNC
are extremely rare in a general clinical population but are associated with a clinically significant and potentially actionable, yet incompletely penetrant, cardiac phenotype marked by ventricular dysfunction and dysrhythmia. Consideration for screening and return of secondary findings may be warranted.
Abstract 13585: Genomics-first Evaluation of Phenotypes Associated With Pathogenic or Likely Pathogenic Transthyretin Variants
Authors: Carry Brendan , Young Katelyn , Kelly Melissa , Sturm Amy C , Avila Jose D ,   Regeneron Genetics Cntr, Fornwalt Brandon , Haggerty Christopher M
Published: May 2021

Introduction:
Hereditary transthyretin (
TTR
) amyloidosis as a cause of cardiomyopathy has historically been challenging to diagnose. With increased genetic testing, quantification of penetrance and disease associations through genomics-first approach provides a first step towards improved diagnosis and treatment.

Methods:
In the Geisinger MyCode Community Health Initiative, we identified pathogenic and likely pathogenic (P/LP) variants in
TTR
from 135,878 individuals with exome sequence data linked to electronic health records (DiscovEHR cohort) using ANNOVAR. We compared diagnoses and imaging findings between
TTR
variant carriers/noncarriers using SAIGE mixed linear models.

Results:
We observed 7 P/LP
TTR
variants (6 P, 1 LP) in 158 individuals (0.12%; 142 P, 16 LP). Median carrier age was 52 (IQR: 37-61) and 43% were male. The most common variant was V122I (i.e., p.V142I; 114, 0.08%). Most
TTR
variant carriers were of African ancestry (58%), all of whom carried V122I, consistent with the frequency of this variant in that population (2.6%). Observed associations with cardiac amyloidosis (odds ratio (OR): 2.8E
20
, p = 0.03) and non-specific amyloidosis (OR: 4E
4
, p = 0.03) were significant, although prevalence was low (n = 1 and 2
TTR
carriers, respectively). No associations were observed with other specified diagnoses (Figure) or imaging findings. Considering only individuals aged ≥60, we observed a significant association with non-ischemic, non-dilated cardiomyopathy diagnoses (OR: 5.8, p=0.04) involving carriers of V122I (n = 3), V30M (p.V50M), T60A (p.T80A), and I68L (p.I88L; n = 1 each).

Conclusion:
Genomics-first screening of a clinical population for P/LP variants in
TTR
has a moderate to high yield depending on population ancestry. In the absence of symptoms or family history, initiating routine surveillance may be most appropriate after age 60. Deeper phenotyping is warranted to better characterize penetrance and ramifications for management.
Abstract 13596: Identifying the Most Important Ecg Predictors of Reduced Ejection Fraction in Patients With Suspected Acute Coronary Syndrome
Authors: Ahmad Abdullah , Alhamaydeh Mohammad , Faramand Ziad , Gregg Richard , Saba Samir , Al-Zaiti Salah S
Published: May 2021

Background:
Non-invasive screening tools of cardiac function can play a significant role in the initial triage of patients with suspected acute coronary syndrome. Numerous ECG features have been previously linked with cardiac contractility in the general population. We sought to identify ECG features that are most predictive for real-time screening of reduced left ventricular ejection fraction (LVEF) in the acute care setting.

Methods:
We performed a secondary analysis of a prospective, observational cohort study of patients evaluated for suspected acute coronary syndrome. The parent study recruited consecutive patients evaluated at the emergency department of three UPMC-affiliated tertiary care hospitals. We included consecutive patients in whom an echocardiogram was performed during indexed encounter. Baseline ECGs were preprocessed using manufacturer specific algorithms. We evaluated 554 automated 12-lead ECG features in multivariate linear regression for predicting LVEF. We then used regression trees to identify the most important predictive ECG features.

Results:
Our final sample included 297 patients (aged 63 ± 15, 45% females). The mean LVEF was 57% ± 13 (IQR 50%-65%). In multivariate analysis, depolarization dispersion in the horizontal plane; global repolarization dispersion; and abnormal temporal indices in inferolateral leads were all independent predictors of LVEF (R
2
= 0.452, F = 6.679, p < 0.001). Horizontal QRS axis deviation and prolonged ventricular activation (VAT) time in left ventricular apex were the most important determinants of reduced LVEF (Figure), while global QRS duration was of less importance.

