bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15537: E2F1 Suppresses Fibrosis Through Serine-threonine Kinase Receptor Associated Protein (Strap)
Authors: Biyashev Dauren , Boriboun Chan , Zhou Junlan , Qin Gangjian
Published: July 2021

Background:
E2F1 is best studied in cell-cycle control and cancer biology. Recently, we have disclosed a novel function of E2F1 that suppresses TGF-beta signaling pathway; however the underlying molecular mechanisms and physiological significance of this regulation remains unknown.

Methods and Results:
In a proteomics approach, Flag-tagged Smad3 protein was overexpressed in the embryonic fibroblasts (MEF) isolated from wild-type (WT) and E2F1-null (E2F1-KO) mice, and the Smad3-interacting proteins were isolated by co-immunoprecipitation and identified by mass spectrometry. Notably, the serine-threonine kinase receptor-associated protein (Strap) was found associated with Smad3 in WT MEFs, but not in E2F1-KO MEFs. This is important because Strap has been shown as inhibitor of canonical TGF-beta signaling pathway by interacting with both TGF-beta receptor I and Smad7 to interfere with Smad2/3 activation. When analyzed by Western blotting, we found that the expression of Strap was significantly higher in WT MEFs than in E2F1-KO MEFs, and similar results were obtained in the cardiac and lung tissues of WT and E2F1-KO mice. Remarkably, both bleomycin and Ang II treatments resulted in a significantly greater degree of lung fibrosis in E2F1-KO mice than in WT mice.

Conclusion:
Our results suggest that E2F1 suppresses tissue fibrosis through Strap expression and Strap-mediated repression of canonical TGF-beta signaling pathway.
Abstract 15545: Incremental Prognostic Value of Echocardiographic Markers of Left Ventricular Remodeling and Diastolic Function in the Surgical Treatment for Ischemic Heart Failure Trial
Authors: Lin Grace , She Lilin , Lee Kerry , Dabrowski Rafal , Grayburn Paul , Rajda Miroslaw , Prior David , Desvigne-Nickens Patrice , Zoghbi William , Miller Diane , Senni Michele , Stefanelli Guglielmo , Hathaway William , Beghi Cesare , Hyunh Thao , Velazquez Eric , Oh Jae
Published: July 2021

Introduction:
Whether echocardiographic (echo) markers of left ventricular (LV) remodeling and diastolic dysfunction contribute incremental and independent prognostic information to clinical risk markers in patients (Pts) with coronary artery disease and severe LV systolic dysfunction is unclear. We sought to determine which echo variables provide the greatest prognostic value in the Surgical Treatment for Ischemic Heart Failure (STICH) population.

Methods:
Pts enrolled in STICH for whom transmitral Doppler (E/A ratio) was available on a baseline echo interpreted by an echo core laboratory blinded to treatment and outcomes formed the analysis cohort. Comprehensive datasets to account for missing echo data were created by multiple imputation and the impact on all-cause mortality was determined with the Cox’s regression model.

Results:
E/A ratio could be measured in 1511 of the 2136 Pts enrolled in STICH. Amongst markers of diastolic dysfunction, E/A ratio was the most significant predictor of mortality (χ
2
41.05, p <0.001) with a non-linear, u-shaped, relationship. Mortality was lowest with E/A ratio = 1.0, and increased for E/A ratio <0.6 and >1.0 up to 2.3, beyond which there was no further increase in risk. The combination of larger LV end-systolic volume index (LVESVI), low or high E/A ratio, and mitral regurgitation severity grade, had highly significant incremental negative effects on mortality (χ
2
69.65, p<0.001) when added to a multivariable model with clinical risk markers. Overall, creatinine (χ
2
30.00, p <0.001), followed by LVESVI (χ
2
27.26, p<0.001), age, and E/A ratio (χ
2
12.46, p<0.001) were among the most significant predictors of mortality and accounted for 74% of the total prognostic information. LVESVI and E/A ratio were stronger predictors of poor prognosis than New York Heart Association (NYHA) functional class, hemoglobin, diabetes, stroke, or atrial fibrillation.

Conclusions:
Echo markers of advanced LV remodeling and diastolic dysfunction add incremental prognostic value to clinical risk markers and are more predictive of poor prognosis than advanced NYHA functional class or anemia. LVESVI and E/A ratio outperformed other echo markers and should be considered standard in assessing risk in Pts with ischemic LV dysfunction.
Abstract 15568: Is the Association of Statin Use and Incident Diabetes Mellitus Still Significant in Primary Prevention Treatment When Accounting for Incident Cardiovascular Events?
Authors: Le Viet T , McCubrey Raymond O , Bair Tami L , Horne Benjamin D , May Heidi T , Knight Stacey , Muhlestein Joseph B , Anderson Jeffrey L
Published: July 2021

Background:
Statins are first line therapy for hyperlipidemia and the preferred treatment for primary and secondary prevention of cardiovascular disease (CVD). Meta-analyses of prior statin studies suggest an association of statin use with incident diabetes (DM). It is unknown whether incident co-morbid disease plays a role in this observed increase in incident DM amongst statin users. We examined the risk of incident DM using a competing risk of time to first event model.

