bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13329: Isolation of Matured Human iPSC-Derived Ventricular Cardiomyocytes Using Synthetic microRNA Switch
Authors: Hatani Takeshi , Tsujisaka Yuta , Miki Kenji , Kimura Takeshi , Saito Hirohide , Yoshida Yoshinori
Published: April 2022

Background:
For disease modeling and drug screening using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), matured iPSC-CMs are required to understand the underlying mechanism of diseases and to get the candidate drug’s deleterious features. We have shown that synthetic mRNAs encoding a fluorescent protein tagged with complementary sequences against specifically expressed microRNA (miRNA-switch) can be efficiently used for purification. Using miRNA-switch, we evaluated the selection method of matured iPSC-CMs from iPSC-CMs.

Methods:
We used miR-208a as a specific miRNA of CMs and miR-Matured CM (miR-MCM). We synthesized miR-208a-responsive GFP-coding mRNA (miR-208a-GFP switch), and miR-MCM-iRFP670 switch and control tagBFP mRNA and transfected them into iPSC-CMs.

Results:
After transfection of these mRNA, 25±5% of miR-208a positive cells were positive for miR-MCM. We also compared miR-208a positive and miR-MCM positive cells to miR-208a positive and miR-MCM negative cells by qPCR and electron microscopy (EM). MiR-208a-positive and miR-MCM-positive cells showed significantly higher expression of matured CM-related genes such as MYH7 and MYL2. In EM observation, miR-208a-positive and miR-MCM-positive cells showed M-bands, while miR-208a-positive and miR-MCM-negative cells did not display M-bands.

Conclusions:
We demonstrated that miR-MCM could be used for the marker of matured iPSC-CMs. The synthetic miR-switch for miR-MCM efficiently isolate matured iPSC-CMs, enabling its application in disease modeling and drug screening using differentiated cells from iPSCs.
Abstract 13378: Preclinical Assessment of the Feasibility of Thoracic Vein Isolation With Sub-Second Pulsed Field Ablation Using a Focal Lattice-Tip Catheter
Authors: Kawamura Iwanari , Koruth jacob s , Turagam Mohit , Musikantow Daniel , Chu Edward , Miller Marc , Whang William , Dukkipati Srinivas , Reddy Vivek Y
Published: April 2022

Introduction:
Focal pulsed field ablation (PFA) using a 9mm lattice-tip ablation and mapping catheter (Sphere-9, Affera, Inc) can be used to deliver focal pulsed field ablation (PFA) at various atrial sites. We have previously shown that lattice-tip PFA using 3-5 sec deliveries creates efficacious atrial lesions. However, lattice-tip PFA still has a potential of shortening the ablation duration using tailored pulse designs. Accordingly, we assessed the feasibility and safety of thoracic vein (TV) isolation using ≤ 1 sec duration focal PFA in swine.

Methods:
A total of 4 swine underwent transfemoral venous access under general anesthesia. PF deliveries ≤ 1s were used to ablate a total of 8 TVs (4 pulmonary veins [PVs], 4 superior vena cava [SVC]) using lattice-tip catheter and its compatible PF generators (HexaPulse, Affera, Inc). TV potentials, venograms and phenic nerve injuries were assessed both acutely and after 24 hours; then, the animals were humanely sacrificed.

Results:
All 8 of 8 targeted veins (100%) were acutely isolated. Mean PFA application time for PVs and SVC was 13.1±4.1 and 12.8±1.0 sec, using 15.5±1.7 and 16.0±4.2 PFA applications, respectively. Persistent isolation was achieved in 7 of 8 (87.5%) TVs at 24 hrs. Gross necropsy demonstrated continuous and transmural lesions along the isolation line. The one SVC with reconnection demonstrated an obvious visual gap in the line. Microbubbles on the intracardiac echography were not seen during PFA applications, venography showed no reduction in vessel diameter, and the phrenic nerves were preserved in all swine.

Conclusion:
Significant shortening of pulse duration was not associated with compromise of acute lesion characteristics and TV isolation in a
porcine
model. But because of the potential discordance between preclinical and clinical outcomes, this strategy should be carefully tested in clinical studies.
Abstract 13405: Prevalence of Cardiac Disease in Duchenne Muscular Dystrophy Patients by Age: A Cardiac Magnetic Resonance Natural History Study
Authors: Lao Kathleen , Hor William , Hor Kan N
Published: April 2022

Introduction:
Duchenne muscular dystrophy (DMD) patients universally develop cardiomyopathy and considered a dilated cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed LGE prior to ventricular dysfunction. Various novel trials including gene therapy are ongoing with growing interest on how it impacts the heart. There is paucity of CMR data at a given age. A major barrier is lack of age specific data.

Hypothesis:
We therefore, sought to determine the prevalence left ventricular (LV) dilation by endiastolic volume (LVEDV), ejection fraction (LVEF) and late gadolinium enhancement (LGE) status at a given age.

Methods:
Retrospective review of CMR studies in DMD. LV dilation is defined as LVEDVi z-score > 2, abnormal LVEF (<55%) and LGE (yes or no). Patients were group by age in one year interval (given smaller numbers patients < 7 years were grouped together as were those ≥ 20 years).

Results:
683 DMD patients were identified with average of 48.8±24 (range 19-94) patients per group divided into 14 age groups. Mean age was 12.3±4 (range 4-39 years). Table 1 summarizes the CMR data by age. LV dilation was uncommon even in older age patients (mean 1.9±2.6%, range 0-8.7%). LVEF is rarely abnormal before 10 years (<5%) but increased with age (69.9% in the ≥ 20 year group). In all groups mean % LVEF < 55% is 24.6±20.6% (range 2.5-69.9). LGE can be found as young as 6.5 years but uncommon before age 10 years (<10%), increased to nearly 20% by age 10 years and incrementally increased to >50% after 11 (4.3% < 7 year group to > 80% by 18 years).