Conclusions:
Poor R wave progression in precordial leads with dominant QS pattern in V3 is the most predictive feature of reduced LVEF in suspected ACS. This feature constitutes a simple visual marker to aid clinicians in identifying those with impaired cardiac function.
Abstract 13597: Association Between Antiarrhythmic Drug Therapy Prescription in the Blanking Period and Recurrent Atrial Arrhythmias After First-time Catheter Ablation for Atrial Fibrillation
Authors: Malladi Chaitanya L , Eskander Michael , Lupercio Florentino , Han Frederick , Hoffmayer Kurt S , raissi farshad , Ho Gordon , Feld Gregory K , Hsu Jonathan C
Published: May 2021

Introduction:
Antiarrhythmic drugs (AAD) are often prescribed in the blanking period (BP) after catheter ablation of atrial fibrillation (AF) to reduce risk of early recurrence (ER) and late recurrence (LR). There are limited data on which AAD to use during the BP.

Hypothesis:
We hypothesize that specific AADs may be associated with reduced risk of ER and/or LR after ablation.

Methods:
A total of 478 consecutive patients (mean age 64.2 years, 67.2% male) undergoing first-time pulmonary vein isolation (PVI) ablation at a single institution were included. Outcomes of interest were: freedom from ER, freedom from LR, initial discontinuation of AAD less than 90 days after ablation, and freedom from second ablation. ER was defined as AF, atrial flutter (AFL), or atrial tachycardia (AT) > 30 seconds within the BP. LR was defined as AF/AFL/AT > 30 seconds occurring after the BP.

Results:
Of 478 patients, 14.9% (n = 71) were on no AAD, 26.4% (n = 126) were on propafenone/flecainide, 34.5% (n = 165) were on sotalol/dofetilide, 10.7% (n = 51) were on dronedarone, and 13.6% (n = 65) were on amiodarone. Patients on amiodarone were older, had higher BMI, and were more likely to have persistent AF, hypertension, diabetes, heart failure, and coronary artery disease. In unadjusted analyses, there were no differences between groups with regards to the risk of ER (log rank P = 0.171), discontinuation of AAD before ninety days post-ablation (log rank P = 0.235), or freedom from second ablation (log rank P = 0.147). After multivariable adjustment, patients on amiodarone or dronedarone were more likely to experience LR than those on no AAD [Adjusted Hazard Ratio (AHR) 1.83, 95% CI 1.10-3.04, p=0.02 for amiodarone; AHR 1.79, 95% CI 1.05-3.05, p=0.03 for dronedarone].

Conclusions:
Following first-time AF catheter ablation, there were no differences between the presence or absence of AAD and risk of ER, while those prescribed amiodarone or dronedarone in the BP were more likely to experience LR than those on no AAD.
Abstract 13771: Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals With Atrial Fibrillation
Authors: Osullivan Jack W , Shcherbina Anna , Justesen Johanne M , Turakhia Mintu , Perez Marco V , Wand Hannah , Tcheandjieu Catherine , Clarke Shoa L , Harrington Robert A , Rivas Manuel A , Ashley Euan A
Published: May 2021

Introduction:
Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA
2
DS
2
-VASc) don’t include family history or genetic risk.

Hypothesis:
A polygenic risk scores (PRS) is both independently, and in integrated with clinical risk factors, predictive of ischemic stroke in patients with Atrial Fibrillation.

Methods:
Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank (UK Biobank), both independently and integrated with clinical risk factors.

Results:
The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Compared with the currently recommended risk tool (CHA
2
DS
2
-VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.04 to 1.21)). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson’s correlation coefficient: -0.018).

Conclusions:
In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.
Abstract 13777: Coexisting Metabolic Syndrome Inhibits Myocardial Mitophagy in Renovascular Hypertensive Pigs, Aggravating Cardiac Injury and Dysfunction
Authors: Aghajani Nargesi Arash , Farah Mohamed C , Zhu Xiang-yang , Zhang Lei , Tang Hui , Jordan Kyra L , Saadiq Ishran M , Lerman Amir , Lerman Lilach O , Eirin Alfonso
Published: May 2021

Introduction:
Subjects with renovascular hypertension (RVH) often manifest with metabolic syndrome (MetS), increasing risk for heart failure, yet the mechanisms underlying cardiac injury remain unknown. Reduced mitophagy and accumulation of impaired mitochondria have been linked to progression of heart failure.