Method:
Patients from an integrated health care system were included if they were > 45 years of age, had no prior history of either CVD or DM and who were started on a statin medication for primary prevention. Patients were followed from January 2002 to November 2012 and assessed at 1, 5, and 10 years (n=14736, 10305, and 2541 respectively) for the association of continuous statin use and incident DM or CV event (MI, CVA, AF, CHF, or coronary revascularization). Time until first event was examined using a competing risks statistical model, where the outcome was incident DM a first CV event, or neither. Risk estimates were adjusted using propensity scores of sex, age, hypertension, hyperlipidemia, renal failure, or tobacco use.

Results:
Patients averaged 55±6 years and were 56% male. Though not statistically significant,
1
-yr follow-up of statin use trended toward an association with incident DM (HR=1.68, 95% CI (0.978, 2.89), p=0.06). 5-yr follow-up of statin use was significantly associated with incident DM (HR=1.48, 95% CI (1.11, 1.97), p =0.008). 10-yr follow-up of statin use was not significantly associated with incident DM (HR=1.01, 95% CI (0.687, 1.47), p =0.97).

Conclusion:
Using a competing risks model, an association between continuous statin use at 5-years and incident DM was observed, with a trend toward an association at 1-year. Although continuous statin treatment through 5 years was associated with risk of DM , these results do not reveal whether that risk outweighs the expected benefit of statin therapy for primary prevention.
Abstract 15582: Patterns of Statin Initiation in Patients Undergoing Intermediate to High Risk Non-Cardiac Surgery
Authors: Patorno Elisabetta , Wang Shirley , Schneeweiss Sebastian , Liu Jun , Bateman Brian
Published: July 2021

Background:
Starting from early to mid 2000s a growing body of literature has been produced on the potential role of statins in reducing perioperative cardiac events in patients undergoing non-cardiac surgery. However, evidence remains inconsistent and little is known regarding the use of perioperative statins in clinical practice.

Objectives:
To examine pattern of statin initiation among patients undergoing non-cardiac elective surgery in the US.

Methods:
Using data from a large US healthcare insurer, we identified patients ≥18 years who underwent moderate- to high-risk non-cardiac elective surgery and initiated statins within 30-days before surgery. We assessed trends of statin initiation over time and predictors of initiation. To ensure statin initiation was precipitated by non-cardiac surgery vs. alternative indications, we also assessed the effect of temporal proximity to surgery on initiation in a matched analysis.

Results:
Of 460,154 patients undergoing surgery between 2003-2012, 5,628 (1.2%) initiated a statin before surgery. Initiation rate increased from 0.8% in 2003 to 1.5% in 2012 (p = .0004). The increase was more pronounced among patients with revised cardiac risk index (RCRI) score ≥2 and patients undergoing vascular surgery, with initiation rates equal to 7.2% and 14.9% respectively by the end of 2012. Proximity to surgery was predictive of statin initiation (p < .0001). Significant predictors of initiation were older age, male sex, revised cardiac risk index (RCRI) score ≥1, vascular or orthopedic surgery. At the most recent estimate, patients undergoing vascular surgery and with a RCRI score ≥2 had initiation rates equal to 19.9%.

Conclusions:
The rate of statin initiation progressively increased from 2003 to 2012, particularly among patients with higher RCRI score and undergoing major vascular surgery. Research is needed to further define the risks and benefits of initiation of statins prior to surgery.
Abstract 15588: Dietary Choline and Betaine Intakes are Associated with Incident Cardiovascular Disease Events and Left Ventricular Mass: The Jackson Heart Study
Authors: Millard Heather R , Musani Solomon K , Hickson DeMarc A , Liu Jiankang , Talegawkar Sameera A , Taylor Herman A , Tucker Katherine L , Bidulescu Aurelian
Published: July 2021

Introduction:
Acute choline deficiency in rodent models causes lipid accumulation in liver, heart and arterial tissues. Alternatively, some studies reported an association between increased blood concentrations of total choline and cardiovascular disease. Several mechanisms have been described through which dietary intake of choline and its derivative betaine may be associated with subclinical atherosclerosis. Thus, we assessed the association between these two essential nutrients and cardiovascular risk.