Conclusions:
This is the first and largest CMR natural history study by individual age showing low prevalence of LV dilation in DMD population. LVEF abnormality and LGE is uncommon before 10 years but increased with age. Future longitudinal assessment is ongoing to determine rate of change at a given age, quantifying LGE and myocardial strain for earlier cardiac disease assessment and modeling for disease progression at different age.
Abstract 13557: Impact of Cardiac Resynchronization Therapy on Clinical Outcomes in Transthyretin Amyloid Cardiomyopathy
Authors: Chandrashekar Pranav , Rashdan Lana , Dale Zack , Warner Scott , Gill Sajan , Burton Yunwoo , Nazer Babak , Masri Ahmad
Published: April 2022

Introduction:
Due to conduction disease and dyssynchrony in transthyretin amyloid cardiomyopathy (ATTR-CM), cardiac resynchronization therapy (CRT) may be beneficial. We aimed to determine the impact of CRT on clinical outcomes in ATTR-CM.

Methods:
We studied 116 consecutive ATTR-CM patients, 23 of whom underwent CRT (70% CRT + defibrillator, median 10 months (IQR 4-20) from ATTR-CM diagnosis). Outcome was a composite of 1
st
cardiovascular hospitalization or all-cause mortality. CRT was treated as a time dependent co-variate and entered into multivariate Cox proportional hazards model.

Results:
Both groups were similar at diagnosis except for a higher proportion with atrial fibrillation (AF) and lower ejection fraction among those who underwent CRT (
Table 1)
. CRT indication in 80% was progressive LV dysfunction with wide QRS [mean 152 ± 36 msec] and the remaining at time of AV node ablation for AF. Half of CRT group were ≥ NYHA class III at device implantation. Older age, higher National Amyloidosis Cohort (NAC) ATTR stage, and not taking tafamidis were significantly associated with the outcome. On multivariate analysis, CRT was associated with a HR of 0.6 (95% CI: 0.32 - 1.16) for all-cause mortality or cardiovascular hospitalization after adjusting for age at diagnosis, NAC ATTR stage, and tafamidis use (
Figure 1).

Conclusion:
CRT implantation maybe associated with improved outcomes in ATTR-CM. Larger prospective randomized, sham-controlled trials are warranted to confirm these findings.
Abstract 13569: A Composite Score Summarizing Use And Dosing Of Evidence-based Medical Therapies In Heart Failure: Application To The DAPA-HF Trial
Authors: Dewan Pooja , Bengtsson Olof , Docherty Kieran , Inzucchi Silvio E , Jhund Pardeep S , Kober Lars , Kosiborod Mikhail N , Langkilde Anna Maria , Martinez Felipe , Ponikowski Piotr , Sabatine Marc S , Sjostrand Mikaela , Solomon Scott , Biering-srensen Tor , Vaduganathan Muthiah , Defilippis Ersilia M , Fiuzat Mona , McMurray John J
Published: April 2022

Introduction:
The Heart Failure Collaboratory consortium (HFC) has developed a score to quantify background guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). One potential use of this score is to test the incremental value of new therapies. We evaluated the effect of dapagliflozin according to a modified HFC score in the DAPA-HF trial.

Methods:
The key inclusion criteria in DAPA-HF were: 1) NYHA class II-IV, 2) LVEF ≤40%, and 3) elevated plasma NT-proBNP and 4) eGFR ≥30 ml/min/1.73m2. The primary outcome was a composite of a first episode of worsening HF (hospitalization for HF or an urgent HF visit requiring iv therapy) or cardiovascular death. The HFC score is calculated based on the use of GDMT and dose of GDMT. The modified HFC score used here also accounted for race (Black/non-Black) and ECG rhythm/rate with a maximum possible score of 100 (percent) for any patient (Panel A).

Results:
Among the 4744 patients (mean age 66 years; 23% women) randomized, an ACEi/ARB was used in 84%, beta-blocker 96%, MRA 71%, ARNI 11%, ivabradine 4.8%, and hydralazine 4.3%. During a median follow-up of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and 502 of 2371 patients (21.2%) in the placebo group (HR, 0.74; 95%CI 0.65 to 0.85; P<0.001). The benefit of dapagliflozin on the primary outcome was consistent across the range of baseline treatment score (Panel B). Examination of the effect of dapagliflozin on the primary outcome by score tertile (T1 ≤40, T2 41-60 and T3 >60) gave HRs for the effect of dapagliflozin, compared with placebo, of 0.75 (0.61-0.93), 0.77 (0.61-0.98), and 0.71 (0.55-0.90), respectively (P-interaction 0.87).

Conclusions:
A composite score for GDMT of the type developed by the HFC can be easily calculated in clinical trials and used to evaluate the incremental effect of new therapies.
Abstract 13615: Mortality Trends And Regional Variations Of Aortic Aneurysm And Dissection In The United States
Authors: Mughal Mohsin S , Nasir Ammar , Ghani Ali , Mirza Hasan , Asbeutah Abdul Aziz A , Hafeez Hamza , Jagdey Harjot S , Ahmad Talha , Ahmad Khansa , Alam Mahboob , Khakwani Muhammad , Usman Mohammed Haris , Wasty Najam , Waxman Sergio
Published: April 2022

Introduction:
Aortic dissection and aortic aneurysm represent significant health risk as they are associated with very high mortality. Incidence of aortic dissection is low and estimated to be 5-30/100,000 hospitalized patients. Similarly, aortic aneurysms have low incidence (depending upon location) and high mortality (over 80%). Combined mortality associated with aortic aneurysm or dissection and its contemporary trends in the U.S. are not well known.