Hypothesis:
We hypothesized that superimposition of MetS on RVH in swine inhibits myocardial mitophagy, aggravating mitochondrial damage, cardiac injury and dysfunction.

Methods:
Pigs were studied after 16 weeks of RVH (renal artery stenosis) with or without diet-induced MetS, and Lean controls (n=6 each). Cardiac function was assessed in vivo (multidetector-CT), and cardiac mitochondrial structure, function, mitophagy, and myocardial fibrosis ex vivo.

Results:
MetS groups developed obesity, whereas RVH groups developed hypertension (Table). Mitochondrial matrix density and ATP production were lower and H2O2 production higher in both RVH groups vs. Lean and MetS (Fig. AB). However, MetS+RVH failed to activate mitophagy and downregulate myocardial expression of mitophagy-related microRNAs achieved by Lean+RVH (Fig. CD). Myocardial expression of the mitophagy marker PTEN-induced kinase (PINK)-1 inversely correlated with myocardial fibrosis (R
2
=0.195, p=0.031). Cardiac fibrosis, hypertrophy, and diastolic dysfunction (decreased E/A ratio) were greater in MetS+RVH vs. Lean+RVH (Table, Fig. E).

Conclusions:
MetS aggravates myocardial mitochondrial damage and dysfunction in swine RVH. MetS+RVH failed to activate mitophagy, resulting in greater cardiac remodeling, fibrosis, and diastolic dysfunction. Mitochondrial injury and impaired mitophagy may constitute important mechanisms and potential therapeutic targets to ameliorate cardiac structural damage and dysfunction in patients with coexisting MetS and RVH.
Abstract 13780: Effects of Op2113 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/reperfusion Model
Authors: Dai Wangde , Le Grand Bruno , Boucard Aurelie , Carreno Juan , Zhao lifu , Kloner Robert A
Published: May 2021

Background:
Despite advances in early reperfusion therapy for acute ST elevation myocardial infarction (MI), mortality rates and prevention of heart failure after the MI are not optimal. There have been many attempts to further reduce the size of acute MI and to limit the no reflow phenomenon after reperfusion, with mixed results. One promising approach may be to target the mitochondria. The purpose of the present study was to determine whether OP2113 and its active principle ATT (Anethol-TriThione, named also 5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione; CAS 532-11-6 ), a pharmaceutical that has been shown to decrease mitochondrial reactive species production from complex I of the mitochondrial respiratory chain, could limit MI size and the no reflow phenomenon in a standardized rat model of 30 minutes of proximal coronary artery occlusion and reperfusion.

Methods and Results:
Anesthetized rats were exposed to MI and received OP2113 as an intravenous infusion starting either 5 minutes prior to coronary artery occlusion (preventive), or 5 minutes prior to reperfusion (curative), or received vehicle starting 5 minutes prior to coronary artery occlusion. Infusions continued until the end of the study (3 hours of reperfusion). MI size ( triphenyl tetrazolium chloride staining technique) , expressed as a percentage of the ischemic risk zone ( blue dye technique) was significantly lower in the OP2113 treated preventive group at 44.5 ± 2.9% versus 57.0 ± 3.6% ( p<0.05) in the vehicle group, with a nonsignificant trend toward a smaller infarct size in the curative group ( 50.8 ± 3.9%). Area of no reflow ( thioflavin S technique) as a percentage of the risk zone was significantly smaller in both the OP2113 treated preventive (28.8 ± 2.4%; p =0.026 vs vehicle) and curative groups ( 30.1 ± 2.3%; p=0.04 vs vehicle) compared to the vehicle group ( 38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes.

Conclusions:
These results suggest that OP2113 is a promising agent to reduce no-reflow as well as to reduce MI size, especially if it is on board early in the course of the MI. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia.
Abstract 13783: Disease Modeling Doxorubicin-induced Cardiotoxicity Using Human Induced Pluripotent Stem Cells-derived Cardiomyocytes From Healthy and Type 2 Diabetic Patients
Authors: Pant Tarun , Narayan Shailendera , Dash Ranjan , Kalyanaraman Balaraman , Bosnjak Zeljko J
Published: May 2021

Introduction:
Doxorubicin-Induced Cardiotoxicity (DIC) is one of the most common clinical complications in cancer patients. Patients with diabetes have a higher incidence of breast cancer, and their risks of developing DIC is also higher as compared to healthy patients. The human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) have the unique potential to recapitulate the genetic background and have emerged as a powerful tool for disease modeling and drug screening.