Methods:
We analyzed data on food frequency questionnaire and baseline visit measurements on 3,924 Jackson Heart Study African American participants. Multivariable linear regression models were used to assess the association between choline and betaine intake with carotid intima-media thickness, coronary artery calcium, abdominal aortic calcium, and left ventricular mass. Cox proportional hazards regression models were used to calculate associations between choline and betaine intake with time to incident coronary heart disease (CHD) and stroke.

Results:
During an average seven years of follow-up, 129 incident CHD events and 100 incident stroke events were documented. Greater choline intake was associated with lower left ventricular mass (p = 0.0006 for trend across the choline quartiles, in women). After adjusting for cardiovascular disease risk factors including age, BMI, smoking, systolic blood pressure, fasting plasma glucose, plasma creatinine, cholesterol fractions, plasma homocysteine and dietary variables (intake of total energy, alcohol, folate, methionine, vitamins B6 and B12), choline intake appeared to be protective against incident stroke in men, HR = 0.19 (0.04, 0.82), when comparing the third quartile of intake to the lowest quartile of intake. In women, unexpectedly, participants in the third quartile of betaine intake showed an increased risk of incident CHD, relative to the lowest quartile, HR = 2.06 (1.02, 4.18).

Conclusion:
Higher dietary choline intake was associated with decreased left ventricular mass in both men and women, and appeared to be protective against incident stroke among men. The observation of greater risk of incident CHD with higher betaine intake among women requires further investigation.
Abstract 15659: Screening of Coronary Artery Disease Among the Young Patients With Type 2 Diabetes
Authors: Darabian Sirous , Khazai Bahram , Luo Yanting , Sheidaee Nasim , Alani Anas , Edwards Mark , Hamal Sajad , Budoff Matthew J
Published: July 2021

Introduction:
Over the last decade, the prevalence of Type 2 diabetes (T2DM) has been significantly increased among the young population. However, the appropriate age to institute statin therapy for treatment of coronary artery disease (CAD) among this population is yet to be defined. In this study, we sought to examine the prevalence, and severity of CAD among the young T2DM population.

Methods:
We enrolled asymptomatic patients within the age range of 25 to 40 who underwent cardiac computed tomography (cardiac CT). Patients with type 1 diabetes, with history of less than 5 years T2DM, or with a history of stent or bypass were excluded. On the day of cardiac CT, self-reported demographic data was collected. All contrast and non-contrast enhanced cardiac CTs were reviewed by two certified expert cardiologists.

Results:
Total of 233 cases with an average age of 35.9 were enrolled. In this population, 38.6% were female, 167 cases (71.7%) were non-diabetic, and 55 cases (25.3%) had abnormal CAC score. There was a very strong trend towards increased prevalence of abnormal CAC score between diabetic and non-diabetic groups (33.8% vs 21.7%, respectively; p=0.06). Based on the cardiac CT angiography, 56.9% of young T2DM patients had coronary atherosclerosis which was significantly greater in comparison to the non-diabetic group (56.9% vs. 35.8%, p=0.007). Regression analyses adjusted for age, gender, dyslipidemia, hypertension, smoking, and family history of premature CAD, showed significantly greater risk of having CAD in T2DM group (OR=3.28, 95% CI: 1.30, 8.29,p<0.05). Both the severity of stenosis and number of involved segments were also significantly greater among T2DM cases. There was no gender or race specific difference in the prevalence of CAD among diabetic patients. Average of CT angiographies’ radiation dose was 2.45 milliSieverts (range:0.8-10.2 mSv).

Conclusions:
In total, more than half of 25-40 years old patients with history for at least 5 years of T2DM had CAD. The difference between positive CAC and CAD by CTA angiography indicates a high prevalence of soft plaques. With mean doses of approximately 2 millisieverts, cardiac CT angiography needs to be considered as a screening method for young T2DM patients.
Abstract 15688: Electrocardiographic Patterns Differentiating "Apical Ballooning" From Anterior Myocardial Infarction
Authors: Schneider Birke , Peters Kay , Desch Udo , Stein Jürgen
Published: July 2021

Introduction:
Left ventricular apical ballooning (AB) mimics anterior myocardial infarction (AMI). This study assessed if the ECG can differentiate between these two syndromes with a similar clinical presentation.

Methods:
Among 2086 patients (pts) with an ACS, 33 (1.6%) with AB were identified (29 f, 4 m, median age 77 years) and compared to 28 consecutive age and sex matched AMI pts undergoing PCI of the LAD with similar findings on LV angiography.