Methods:
In this retrospective study death certificate data were retrieved from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database for 1999-2018. Mortality for aortic aneurysm and dissection ICD-10 code-I71 as an underlying cause of death were queried from 1999-2018. This duration was further stratified into five-year periods. WONDER database is publicly available de-identified data collected by CDC that reports the underlying cause of death across the United States. Crude mortality rate and age-adjusted mortality rate per 100,000 were calculated in four U.S census regions (CR1 Northeast, CR2 Midwest, CR3 South, CR4 West).

Results:
From 1999-2018 AAMR for aortic aneurysm and dissection showed a downward trajectory. Regional variations were observed and are illustrated in figure 1. For Northeast (CR-1) AAMR declined by 54%, for Midwest (CR-2) it declined by 48%; for South (CR-3) it declined by 53%, and for West (CR-4) it declined by 52%. (Table-1)

Conclusions:
Our study shows a downward trajectory of AAMR for aortic aneurysm and dissection. Which reinforces the continuation of guideline based screening.
Abstract 13632: The Relationship Between Health Information Technology Use and Pneumococcal Vaccine Uptake in Adults With Heart Disease
Authors: kesiena onoriode , Singireddy Shreyas , Atarere Joseph , Famojuro Oluwaseun
Published: April 2022

Introduction:
Health information technology (HIT) has been shown to influence medication adherence and healthy behaviors. This influence may increase the uptake of vaccines especially in high risk groups.

Hypothesis:
HIT use may be associated with increase pneumococcal vaccine uptake in adults ≥ 40 years with heart disease.

Methods:
Using the National Health Interview Survey data, 2,134 united states adults ≥ 40 years with heart disease were analyzed in this cross-sectional study. The independent variables were: Use of the internet to (1) to look up health information (2) to fill a prescription and (3) to schedule a medical appointment and use of an email (4) to communicate with a healthcare provider, which were dichotomous. The dependent variable was pneumococcal vaccine uptake which was also dichotomous. Chi-square analysis was used to identify group differences. Multiple logistic regression was used to analyze the association between HIT utilization and pneumococcal vaccine uptake.

Results:
Those who use the internet to fill up prescription and to communicate with their healthcare provider were more likely to take up the PCV [AOR 1.56; 95% CI 1.03, 2.37, p =.035] and [AOR 1.95; 95% CI 1.23, 3.10, p =.005] respectively. Compared to those who did not use HIT in any form, those who used HIT in at least three or four forms had a higher PCV uptake [AORs 1.93; 95% CI 1.19, 3.13, p-value .008] and [AOR 2.33 95% CI 1.22, 4.47, p-value .011] respectively.

Conclusions:
Our analysis shows a positive association of HIT utilization and pneumococcal vaccine uptake. It further stresses the importance of electronic health in preventive medicine. Larger studies should evaluate the relationship between different uses of health information technology and different vaccines uptake.
Abstract 13633: Cardiac Arrhythmias in Hospitalized Patients With Hereditary Hemochromatosis
Authors: Patel Krunalkumar , Dalal Shivani , Khan Muhammad Zubair , Shah Jay , Tran Daniel , Patel Umang , Kutalek Steven
Published: April 2022

Introduction:
Cardiac iron overload in Hereditary Hemochromatosis (HH) can lead to conduction disturbances, arrhythmias, and rarely, cardiac arrest. There is a paucity of data on HH and the burden of cardiac arrhythmias and its repercussions.

Hypothesis:
To determine baseline characteristics of HH patients with and without arrhythmias, frequency of subtypes of arrhythmias, and related in-hospital outcomes such as mortality, length of stay (LOS), and total hospital costs.

Methods:
An HH-related adult hospitalizations with or without arrhythmias were analyzed using the National Inpatient Sample database from 2016 to 2018. We used propensity score matching to balance out the differences in baseline characteristics among the 2 groups.

Results:
Out of 10455 HH hospitalizations, 2525 (24.2 %) had concurrent arrhythmias. The arrhythmia cohort consisted of older patients (mean age, 68.9 vs 59.8 years), predominantly males (71.1% vs 61.5%), and Caucasians (92.5% vs 89.3%) compared to those without arrhythmia (p<.001). HH patients with arrhythmias had an almost 3-fold higher prevalence of congestive heart failure (11.5% vs 3.7%) and coronary artery disease (33.3% vs 12.2%) (p<.001). Atrial fibrillation (AF) (73.3%) was the most common arrhythmia followed by atrial flutter (8.3%), ventricular tachycardia (8.1%), and supraventricular tachycardia (7.7%). The arrhythmia cohort had higher mortality (6.7% vs. 2.3%) and mean hospital cost ($ 25,957 vs $16,742) as compared to the non-arrhythmia cohort (
P
< .001). Mean LOS (6.7 vs 5.7 days, p=0.007) was comparable between the groups.

Conclusions:
Our study suggests a high burden of arrhythmia in HH-hospitalizations with AF being the most common arrhythmia. The arrhythmia cohort had significantly higher in-hospital mortality, and hospitalization cost. This warrants further studies to better delineate pathogenesis and early diagnosis and treatment strategies specifically curated for HH-associated arrhythmias.
Abstract 13639: The Impact of Income Level on All-Cause and Cardiovascular Mortality Across the Spectrum of Cardiovascular Health & Disease Among Adults in the United States
Authors: Khan Madiha , Acquah Isaac , Javed Zulqarnain , Taha Mohamad , Khan Najah , Cainzos-Achirica Miguel , Hagan Kobina , Khan Safi U , Shapiro Michael D , Blaha Michael J , Blankstein Ron , Virani Salim S , Sharma Garima , Elizondo Javier , Nasir Khurram
Published: April 2022

Introduction:
There is increasing interest in the role of income level as a social determinant of health for cardiovascular disease (CVD). In this study we examine the interplay of household income, all-cause mortality, and CVD mortality in a representative US adult population.