Hypothesis:
We hypothesized that cardiomyocytes derived from T2 diabetic patients will recapitulate greater sensitivity to DIC as compared to CMs derived from non-diabetic individuals.

Methods:
The patient specific iPSCs were differentiated into CMs with modifications to enhance cardiomyocyte purity (Fig. 1A, n=4 cell lines in each group). After 30 days from the initial differentiation, CMs were exposed to different concentrations of doxorubicin (DOX) based on the pharmacokinetic characteristics of doxorubicin in humans. The DOX-induced stress on the CMs after 24h and 48h was investigated via the analysis of 1) Cellular LDH release 2) Cellular viability using Alamar Blue assay and 3) CM-markers using real-time PCR.

Results:
Following the treatment with DOX the (iPSC)-derived cardiomyocytes (CMs) from the diabetic patients were more sensitive as compared to control CMs by: 1) An increase in the LDH release, Fig. 1B, 2) Decrease in the cellular viability, Fig. 1C, and 3) Greater downregulation of cardiac specific structural genes including Troponin T and Troponin I mRNA expression.

Conclusions:
For the first time, we demonstrate the ability of hiPSC-CMs derived from diabetic individuals to recapitulate greater sensitivity to DOX
in vitro
, validating this platform for predicting DIC severity
in vivo
.
Abstract 13798: Influence of Advanced Pulmonary Vascular Remodeling on Accuracy of Echocardiographic Parameters of Left Ventricular Filling Pressure
Authors: Chiba Yasuyuki , Iwano Hiroyuki , Kaga Sanae , shinkawa mio , Murayama Michito , Ohira Hiroshi , Motoi Ko , Ishizaka Suguru , Tsujinaga Shingo , Yokoyama Shinobu , Nakabachi Masahiro , Nishino Hisao , Okada Kazunori , Kamiya Kiwamu , Nagai Toshiyuki , Anzai Toshihisa
Published: May 2021

Introduction:
Evaluation of left ventricular (LV) filling pressure (FP) plays an important role in the clinical management of pulmonary hypertension (PH). However, the accuracy of echocardiographic parameters for the estimation of LV FP in the presence of pulmonary vascular lesions has not been fully addressed.

Methods:
We investigated 87 patients diagnosed with PH due to pulmonary vascular lesions (non-cardiac PH; PH
NC
) (PH
NC
group) and 117 patients with ischemic heart disease without reduced LV ejection fraction (<40%) (control group). Mean pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR) were obtained by right heart catheterization. As echocardiographic parameters of LV FP, the ratio of early- (E) to late-diastolic transmitral flow velocity (E/A), ratio of E to early-diastolic mitral annular velocity (E/e'), and left atrial volume index (LAVI) were measured. The PH
NC
group was subdivided into non-severe and severe groups according to median PVR (5.3 Wood units).

Results:
PAWP was 12±5 mmHg in controls, 9±4 mmHg in non-severe PH
NC
, and 8±3 mmHg in severe PH
NC
. In the control and non-severe PH
NC
groups, positive correlations were observed between PAWP and E/A (R=0.66 and R=0.41, respectively), E/e' (R=0.36 and R=0.33), and LAVI (R=0.38 and R=0.62). In contrast, in the severe PH
NC
group, PAWP was only correlated with LAVI (R=0.41, p=0.006). In the control group, PAWP determined E (β=0.45, p<0.001) but PVR did not, whereas both PAWP and PVR were independent determinants of E (β=0.32, p=0.001; and β=-0.35, p<0.001, respectively) in the PH
NC
group.

Conclusions:
In the presence of advanced pulmonary vascular lesions, conventional Doppler echocardiographic parameters may not accurately reflect LV FP. Importantly, elevated PVR would lower the E value, even when PAWP is elevated, resulting in blunting of these parameters for the detection of elevated LV FP. LAVI might be a reliable parameter for estimating LV FP in patients with severe non-cardiac PH.
Abstract 13806: Catheter Ablation Improves Quasar-Arterial Spin Labeling Based Regional Brain Perfusion in the Posterior Cingulate Cortex and Auditory-verbal Memory Function in Elderly Patients With Atrial Fibrillation
Authors: Tatewaki Yasuko , Mutoh Tatsushi , Sato Hirokazu , Enoki Ryo , Kobayashi Akiko , Muranaka Michiho , Yamamoto Shuzo , Yagi Tetsuo , Taki Yasuyuki
Published: May 2021

Introduction:
Recent epidemiological studies suggest that atrial fibrillation (AF) is a risk factor for cognitive decline and dementia in elderly population, which may be attributable to reduced stroke volume and related brain hypoperfusion as a potential cause. Catheter ablation therapy is an option for radical cure of AF. Although several researchers mentioned the possibility to improve cognition after the intervention, specific topographic features of the brain perfusion have not been well investigated.