Results:
AB pts arrived at the hospital later after symptom onset (median 21 vs 5 hours; p<0.001). On the admission ECG, the number of leads with ST-segment elevation (4 [3-6] vs 5 [5-7], p=0.005) and the magnitude of ST-segment elevation (0.7 [0.5-0.9] vs 0.9 [0.7-1.5] mV, p=0.002) were greater in AMI. Reciprocal ST-segment depression was similar (27% vs 54%, p=ns). A positive T wave in aVR was more frequent in AB (49% vs 7%, p<0.001).

During follow-up, AB pts had more leads with T-wave inversion (8 [8-9] vs 6 [5-8], p<0.001) and a larger magnitude of T-wave inversion (2.9 [2.2-4.6] vs 1.4 [0.9-2.3] mV, p<0.001). T-wave inversion was similar in I, aVL and V2-V5. AB pts, however, showed negative T-waves also in lead II (74% vs 22%, p<0.001), III (34% vs 4%, p=0.004), aVF (51% vs 11%, p=0.001) and a positive T wave in aVR (100% vs 70%, p=0.005). The QTc interval was longer in AB (515 [482-543] vs 458 [435-484] ms, p<0.001). An abnormal Q wave on admission was more frequent in AMI (21% vs 79%, p<0.001) and persisted but was absent in AB at discharge (0% vs 61%, p<0.001). Ventricular tachycardia was similar (2% vs 14%, p=ns) but atrial fibrillation occurred only in AB (21% vs 0%, p=0.013). The ECG normalized in all AB but in only 1 AMI pt (p<0.001).

Overall, despite a similar ejection fraction (54±15 vs 55±13 %) and lower troponin I values (7.5±6.9 vs 238±221 ng/ml, p<0.001), AB pts developed significantly more adverse events compared to AMI pts (52% vs 18%, p<0.008).

Conclusion:
ECG patterns in AB are significantly different from those in AMI. On admission, the extent of ST-segment elevation and the number of Q waves are greater in AMI. During follow-up, no Q wave, a longer QTc interval, a greater extent of T-wave inversion and a positive T wave in aVR are typical findings in AB. Adverse events are more frequent in AB than in AMI.
Abstract 15719: Right Ventricular Dysfunction After Transcatheter Aortic Valve Replacement (TAVR)
Authors: Ito Saki , Pislaru Sorin V , Nkomo Vuyisile T , Oh Jae K , Greason Kevin L , Mathew Verghese , Holmes David R , Rihal Charanjit S , Suri Rakesh M
Published: July 2021

Background:
Transcatheter aortic valve replacement (TAVR) is an alternative to surgical aortic valve replacement in patients at high surgical risk. We investigated the impact of TAVR on left (LV) and right ventricular (RV) function using conventional echocardiography parameters.

Methods and results:
A total of 202 consecutive patients (age 80.6±8.0 years, aortic valve area 0.80±0.16cm
2
) who underwent TAVR at Mayo Clinic between 2008 and 2013 were included in the study. LV ejection fraction (EF) and RV systolic function including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC) and, systolic excursion velocity (S’) were compared before (median 33.5 days) and after TAVR procedure (median 30 days). Patients who underwent pacemaker implantation after TAVR were excluded. LV EF significantly improved following TAVR (55.3±12.6% pre vs 58.5±11.1% post; p<0.05). In contrast, RV systolic function significantly decreased after TAVR (pre vs post; TAPSE: 18.8±6.3 mm vs 17.4±6.3 mm, FAC: 42.6±9.8% vs 37.3±8.2%; S’: 10.7±2.6 cm/s vs 10.2±2.6 cm/s; p<0.05 for all). Stratifying RV functional change by TAVR approach site, patients undergoing trans-femoral TAVR (n=100) showed RV deterioration only by FAC (see Table). In contrast, RV systolic dysfunction was more prominent in trans-apical approach group (n=87) with significant decline in all parameters of RV systolic function (see Table).

Conclusion:
TAVR is associated with early enhancement in LV systolic function. However, there is evidence of worsening RV function in a significant number of patients. Further studies are necessary to determine whether this deterioration in RV function is related to anatomic access site or to other factors, and to evaluate its prognostic significance.
Abstract 15785: The Natural History of Doppler-Derived Left Ventricular Outflow Tract Gradients in Patients With Congenital Valvar Aortic Stenosis Before and After Balloon Valvuloplasty
Authors: Kuebler Joseph D , Shivapour Jill , Gauvreau Kimberlee , Colan Steven D , McElhinney Doff B , Brown David W
Published: July 2021

Introduction:
Congenital aortic stenosis (AS) has been reported to manifest a slow rate of progression in mild disease with a greater likelihood of progression in patients with moderate-severe disease. The natural history of the Doppler estimated peak gradient (DEPG) in patients after balloon aortic valvuloplasty (BAV) has not previously been studied on a large scale.