Methods:
We used National Health Interview Survey data from 2006-2014 including adults ≥18 years. Mortality data with follow-up till December 2015 was derived from the National Death Index. We evaluated age-adjusted all-cause, CVD and non-CVD mortality rates across income levels (lowest, low, middle, and high; defined based on based on the percentage of family income relative to the federal poverty level), among people with and without ASCVD at baseline. We further classified participants without ASCVD as having optimal (0-1 risk factors), average (2-3), and poor (>3) cardiovascular risk factor (CRF) profile. Cox regression models were used to evaluate the association between income and mortality.

Results:
The analysis included 256,991 adults, representing ~230 million adults annually. Mean age was 46.3 (SD=17.7), 52% were women, 13% NHB, and 8% had ASCVD. Overall, 18% were in the lowest income category compared to 39% in highest group. During the 10 years of follow up, participants with highest income and optimal CVH had the lowest all-cause and cause-specific mortality rates, whereas those with lowest income and poor CVH had the highest rates (Figure). Additionally, multivariate adjustment for demographics and CRF, lower income was associated with increased all-cause mortality (lowest/low vs middle/high income, HR: 1.22; 95% CI: 1.11-1.35 CVD vs non-CVD HR: 1.24, 95% CI: 1.16-1.33) and CVD mortality (lowest/low vs middle/high income: HR: 1.29, 95% CI: 1.07-1.56 CVD vs non-CVD HR: 1.44, 95% CI: 1.23-1.67).

Conclusions:
In a US representative population, lower income adults were consistently associated with increased risk of all-cause and CVD mortality irrespective of baseline CVD status.
Abstract 13642: Mortality and Readmissions Following Pericardiectomy
Authors: Warren Blair , Radaideh Qais , Daoud Hussein , Venkat Pajjuru , Walters Ryan , Alla Venkata
Published: April 2022

Introduction:
Pericarditis is a relatively common cause of chest pain and is the most common pericardial syndrome in clinical practice. Pericardiectomy is the treatment of choice for patients with chronic or recurrent pericarditis refractory to medical therapy. However, perioperative morbidity and mortality rates for pericardiectomy remain high. Several factors, such as etiology, duration of disease, patient functional status, and operator/center experience, can impact outcomes.

Objectives:
In this study, we explore the national trends in perioperative complication rates, in-hospital mortality, readmission rates, and impact of center volumes on these endpoints in patients undergoing pericardiectomy.

Methods:
Using the Nationwide Readmissions Database (NRD), we identified patients who underwent isolated pericardiectomy from 2010 to 2018. Year-over-year trends in mortality and readmission rates were assessed using orthogonal polynomial contrasts, with non-linear trends evaluated as needed. Multivariable logistic regression models were constructed to identify independent predictors of mortality and readmission. All analyses accounted for NRD sampling design and were performed using the SAS v. 9.4 with a p < .05 to indicate statistical significance.

Results:
A total of 23,230 hospitalizations for pericardiectomy were identified during the study period. Median age was 59 years and 44% were female. In-hospital mortality was 5.3%, median length of stay was 7 days, and 18% were readmitted within 30 days. While rates were relatively consistent early on, between 2015 and 2018, there was a slight increase in the hospitalizations for pericardiectomy, decrease in in-hospital mortality and an uptick in 30 day all-cause readmission rates. Advanced age, higher comorbidity index, and lower annual facility pericardiectomy volume were independent predictors of in-hospital mortality.

Conclusion:
Isolated pericardiectomy rates have remained largely constant with relatively small changes in in-hospital mortality and 30-day readmission rates over the last decade. Advanced age, facility pericardiectomy volume, and the Elixhauser Comorbidity Index are independent predictors of surgical mortality.
Abstract 13643: Home Blood Pressure Monitoring in Pregnant Women and Women of Child-Bearing Age With Hypertension From 2009-2014
Authors: Maxner Ben , Lemon Stephanie C , Moore Simas Tiffany A , PERSON Sharina D , McManus David D , Juraschek Stephen P , Kovell Lara C
Published: April 2022

Introduction:
Hypertension (HTN) is a leading cause of maternal mortality, and HTN guidelines recommend home blood pressure monitoring (HBPM) to help achieve blood pressure (BP) control. Evidence suggests that HBPM be coupled with a care team to maximize its effectiveness. HBPM and provider counseling in pregnant women with HTN are unknown.

Objective:
To assess HBPM use and provider counseling in pregnant women and women of child-bearing age with HTN

Methods:
We used data from 3,614 women in the National Health and Nutrition Examination Surveys 2009-2014 to determine HBPM use and provider counseling for pregnant women and women of child-bearing age (20-50 years) with HTN. HBPM use and provider counseling were self-reported.

Results:
For pregnant women with HTN, the mean (SE) age was 33.3 (1.6) years, the mean (SE) BMI was 44.8 (6.3) kg/m
2
, and 47.5% were on BP medication (Table). Among pregnant women with HTN, 51.2% reported HBPM in the past year, and 46.3% used HBPM at least weekly. However, only 9.6% of pregnant women with HTN received provider counseling. Among women of child-bearing age with HTN, 49.6% reported HBPM in the past year and 40.4% received provider counseling.

Conclusions:
While over half of pregnant women with HTN have adopted HBPM, less than 10% of this population received provider counseling. This gap highlights a need and opportunity for providers to improve BP management by supporting a popular monitoring approach among pregnant women with HTN.
Abstract 13840: Trends in Incidence and Long-Term Prognosis of Acute Kidney Disease Following Coronary Angiography in Chinese Cohort With 9,665 Patients From 2008 to 2017: An Observational Study
Authors: Li Qiang , Liu Jin , Huang Haozhang , Chen Weihua , Shi Shanshan , Liu Yong
Published: April 2022

Introduction:
Acute Kidney Disease (AKD) is a disease that recently received close attention and was found prone to a poor prognosis. However, few studies have explored the trends of the incidence and prognosis of AKD over the last decade.