Hypothesis:
To visualize hemodynamic alteration in regional cerebra blood flow (rCBF) associated with catheter ablation therapy using noninvasive MRI voxel-based analysis method and to clarify the relationship between AF and cognitive decline.

Methods:
Eight patients with persistent AF (2 male, average age 63.4±7.3) underwent noninvasive brain MRI perfusion imaging with a novel dynamic model-free arterial spin-labeling (ASL) technique (quantitative STAR labeling of arterial regions [QUASAR]) and cognitive tests including Mini-Mental State Exam (MMSE) and Ray Auditory Verbal Learning Test (RAVLT) before and after 6-months of intervention. QUASAR-ASL images were spatially normalized with SPM 12 applied by partial volume correction, followed by comparison of rCBF of each brain areas with voxel-based paired-t test.

Results:
After the ablation therapy, QUASAR-ASL showed significantly increased rCBF in the left posterior cingulate gyrus (PCC) (FWE,
P
< 0.05, MNI coordinates = -9 -45 5, Figure), which was accompanied by improved scores of the RAVLT (
P
< 0.001).

Conclusions:
The PCC is a critical part of the limbic system initially affected focal energy metabolism by Alzheimer’s disease. Improved rCBF in left PCC in patients with AF after catheter ablation therapy, as demonstrated by QUASAR-ASL method, may prevent episodic memory decline related to the auditory-verbal cognitive function.
Abstract 13808: Implementation of Cardiopulmonary Exercise Testing and Its Impact on 2-year Outcomes in Acute Coronary Syndrome From Mie ACS Registry
Authors: Murakami Hiroaki , Fujimoto Naoki , Takasaki Akihiro , Kurita Tairo , Hoshino Kozo , Sawai Toshiki , Kambara Atsushi , Kitamura Tetsuya , Ichikawa Takehiko , Ito Masaaki , Dohi Kaoru
Published: May 2021

Introduction:
Cardiopulmonary exercise testing (CPET) determines intensity for exercise rehabilitation which may improve outcomes in patients with acute coronary syndrome (ACS). However, it is unclear how many patients are given exercise education based on CPET around hospital discharge.

Purposes:
To assess the implementation of CPET and to evaluate the impacts of clinical parameters including CPET variables on 2-year outcomes in ACS patients.

Methods:
We enrolled 3146 ACS patients without hemodialysis (age, 68±12 yrs; 78% male) 30 days after onset using data from Mie ACS registry, a prospective and multicenter registry, between 2013 and 2017. We compared clinical characteristics in patients with and without CPET at hospital discharge. Prognostic factors including CPET variables during the 2-year follow-up were determined.

Results:
Forty percent of the hospitals had CPET equipment. Out of 3146, 431 patients (12%) underwent CPET and were given CPET-based exercise education. Implementation of CPET was associated with younger age, male, ST-elevation myocardial infraction, and higher peak creatine phosphokinase (p≤0.03). While, hospitalization length <7 days or >21 days was inversely associated with CPET. During the 2-year follow-up, 198 all-cause deaths (6%) and 103 heart failure (HF) hospitalization were observed. Multivariate Cox regression analysis demonstrated that age, male, hospitalization length >21 days, Killip ≥2, mechanical circulatory and/or ventilator support were positive predictors of all-cause death. While, CPET around hospital discharge (hazard ratio, 0.52; 95%CI, 0.27-0.99, p<0.05) and hemoglobin level were independent negative predictors of all-cause death. Although patients with CPET tended to have greater myocardial damage, they did not have increased rate of HF hospitalization or major adverse cardiovascular events (MACE). When analyzed only in patients with CPET, peak oxygen uptake was the only independent predictor for all-cause death.