Methods:
A retrospective review was performed of 360 patients from 1984-2012 with AS providing a total of 2051 echocardiograms before and after BAV. Patients were excluded if they had an intervention within the first 30 days of life. The relationships between the AS DEPG and several predictors (age at time of initial echocardiogram, valve morphology, and history of intervention) were explored using linear mixed effect models. The DEPG slope was then calculated in patients who had at least 2 echocardiograms before and after balloon dilation using linear regression modeling.

Results:
The rate of increase in the DEPG for all patients with AS was 5.6 mmHg per 10 years of age (p<0.001). The DEPG increased over time regardless of age at presentation with the greatest mean increase in patients presenting from 10-14.9 years (n=59; 11.9 mmHg per 10 years; p<0.001). Patients who went on to have a BAV or surgical intervention on the aortic valve had a significantly higher rate of AS progression than the overall patient cohort (n=59; 18.0 mmHg/10 years and n=36; 13.1 mmHg/10 years). Patients with a unicommissural (n=39) aortic valve had a significantly higher rate of progression compared to those with a bicommissural (n=270) aortic valve (8.1 mmHg/10 years and 4.5 mm Hg/10 years; p<0.001). The median rate of progression in the post-BAV group was significantly lower than the median pre-BAV rate of progression (n=34; pre-BAV 3.97 (1.69-8.7) mmHg/year; post-BAV 0.40 (-1.80-3.88) mmHg/year; p<0.01).

Conclusions:
The DEPG of native valve congenital aortic stenosis shows a slow, linear rate of progression prior to intervention. The rate of progression is significantly higher in patients with a unicommissural aortic valve as well as those patients that go on to have a BAV and/or surgical intervention. The rate of the DEPG progression is significantly lower after BAV.
Abstract 15789: Cardiac MRI With Adenosine Identifies Coronary Stenosis, Perfusion Defects, and Delayed Enhancement in Pediatric Patients With Anomalous Aortic Origin of a Coronary Artery Before and After Surgical Repair
Authors: Brothers Julie A , Kim Timothy S , Fogel Mark A , Whitehead Kevin K , Paridon Stephen A , Harris Matthew A
Published: July 2021

Background:
Anomalous aortic origin of a coronary artery (AAOCA) with an interarterial course is associated with sudden cardiac death in children.

Objectives:
Using cardiac MRI with adenosine, we evaluated coronary ostial stenosis, proximal coronary size, and left ventricular (LV) function in children with AAOCA.

Methods:
We prospectively enrolled children 5-18 years old with interarterial AAOCA. MRIs were reviewed for coronary artery origin, proximal course, dimensions, and cardiac function. Surgery consisted of the modified unroofing procedure. We used descriptive statistics and paired t-tests to evaluate for statistical significance.

Results:
Between 2/2009 and 5/2014, 24 subjects with AAOCA underwent 29 MRIs. The majority were male (N=19, 79%) with anomalous right coronary artery (AAORCA, N=20, 83%). Mean age was 12.8 years at time of initial MRI. MRI was performed an average of 7 months post-operatively in 8 subjects who underwent surgery. In all, the proximal anomalous coronary arose tangential to the aorta with an elliptical, slit-like ostium. The anomalous coronary measured smaller proximally (0.20 mm) compared to distally (0.31 mm, P=< 0.0001), and after surgical repair, the post-operative origin was significantly larger (0.36 vs. 0.21 mm, P=0.02). Other abnormalities at initial MRI included fixed inferior wall (N=1) and reversible subendocardial septal/inferior wall (N=1) perfusion defects. Post-operatively, the neo-ostium was round in 6 (see Figure), but in 2, the orifice remained elliptical. One patient had a new small mid-myocardial scar and one had dyskinetic septal wall motion. LV function was normal both before and after surgery (mean ejection fraction =68.1% vs. 67.5%, P=0.85).

Conclusions:
Cardiac MRI with adenosine is an important tool for the evaluation of anomalous anatomy, myocardial function, and ischemia/injury and should be considered for the initial and, when applicable, post-operative assessment of children with AAOCA.
Abstract 15798: Real Time MRI Based Atrial Cryoablation
Authors: Ranjan Ravi , Kholmovski Eugene , Coulombe Nicolas , Silvernagel Joshua , Marrouche Nassir
Published: July 2021

Introduction:
Balloon cryoablation is being increasingly used for pulmonary vein isolation. Acute determination of lesion permanency cannot be ascertained directly, but is inferred by PV occlusion and acute PV isolation. We aimed to determine if direct confirmation of vessel occlusion and lesion formation could be visualized in real time in a MRI system using a novel MRI compatible cryo balloon catheter.