Methods:
This retrospective cohort study collected data from 9,665 patients who underwent CAG. Their preoperative and postoperative serum creatinine (Scr) values within 7-90 day were analyzed for the period of January 2008 to December 2017. Univariate and multivariate logistic regression analyses were used to estimate the odds ratio of AKD between 2008 and 2017. Survival data were evaluated using univariate and multivariate Cox regression analyses.

Results:
The research team analyzed a total of 9,665 patients in Guangdong Provincial People’s hospital, with an average age of 61.6±9.6 years and 40.1% (3,876) females. The overall incidence of AKD in that decade was 18.8%, and the overall mortality rate was 323.0 per 1,000 person-years. Compared with 2008, the incidence of AKD in 2017 decreased from 25.1% to 12.8% (Adjusted odds ratios [a OR], 0.40, 95%CI, 0.31-0.51, P-value <0.01, P for trend <0.01). On the contrary, 323.0‰ AKD patients died in total, significantly increased from 138.2 to 544.1 per 1,000 person-years in 2008 (Adjusted hazard ratio [a HR], 2.85; 95%CI, 1.20-6.73; P-value =0.02, P for trend=0.02). These findings were consistent across different gender and age groups.

Conclusions:
From 2008 to 2017, the incidence of AKD decreased significantly, while AKD associated mortality showed a notably increased trend. Our findings support more active measures to prevent AKD and improve the prognosis of AKD patients
Abstract 13849: Association of Optimal Blood Pressure and Risk of Atrial Fibrillation in Aged Type 2 Diabetes Mellitus Patients: From the JPAD Cohort Study
Authors: Matsumoto Chisa , Ogawa Hisao , Saito Yoshihiko , Okada Sadanori , Soejima Hirofumi , Sakuma Mio , Masuda Izuru , Nakayama Masafumi , Doi Naofumi , Jinnouchi Hideaki , Waki Masako , Morimoto Takeshi
Published: April 2022

Introduction:
Even, both type 2 diabetes (T2DM) and hypertension are important risk factors for nonvalvular atrial fibrillation (NVAF), the efficacy of strict blood pressure control for prevention of NVAF have not been established.

Hypothesis:
We assessed the hypothesis that optimal blood pressure is associated with lower risk of NVAF among T2DM patients in long term cohort of aged Japanese T2DM patients, JPAD cohort study.

Methods:
The JPAD cohort study was a follow-up cohort study of the JPAD trial, which was a randomized, standard-care controlled trial examining whether low-dose aspirin prevented cardiovascular disease (CVD) events in 2535 Japanese patients with T2DM from 2002. After that trial ended in 2008, we followed up the patients until 2019. Optimal blood pressured was defined as systolic blood pressure < 120 mm Hg at baseline regardless of use of antihypertensive drugs. The association of optimal blood pressure and risk of NVAF was evaluated by Cox proportional hazard model adjusted for conventional risk factors for CVD. We also performed subgroup analysis by use of antihypertensive drugs.

Results:
Mean age of participants was 65 ± 10 years. During the median follow up of 10.9 years, 132 patients developed NVAF. The adjusted hazard ratio (HR) and its 95% confidence interval (CI) of NVAF of T2DM patients with optimal blood pressure comparing to those with higher blood pressure was 0.89 (0.45-1.75). In subgroup analysis by use of antihypertensive drugs, the results were not altered. The risk of NVAF among patients with optimal blood pressure comparing to those with higher blood pressure among patients using antihypertensive drugs and those not using antihypertensive drugs were 1.08 (0.34-3.45) and 0.78 (0.34-1.79), respectively.

Conclusions:
Optimal blood pressure was not associated with lower risk of NVAF among aged T2DM patients. However, due to high risk profile of NVAF among aged T2DM patents, careful follow up may be still necessary for prevention of CVD.
Abstract 13869: The Impact of Genotype on Aortic Dilation in Pediatric Patients With RASopathy
Authors: Khan Rabia S , Weaver Kathryn N , Martin Lisa , Prada Carlos , Villa Chet
Published: April 2022

Introduction:
Proximal aortic dilation is an important cause of morbidity and mortality secondary to rupture, dissection, and complications of repair. It has been described as a rare finding in RASopathy, but data is limited regarding prevalence, severity, and genetic factors. This study aims to examine outcomes and genotype associations in pediatric patients with aortic dilation and RASopathy.

Methods:
A retrospective review performed at a single pediatric referral center. Study population included children with a molecularly confirmed RASopathy diagnosis evaluated between January 2000 and August 2019. Baseline data included demographics, genetic data, cardiac diagnostic data, clinical course, and mortality outcome.

Results:
Ninety patients were identified (mean age 10.4, female 48%). Aortic dilation was found in 28%. Of these, 68% had mild dilation, while moderate and severe dilation were each seen in 16%. Aortic dilation occurred in all major RASopathy types (Noonan, Noonan with Multiple Lentigenes, Costello, and Cardiofaciocutaneous). Hypertrophic cardiomyopathy was seen in 30% and pulmonary stenosis in 53% of RASopathy patients, with similar prevalence among those with aortic dilation (p=1 and 0.45, respectively). Aortic dilation was more prevalent in RAS (
KRAS
,
HRAS
,
NRAS
) variants (4/9 versus 12/81, p=0.0494). It was also seen in 16 of 60 patients with
PTPN11
variants in association with all three commonly involved regions (exon 3 of N-SH2 region and exons 8 and 13 of PTP domain). The two patients with extreme dilation (z-score > 6) had variants of amino acids 61 and 63 in exon 3 of
PTPN11
. No surgical interventions targeting aortic dilation were performed in any patient, and there were no reports of dissection or rupture. There was no clear progression of dilation, and two patients had complete resolution with time.