Conslusions:
The number of patients who underwent CPET at discharge was small in our registry. Although the rate of HF hospitalization and MACE were similar in patients with and without CPET, CPET and CPET-based exercise education did reduce all-cause mortality in ACS patients.
Abstract 13819: Is an Adult Familial Hypercholesterolemia, Swine Model Suited to Test Safety and Efficacy of Drug-eluting Coronary Stents?
Authors: Razzi Francesca , Regar Evelyn , Dijkstra Jouke , Witberg Karen , Ligthart Jurgen , ramlal sharad A , Stam Mathijs , Krabbendam-Peters Ilona , Hoogendoorn Ayla , Wentzel Jolanda J , van Soest Gijs , Van Esch Jan , Duncker Dirk J , van Steijn Volkert , Van Beusekom Heleen M
Published: May 2021

Introduction:
Safety and efficacy of novel drug-eluting coronary stents (DES) are often preclinically tested using healthy swine coronary models. These only show fibrotic neointima (NI) response, while in humans we also observe uncovered struts and minimal NI thickening. Therefore, healthy swine models only allow limited conclusions.

Hypothesis:
In an adult familial hypercholesterolemia (FH) swine model, NI healing after coronary DES implantation mimics the range of human NI responses to DES.

Methods:
Adult FH swine (n=6 French Bretoncelles-Meishan) were given a high fat diet for 12 months to develop coronary atherosclerosis. DES (n=14) were implanted under guidance of OCT at sites of confirmed atherosclerotic plaque. Swine were sacrificed at 28 days follow-up (FU). Serial OCT imaging was performed before, after and 28 days FU. Lumen area, stent area, plaque burden (PB) and NI burden were evaluated for each time point and frame and averaged per stent. PB prior to stenting was evaluated using coronary side branches as references. The percentage uncovered struts at FU was assessed on a strut-by-strut basis.

Results:
The NI response showed uncovered struts, minimal coverage and fibrotic NI thickening. We found an association between baseline lesion PB and FU findings (Figure). Low PB (<40%) prior to stenting resulted in a thick NI at FU, reminiscent of healthy coronary models. In contrast, high PB (>40%) resulted in thin NI coverage and more uncovered struts at FU, uniquely showing similarities to human responses.

Conclusions:
In this adult FH swine model, the NI response presents the whole spectrum that is seen in humans, from uncovered struts, to minimal, to fibrotic intimal thickening. Interestingly, pre-existing coronary atherosclerotic PB is negatively associated with NI thickness and strut coverage after DES implantation. This underscores the importance of advanced disease, versus healthy, animal models for safety and efficacy testing of DES.
Abstract 13827: Sleep Quality Improved After Intensified Blood Pressure Lowering Therapy
Authors: Schmieder Roland E , Striepe Kristina , Bosch Agnes , Högerl Karin , Veelken Roland , Kolwelter Julie
Published: May 2021

Insufficient and poor sleep on a chronic basis raises blood pressure (BP), the risk of hypertension and cardiovascular disease which in turn further leads to sleep disturbances.In a prospective observational study we tested the hypothesis whether intensification of antihypertensive therapy improves sleep quality Patients with arterial hypertension on multiple drug medication were followed for 3 months if according to the physician‘s perception BP control was insufficient or patients profit from simplification of drug therapy. Intensification of antihypertensive therapy consisted of switching from multiple pills per day to a single pill combination. Office BP readings and out-of-BP measurements were monitored. The abbreviated PITTSBURGH SLEEP INVENTORY (PSQI) was applied to assess sleep duration and quality Results: In 229 patients (mean age 65 years, 62 % were males) office BP decreased from 158 ± 15/92 ± 8 to 132 ± 10/87 ± 8 mmHg (both p<0.001). In parallel, sleep quality improved in 45 % and remained equal/worse in 53 % (p<0.001) after 3 months In patients whose sleep quality improved (N=95) office BP dropped from 160±15/94±10 to 131±8.6/80±7 mmHg (both p<0.001), whereas in patients with equal or worse sleep quality (N=119) BP fell only from 156±15/90±5 to 133±10/80±8 mmHg (both p<0.001). BP fall was significantly greater in those with improved sleep quality as opposed to those with equal/worse sleep quality after 3 months of therapy (4.98±1.5/2.71±0.94 mmHg, p<0.001 and p=0.005, respectively). Change in out-office systolic BP measurements was greater in those with improved as opposed to those with equal/worse sleep quality (5.80±1.9 mmHg, p=0.003). Thus, intensification of antihypertensive treatment by using single pill combination resulted in significant fall in BP accompanied by an improvement in sleep quality.