Methods:
We used a canine model (n=3) and a MRI compatible cryo balloon catheter built for animal use (Medtronic CryoCath, Montreal, Canada). The procedure was performed in a 3T (Verio, Siemens) MR scanner. The MRI compatible 28 mm cryo balloon was advanced into the right atrium (RA) via the femoral vein under MRI guidance. Gadolinium based contrast (Multihance) was injected to confirm vessel occlusion. The superior vena cava (SVC) - RA junction was frozen for 3 mins. Post ablation, late gadolinium enhancement MRI (LGE-MRI) was obtained acutely to confirm the ablation. The heart was excised to confirm the tissue changes.

Results:
Panel A shows the inflated balloon at the SVC ostium. Panel B shows contrast injected in the SVC confirming its occlusion. Panel C is an MR image taken during the freeze cycle. Panel D is an LGE-MRI showing enhancement along the SVC wall confirming ablation. Panel E is an axial view of the SVC confirming circumferential ablation with no apparent gaps. The ablation completeness was confirmed in pathology.

Conclusion:
A real time MR-based balloon cryo ablation system was implemented. It allows real time confirmation of vessel occlusion, visualization of a freeze zone and visual confirmation of tissue changes from ablation in the pre-clinical setting.
Abstract 15839: Effect of Serotonin Neuron Depletion on Arterial Blood Pressure Regulation in Young Rats
Authors: Magnusson Jennifer , Cummings Kevin
Published: July 2021

Infants dying of Sudden Infant Death Syndrome (SIDS) have reduced brainstem serotonin (5-hydroxytryptamine, 5-HT) where some cases die following episodes of severe bradycardia and hypoxemia. The specific role of central 5-HT in resting arterial blood pressure (BP) and on baroreflex sensitivity during neonatal life has not been studied. In adult animals, systemic depletion of 5-HT increases BP with no effect on heart rate (HR) and reduces the sensitivity of the baroreflex. Other studies have also shown that a loss of central 5-HT beginning in embryogenesis reduces resting BP and HR in adulthood. Based on these reports, we hypothesized that loss of brainstem 5-HT neurons in the neonatal period would reduce baseline BP and HR as well as reduce baroreflex gain. To test this, we utilized 3-week old Sprague Dawley rats treated centrally with 5,7-dihydroxytryptamine (5,7-DHT, n=4; ~120 ug in saline, i.c.v.), a chemical that is toxic to serotonergic neurons. Littermate controls were injected with saline (CTRL, n=5, ~3ul, i.c.v.). We measured BP with a femoral artery catheter. HR was derived from BP. Following a recovery period, we measured resting variables for 15 minutes and then injected phenylephrine (PE; 3mg/kg s.c.) followed by sodium nitroprusside (SNP; 2.5mg/kg s.c.), separated by 15 minutes, to induce pressor or depressor responses, respectively. For both responses, baroreflex gain was calculated as the [[Unable to Display Character: ∆]]HR at the maximum [[Unable to Display Character: ∆]]BP following drug injection. We found that a loss of 5-HT neurons did not alter baseline BP (p>0.05) but did reduce baseline HR when compared to control littermates (p<0.02). 5-HT neuron deficiency tended to reduce baroreflex gain in response to PE (CTRL: -2.756 ± 0.483 beats/mmHg; 5,7-DHT: -1.499 ± 0.348 beats/mmHg; p=0.058), but not SNP (CTRL: -2.408 ± 0.351 beats/mmHg; 5,7-DHT: -3.316 ± 1.214 beats/mmHg; p>0.05). Our data indicate that brainstem 5-HT maintains resting HR, and is involved in baroreflex control of HR in response to hypertensive stimuli. Reduced brainstem 5-HT may predispose an infant to SIDS via altered autonomic control of BP and HR. The role of 5-HT in BP regulation during hypoxic conditions remains to be elucidated.
Abstract 15848: Restoration of Normal Cardiomyocyte Basal and β-Adrenergic Receptor (AR) Subtype Modulation in Heart Failure by Chronic Phosphodiesterase Type 5 Inhibition With Sildenafil
Authors: Li Tiankai , Cheng Heng-Jie , Qasem Shadi A , Callahan Michael , Li Wei-Min , Cheng Che Ping
Published: July 2021

Background:
We have shown that Sildenafil (SIL), a selective PDE5 inhibitor reversed left ventricular (LV) dysfunction and β- adrenergic receptors (AR) desensitization in heart failure (HF). However the mechanism is not yet clear. Recent evidence suggests that normal myocardial performance depend on the balance in cardiomyocyte β
3
-,

β
1
-, and β
2
-AR. Pivotal restructuring of β-AR system resulting in decline of β-adrenergic reserve plays a crucial role in the development of HF. We assessed the hypothesis that chronic SIL would prevent HF-induced abnormalities of β-AR subtype-stimulated regulation on intrinsic LV myocyte function and [Ca
2+
]
i
regulation, thus restoring cardiac function.