Discussion:
Aortic dilation occurred in all four major types of RASopathy and was associated with most of the affected genes, with distribution along the
PTPN11
gene being similar to the distribution of RASopathy. The dilation was not progressive and there were no complications or interventions. RAS genes and exon 3 of the
PTPN11
gene demonstrated a possible higher association with aortic dilation and warrant further investigation.
Abstract 13874: A Mitochondrial Polygenic Risk Score is Associated With Metabolite Levels Implicated in Heart Failure
Authors: Truby Lauren K , Giamberardino Stephanie , Kwee Lydia , Kraus William E , Abdulrahim Jawan , Regan Jessica A , Shah Svati H
Published: April 2022

Introduction:
Heart failure (HF) is characterized by metabolic inflexibility in fuel substrate selection and results in dysregulation of downstream mitochondrial processes. Prior work has identified greater plasma concentrations of circulating long-chain acylcarnitines (LCAC) in HF. LCAC are metabolites reporting on impaired mitochondrial fatty acid catabolism and predict incident adverse events in HF.

Hypothesis:
We hypothesized that a polygenic risk score (PRS) of genetic variation in mitochondrially-associated genes may be associated with circulating LCAC as well as HF phenotypes.

Methods:
The study population consisted of 2277 European-ancestry participants from the CATHGEN (CATHeterization GENetics) cohort, consisting of sequential individuals undergoing cardiac catheterization at Duke University. Using PRSice software, a PRS was generated from variants in 1462 nuclear genes implicated in mitochondrial function; weights were derived from the HERMES HF GWAS meta-analysis. Linear regression was used to test the association between the mitochondrial function PRS and plasma metabolite levels, as well as HF phenotypes, in models adjusting for ancestry principal components and batch.

Results:
The analysis cohort included 515 participants with HF, with 39% females and a mean age 61.2 11.8 years. The mitochondrial PRS was associated with three LCAC: C10, C10:1 and C12:1 (nominal p-values 0.02-0.008, 18-70 variants). The PRS was not associated with prevalent cardiomyopathy (p=0.097) or HF (p=0.16).

Conclusions:
We have generated a focused PRS inclusive of mitochondrial nuclear genetic variants weighted on HF association and found it to be associated with relevant circulating metabolites of mitochondrial fatty acid metabolism. These results highlight the utility of a novel biology-focused PRS in cardiovascular disease traits.
Abstract 13887: Cardio-Oncology in a Dish: Cardiovascular Tissue Engineering Strategies for Modeling Cancer Therapy Related Cardiac Dysfunction
Authors: Bashai Caroline , Kazma Noam , Haiim Idan , Libai Yaara , Nevo Anastasia , Arbel Gil , Gepstein Amira , Caspi Oren
Published: April 2022

Cardio-oncology in a dish: cardiovascular tissueengineering strategies for modeling cancer therapyrelated cardiac dysfunction.Over the recent years, there was a robust proliferation of oncological therapies leading to asignificant reduction in cancer related death. Unfortunately, there was a parallel increase in thenumber of patients developing cardiotoxicity & heart failure making it the main cause of deathamong cancer survivors. Current strategies for predicting cardio-toxic side effects are limitedand robust pre-clinical, personalized platforms for assessing both harmful drugs and protectiveagents are lacking.In the current study by using human pluripotent stem cells technology, we developed a uniquehuman-engineered cardiac tissue (ECT) platform generated from cardiomyocytes, endothelialcells and authentic cardiac fibroblasts derived from the epicardial cell layer. Using this platform,we are examined the ability of the model to recapitulate the cardio-toxic effects of Doxorubicinand the cardio protective capabilities of Dexrazoxane and SGLT2i; a novel agent, that wasrecently shown to prevent heart failure in patients with diabetes and high risk forcardiovascular diseases.p<0.001

Results:
Paired, long-term, consecutive force evaluations of the ECTs demonstrated the cardio-toxiceffect of Doxorubicin resulting in a lower total active force for each preload compared toBaseline control. Moreover, concomitant exposure to Doxorubicin and the cardio-protectiveagents (Dexrazoxane and SGLT2 inhibitor ‘Empagliflozin’) resulted in considerable recovery ofthe active force generation compared to control.

Conclusion:
This report is an initial proof of concept demonstrating the ability of ECTs to serve as a modelfor functional evaluation induced by cardio toxic drugs as well as the effect of cardio-protective agents. High-throughput based on this platform may be used for identifying novel cardio-protective agents as well as for evaluating patient-specific cardio-toxic effects.
Abstract 14000: Identification of Circulating Surrogate Biomarkers for Risk Prediction of Breast Cancer Treatment-Related Cardiotoxicity
Authors: Pant Tarun , Juric Matea , Zielonka Jacek , Benjamin Ivor J , Bosnjak Zeljko J
Published: April 2022

Introduction:
Although anthracyclines, including doxorubicin (DOX), are among the most effective anticancer drugs to date, they cause dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). We utilized patient-specific PBMC/Neutrophils to prospectively assess patient-and tissue-specific effects of high-risk therapeutic regimens and compare the results with patient outcomes after receiving chemotherapy for breast cancer.

Hypothesis:
We hypothesized that the PBMC/Neutrophils could recapitulate the predisposition of the patients towards DIC.

Methods:
The PBMC/Neutrophils were isolated from breast cancer patients with and without cardiotoxicity, and exposed to varying concentrations of doxorubicin (DOX). The
in vitro
DIC in breast cancer patients specific PBMC/Neutrophils after 24 hrs was assessed via analysis of: (a) Cytotoxicity determined via Alamar Blue cell viability assay kit; (b) Cytotoxicity determined using ATP based luminescence assay; (c) Oxygen consumption rate (OCR); and (d) Genome wide transcriptomic analysis of PBMCs.