Abstract Sleep quality improved after intensified blood pressure lowering therapy.docx
Abstract 13837: Evaluating Predictors of Pulmonary Valve Replacement Failure in Congenital Heart Disease Patients
Authors: McEachern William A , Sunthankar Sudeep , Ghani M. O , Nicholson George T , Doyle Thomas P , Bichell David , Parra David A
Published: May 2021

Introduction:
We aimed to determine predictors of reintervention after pulmonary valve replacement (PVR) at our center with the novel consideration of valve angulation within the outflow tract.

Methods:
Patients with a history of PVR between 06/2007 and 06/2019 and subsequent cardiac catheterization, cardiac MRI, or chest CTA since PVR were eligible for inclusion, as stored images allowed for valve angle measurement. The angle relative to the patient’s anterior-posterior (horizontal) plane was measured using lateral angiography and sagittal cross-sectional images. Valve orientation was analyzed as follows: 1.) the measured angle, 2.) the difference in that angle from the mean of 40 control patients, and 3.) whether that angle was outside of 2 standard deviations from the mean. Other variables included: original cardiac anatomy, valve type, true internal valve diameter indexed for weight at PVR, and immediate post-operative peak systolic gradient and valve insufficiency. Freedom from reintervention was evaluated using the log-rank test and Cox proportional-hazards with multiple imputation of modest missing echocardiographic data.

Results:
Of 168 patients who underwent PVR during that period, 52 patients met inclusion criteria. Over a median follow-up time of 6.0 years (bootstrapped 95% CI [4.6, 7.4]), 14 of those 52 (26.9%) underwent reintervention (valvuloplasty or valve replacement). In both univariate analysis as well as bivariate analysis controlling for indexed valve diameter, no measure of valve orientation was associated with freedom from reintervention. Potential associations of valve type with the outcome disappeared in bivariate analysis. Higher internal valve diameter indexed for weight at PVR was consistently associated with earlier reintervention. Results for freedom from valve revision were similar to those for any reintervention, while acknowledging that we may be underpowered to detect certain associations.

Conclusions:
Valve orientation does not appear to impact freedom from reintervention following PVR; however, higher indexed internal valve diameter is associated with decreased time to reintervention. An augmented sample size through multicenter collaboration may allow for a more robust multivariate analysis.
Abstract 13862: Testing of a Health-related Quality of Life Model
Authors: Heo Seongkum , Lennie Terry A , Moser Debra K , Dunbar Sandra B , Pressler, Susan J , Kim JinShil
Published: May 2021

Introduction:
In patients with heart failure (IHF), health-related quality of life (HRQOL) is as important as longer survival. Deaths are inevitable for all human beings, but clinicians may help patients with HF to maintain or improve HRQOL until almost at the end of their lives. Psychological and physical symptoms can impact HRQOL through different pathways, and behavioral factors can indirectly impact HRQOL, but the relationships have not been tested in prior theoretical models.

Hypothesis:
Sociodemographic (i.e., age), biological/physiological (i.e., comorbidity), psycho-social (i.e., depressive symptoms and social support), physical (i.e., physical symptoms and functional status), and behavioral factors (i.e., dietary adherence) in Heo-Moser model will be associated with HRQOL directly and indirectly in patients with HF through different pathways.

Methods:
This is a secondary analysis of baseline data from two observational studies in which baseline data were collected using the same instruments (N = 358 patients with HF, mean age: 60.4 years). Structural equation modeling (SEM) was used to test the hypothesis.

Results:
In the SEM, the analysis showed desirable model fit: Chi-square = 7.710, p = .260, RMSEA = .028 (95% confidence interval = 0.00, 0.078), CFI = 0.998, TLI = 0.989, and SRMR = 0.023. Age, depressive symptoms, physical symptoms, and functional status were directly associated with HRQOL. Age, comorbidity, depressive symptoms, social support, dietary adherence, and physical symptoms were indirectly associated with HRQOL through different pathways (Figure 1).

Conclusions:
All the factors in the model were directly and/or indirectly associated with HRQOL through different pathways. The pathways of physical symptoms, depressive symptoms, and dietary adherence differed. This model can be used to develop interventions targeting improvement in HRQOL in patients with chronic diseases.