Methods:
Studies were conducted in 3 groups (10/group) of rats: 1) HF, 12 weeks (W) after receiving isoproterenol (ISO) (170 mg/kg sq for 2 days); 2) HF/SIL, 8W after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and 3) controls. After 12W, we compared LV myocyte contractile and [Ca
2+
]
iT
responses to β-AR subtype stimulation by random exposure of myocytes to ISO (10
-8
M) or a selective β
1
-, β
2
-, or β
3
-agonist, Norepinephrine (NE, 10
-7
M), Zinterol (ZIN, 10
-5
M) and BRL-37,344 (BRL, 10
-8
M), respectively, during drug superfusion.

Results:
Only ISO-treated rats had HF showed 46% decreased LV contractility (E
ES
) and extensive LV myocardium fibrosis. Compared with normal myocytes (N), in HF myocytes, basal cell contractility (dL/dt
max
, HF: 77 vs N: 136 μm/s), relaxation and [Ca
2+
]
iT
all significantly decreased. ISO-stimulated dL/dt
max
(31% vs 67%) was attenuated accompanied by a diminished NE-mediated increase in dL/dt
max
(13% vs 49%), but enhanced BRL-induced decreases in dL/dt
max
(-29% vs -16%).The response of dL/dt
max
(25% vs 15%) to ZIN was increased. Importantly, in HF/SIL myocytes, the basal dL/dt
max
(139 μm/s) and [Ca
2+
]
iT
remained close to control

values with preserved β-stimulated positive modulation on cell contraction. The increases in dL/dt
max
in response to ISO (70%) and NE (44%) were similar as in normal myocytes, but repose to ZIN (27%) was enhanced.

Conclusions:
Chronic SIL reverses β-adrenergic

signaling defects, resensitizing the β-AR subtype system modulation on LV myocytes function, thus playing a salutary role in HF.
Abstract 15892: mRNA Stability Hu Proteins Regulate Human Cardiac Sodium Channel Expression
Authors: Zhou Anyu , Greener Ian , Xie An , Shi Guangbin , Yang Kai-Chien , Liu Hong , Rutledge Cody , Dudley Samuel
Published: July 2021

Human heart failure has been associated with reduced cardiac Nav1.5 Na+ channel current and SCN5A mRNA abundance. We hypothesized that reduced mRNA stability would contribute to the reduction of SCN5A mRNA. Hu proteins are known to contribute to mRNA stability The SCN5A mRNA 3’-untranslated region (UTR) contains two sets of putative Hu protein binding site. Over-expression of HuR and HuB in cardiomyocytes derived from primary human fetal ventricle increased wild-type SCN5A mRNA 46.3% (P=0.004) and 60.7% (P=0.008), respectively. Knocking down of HuR or HuB by siRNA decreased SCN5A mRNA by 27.5% (P=0.000) and 20.4% (P=0.02). RNA immunoprecipitation showed HuR associated with SCN5A mRNA. This suggested Hu family proteins might play an important role in upregulation of SCN5A expression by stabilizing SCN5A mRNA. In addition, we found HuR mRNA decreased 38.9% (P=0.034) in peripheral white blood cells of heart failure patients with implanted cardioverter-defibrillator (ICD) and evidence of appropriate event-driven therapy compared to control subjects. The decrease of HuR mRNA correlated with a reduction of wild-type SCN5A mRNA abundance in white blood cells from these patients. Our results demonstrate an additional layer of SCN5A posttranscriptional regulation in addition to alternative splicing that can contribute to sodium channel down-regulation in heart failure. Our results also suggest that circulating HU protein assessment may be useful in arrhythmic risk stratification and that exogenous HU protein overexpression may help reduce arrhythmic risk in heart failure.
Abstract 15920: The Prevalence of Atherosclerotic Disease in Those With Connective Tissue Disease as a Function of Age, Race, and Traditional Risk Factors
Authors: Alenghat Francis J
Published: July 2021

Background:
Atherosclerosis is a multifactorial disease with an intrinsic inflammatory component, but it may also be influenced by systemic inflammation. There is cardiovascular risk associated with rheumatoid arthritis (RA), but there is still a need to clarify the contributions of traditional risk factors in those with inflammatory connective tissue diseases (CTD, which includes RA) in the development of atherosclerotic cardiovascular disease (ASCVD). It would also be useful to identify particular groups of patients that are at disproportionately greater conferred risk for ASCVD owing to their CTD. For these reasons, a cross-sectional analysis of a diverse patient population could help develop finer ASCVD risk estimations in those with and without CTD.