Results:
Patient specific PBMC/Neutrophils recapitulate the predilection of the patients towards DIC. The PBMC/Neutrophils derived from breast cancer patients who experienced clinical doxorubicin-induced cardiotoxicity were more sensitive to doxorubicin toxicity depicting: (1) An increased response to DOX with neutrophils being more sensitive to DOX at lower concentrations than PBMCs; (2) Decreased ATP production indicating lower cellular viability; and (3) Lower OCR associated with basal mitochondrial respiration, ATP production, maximal respiration and spare respiratory capacity (representing mitochondrial function), as compared to breast cancer patients without cardiotoxicity.

Conclusions:
Together, our data indicate that this
in vitro
approach may represent a fast, cost-effective, and high throughput means to assess the future cardiotoxic effects of chemotherapy drugs. Furthermore, it offers the opportunity to understand the on-target and off-target molecular mechanisms to optimize the efficacy and safety of the cancer drugs.
Abstract 14004: Long Term Outcomes of Ambulatory Outpatient Management of Acute Decompensated Heart Failure in a Heart Failure Specialist Nurse Delivered Consultant Led Unit versus Inpatient Management
Authors: Salmon Thomas , essa Hani , brousas sophia , Whybrow-huppatz Isobel , balu ashwin , jackson carolyn , Nyjo Siji , kelly annmarie , oguguo emeka , douglas homeyra , sankaranarayanan rajiv
Published: April 2022

Introduction:
Acutely decompensated heart failure (ADHF) usually results in hospitalisation for intravenous diuretics. The safety and efficacy of ambulatory or outpatient management of ADHF by heart failure specialist nurses has not been described before.

Methods:
This retrospective analysis compared 2 cohorts of consecutive ADHF patients - hospitalised in-patients (IP) versus outpatients (OP) who were treated with bolus intravenous diuretics in a specialist heart failure nurse delivered consultant led OP HF unit (Ambulatory HF Unit -AHFU) with input from various specialties (renal, diabetes, elderly care, chest, pharmacy, palliative, ascitic, pleural teams) from 2016 to 2020. Mean follow-up duration was similar for both groups (IP=46±8.1 months; OP=45.5± 7 months, p=0.1). We compared clinical risk scores using the Get With the Guidelines (GWTG) score, comorbidities using the Charlson Comorbidity Index (CCI) and frailty using the Rockwood Clinical Frailty Index (CFI). Results were expressed as mean±SD, analysed using the Student’s T test and Chi-squared test.

Results:
1012 patients were treated in our specialist outpatient AHFU and 1889 patients were hospitalised. Mean number of visits per ambulatory spell was 5.1±-2.2 days and the median dose of furosemide was 220 mg (range 80-480). Average hospital stay for IP was 12.1±5 days. CCI (IP=6.5±2; OP=6.4±1.9; p=0.19) and mean GWTG scores were similar (IP=40.4±7.9; OP=39.9±7.1; p=0.09) between the 2 groups but mean Frailty Index was higher amongst the IP group (IP 5.1±1.2; OP 4.9±1; p=0<0.001). 30 day hospitalisation and mortality (30 day,1 year and overall mortality) were lower in the OP cohorts.

Conclusions:
Ambulatory management of ADHF using bolus IV diuretics in a heart failure specialist nurse delivered consultant led multidisciplinary unit offers an effective alternative to hospitalisation and also leads to improved outcomes. Frailty Index can help assess suitability for outpatient management of ADHF.
Abstract 14010: Tipifarnib Reduces Circulating Exosomes And Protects Against Pressure Overload-mediated Cardiac Hypertrophy
Authors: Mallaredy Vandana
Published: April 2022

Clinically, Hypertrophic cardiomyopathy (HCM) in response to pathophysiological stress is one of the major initiating factors for the onset of cardiac remodeling leading to heart failure. Studies have revealed that HCM characterized by left ventricular hypertrophy, hypercontractility, and impaired relaxation is mainly driven by intricate crosstalk among the multiple cellular and molecular mechanisms, which leads to heart failure. In agreement with this observation, we investigated if the Tipifarnib-mediated reduction/alteration of circulating exosomes facilitates cardiac cell communication during HCM. Several studies have shown Tipifarnib as a potential Farnesyl transferase inhibitor. However, in recent pastTipifarnib has been shown to target exosomes biogenesis by several mechanisms such as inhibiting Raspathway, ESCRT complex etc. Tipifarnib treatment in mice significantly reduced the number of circulating plasma exosomes. We examined the response of Tipifarnib treatment (10 mg/kg body weight) in C57BL6Jmale mice subjected to transverse aortic constriction (TAC) surgery. Untreated TAC mice had worsening of systolic Left Ventricular function at 4 weeks that further deteriorated at 8 weeks, while the treatment with Tipifarnib substantially improved cardiac functions by reducing cardiac hypertrophy and fibrosis. Exosomes isolated from the serum of sham and TAC mice with or without tipifarnib were used for
in vitro
cell based analyses. We observed that the exosomes isolated from Tipifarnib treated TAC mice reduced isoproterenol (ISO)-induced cardiomyoblast hypertrophy and fibrosis-associated genes in adult cardiac fibroblasts. Taken together, our studies suggest Tipifarnib protects against pressure overload-induced cardiac remodeling and dysfunction by altering hypertrophic and fibrotic gene expression, by potentially reducing circulating exosomes or by altering exosome contents. Ongoing studies will clarify the molecularmechanisms of these observations.
Abstract 14025: Atrial Fibrillation is Associated With Reduced Telomere Length
Authors: Sinner Moritz F , Kupka Danny , von Falkenhausen Aenne Solvejg S , Wilfert Wolfgang , Waldenberger Melanie , Peters Annette , Holdt Leska M , Kaab Stefan
Published: April 2022

Background:
Atrial Fibrillation (AF) is common pathophysiologically complex. Age is among the most important AF risk factors. However, some young patients develop early-onset AF, whereas many others do not despite an advanced age. Advanced biological aging as opposed to advanced calendar age may be an explanation. Telomere length is associated with age and may be considered a measurable marker of biological age. AF and telomere length have previously been associated, but results remained inconclusive.

Hypothesis:
AF is age-related and associates with telomere length in a large case-control cohort.

Methods:
Between 2005 and 2018, we enrolled 2475 early-onset AF patients into the prospective AFLMU cohort. 3077 AF-free individuals from the community-based KORA study (enrollment 2006-08) served as controls. Clinical characteristics, an electrocardiogram, and a blood sample was obtained in all participants. We determined telomere length by a qPCR-based method using a multiplex TaqMan assay. Telomere length was expressed as delta-CT referenced to the single copy gene
36B4
.Lower CT values indicate shorter telomere length. Telomere length in cases vs. controls was assessed using multi-variably adjusted logistic regression.

Results:
Mean age was 58 years in AFLMU and 56 years in KORA. Men accounted for 72.3% in AFLMU and for 51.7% in KORA. For quality control, we confirmed a reduction of telomere length with age and demonstrated shorter telomere length in men compared to women. Median telomere length was also significantly shorter in AF patients compared to controls (9.81 [5.98, 13.1] vs. 13,10 [12.60, 13.63], p<0,001). The association remained significant after adjustment for sex, body mass index, hypertension, and diabetes (odds ratio per telomere length unit 0.77 [95% confidence interval 0.74-0.77], p<0.001).

Conclusion:
In a large case-control cohort, AF significantly associates with telomere length. Information on telomere length may help to inform if a patient develops AF due to premature biological aging. The underlying pathomechanisms for premature aging remain to be elucidated.
Abstract 14026: Systemic Delivery of SOD2 mRNA to Experimental Abdominal Aortic Aneurysm Mitigates Expansion
Authors: Yan Huimin , Hu Ying , Akk Antonina , Pan Hua , Wickline Samuel , Pham Christine
Published: April 2022

Rationale:
Oxidative stress and the overproduction of reactive oxygen species are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest. Yet, despite promising experimental studies, clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient levels locally at the site of AAA. Herein, we explore a nanoparticle (NP)-based approach for the systemic delivery of antioxidants.

Methods and Results:
We employ a peptide-based NP that allows efficient
in vivo
delivery of mRNA to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The SOD2 mRNA sequence containing the appropriate endcaps, poly-A tail, and base modifications (~1,000 nt) to enhance translation was mixed with p5RHH (an amphipathic peptide capable of efficiently delivering nucleic acids
in vivo
) at a ratio of 3,200:1 (peptide:mRNA) to form a self-assembled NP of ~50-55 nm in diameter. The NP was further stabilized by a coating of hyaluronic acid (HA), which binds to CD44 expressed on a wide range of cells, enhancing targeting and uptake. Delivery of SOD2 mRNA suppresses expansion of small AAA. Mitigation of AAA following SOD2 mRNA delivery was accompanied by enhanced SOD2 protein expression in aortic wall tissue, decreased inducible nitric oxide synthase expression, lower nitric oxide production and cell death.

Conclusions:
The results will serve as proof-of-concept that the delivery of mRNA using the p5RHH-based NP holds promise to overcome challenges associated with systemic delivery of antioxidants in AAA medical management.

Figure 1. Mice were perfused with elastase and administered NP iv (1 μg mRNA) on days 5, 8, 11. (A) Increase in (AD), measured on day 14 as increase in mm or %. Day 14 aortic sections (n = 5-6 aortas) were stained for SOD2 (red) and nitrotyrosine (green, NO) and expressed as relative ratios. *
P
<0.05, **
P
<0.01, ***
P
<0.01.
Abstract 14032: Racial Differences in Clinical Manifestations and Events in Fibromuscular Dysplasia: A Report of the United States Registry for FMD
Authors: Shah Kajal , Gornik Heather L , Gu Xiaokui , Mace Pamela D , Kline-rogers Eva M , Bacharach Michael , Fendrikova Mahlay Natalia , Froehlich James B , gupta Kamal , Gray Bruce , Kim Esther , Wells Bryan , Weinberg Ido , Olin Jeffrey W , Sharma Aditya M
Published: April 2022

Introduction:
Fibromuscular dysplasia (FMD) is a non-inflammatory vasculopathy associated with arterial stenosis, aneurysm, dissection, and tortuosity. We investigated racial differences in clinical manifestations and events of multifocal FMD.

Methods:
Demographics, medical history, presenting signs and symptoms, and major vascular events were queried from the US Registry for FMD and stratified into White or Black based on self-identified race.

Results:
Of the 1897 female patients (pts) with multifocal FMD and race reported from 14 sites as of 12/23/2020, there were 1697 (89.5 %) White, 123 (6.5 %) Black, 52 (2.7%) Hispanic, and 25 (1.3%) pts of other races. Given a small number of pts in other groups, analysis was only performed between White and Black pts. Age at diagnosis and at first sign/symptom was similar between the two groups. Black pts were more likely to have a history of hypertension (p=0.009), stroke (p=0.002), and subarachnoid hemorrhage (p<0.001) than White pts. While Black pts were less likely to have had any arterial dissection (p=0.010), a higher percentage had aortic dissection (p=0.015). Family history of FMD was less common among Black pts (p=0.018). There were differences in the distribution of vascular bed involvement and aneurysms between Black and White pts, though not all patients underwent comprehensive vascular imaging.

Conclusion:
We noted a low number of Black patients enrolled in the US Registry for FMD at FMD specialty centers. There were differences in clinical manifestations, events, and pattern of vascular involvement among Black and White patients enrolled in US Registry, the mechanisms for which require additional study.