Results:
A systematically queried warehouse of de-identified data from over a quarter-million adult patients at our urban medical center over the past six years showed that prevalence of ASCVD steadily increases with age, consistent with rates found in other large cohorts, in both white and African-American patients. Amongst the ~9,000 patients with CTD (RA, other inflammatory polyarthropathy, lupus, Sjögren’s syndrome, systemic sclerosis, dermatomyositis, polymyositis), the overall prevalence of ASCVD was higher than amongst those without CTD with a rate ratio of 1.9 [95% CI 1.8-2.1] for white patients and 3.3 [95% CI 3.1-3.5] for African-American patients. Subgroup analysis revealed that the rate ratio was particularly high for young adults, and especially young African-American patients (ages 18-44; rate ratio for women: 10.7 [95% CI 8.5-13.5], for men: 9.9 [95% CI 6.8-14.5]). Rate ratios of ASCVD in those with vs. without CTD declined with age as traditional risk factors became more prevalent. Importantly, in those without any documented traditional risk factors (smoking, hypertension, diabetes, dyslipidemia), a diagnosis of ASCVD was found nearly three times more frequently in those with CTD than without [rate ratio 2.9, 95% CI 2.4-3.5].

Conclusions:
CTD is associated with increased ASCVD rates, and major traditional risk factors do not fully account for these increased rates. African-Americans and young adults have a disproportionately strengthened association between CTD and ASCVD.
Abstract 15961: Syncytial Model of Type 2 Long QT Syndrome Derived From Human iPS Cells Can Be Paced and Responds to Ikr Block and Activation
Authors: Zhu Renjun , Joshi-Mukherjee Rosy , Blazeski Adriana , Boheler Kenneth R , Tomaselli Gordon F , Tung Leslie
Published: July 2021

Type 2 long QT (LQT2) syndrome is a cardiac disorder associated with hERG channel mutation that may lead to tachyarrhythmia and sudden death. We developed a syncytial model of cardiomyocytes (CMs) differentiated from iPS cells derived from an LQT2 patient harboring an A422T mutation. The A422T mutation has been shown to cause a marked decrease in IKr current mainly due to a trafficking defect in the hERG channel. Immunostaining of cTnI revealed that CMs were isotropically distributed with well-formed sarcomeres. Both wild type (WT) and LQT2 monolayers were stable in culture for at least 60 days with spontaneous activity, and could be paced at cycle lengths (CL) from 2000 down to 300 ms. After staining the monolayers with di-4-ANEPPS, optical mapping showed that all monolayers formed a functional syncytium that supported propagating action potentials. LQT2 monolayers had longer APD80s than WT monolayers (332±43 ms, n=6, vs. 267±46 ms, n=18, mean±SD, CL = 700 ms, p<0.005), showing the delayed repolarization expected of the LQT2 phenotype. Reentrant spiral waves were observed in LQT2 (n=2), but not WT monolayers.

Application of 0.2μM E-4031 (IKr blocker) slowed repolarization and prolonged APD80 in both WT and LQT2 monolayers, and slowed conduction velocity in WT monolayers (4.7±1.0 cm/s, n=6 vs. 10.4±1.4 cm/s, n=11 control, CL = 1000 ms). The slowing effect may reflect a role of IKr in setting the maximum diastolic potential in these CMs where IK1 is weakly expressed, as has been recently suggested. Application of 10μM ML-T531 (IKr activator) shortened APD80 in LQT2 monolayers (313±36 ms vs. 162±19 ms, n=4, p<0.0001), showing successful reversal of the LQT phenotype. ML-T531 also shortened APD80 in WT monolayers (202±43 ms vs. 154±26 ms, n=4, p<0.04). These results indicate that syncytial models of heritable cardiac disease are feasible and may be useful for studying drug effects that affect electrophysiology and arrhythmogenesis.
Abstract 15991: Chronic Asthma Predicts Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Tattersall Matthew C , Guo Mengye , Korcarz Claudia E , Gepner Adam D , Barr R. Graham , Donohue Kathleen M , McClelland Robyn L , Delaney Joseph A , Stein James H
Published: July 2021

Background:
Chronic asthma and cardiovascular disease (CVD) share a common inflammatory pathophysiology. We hypothesized that chronic asthma requiring daily controller medications is associated with higher CVD risk.

Methods:
Presence of chronic asthma and use of controller medications (CM; inhaled corticosteroids, leukotriene inhibitors, oral corticosteroids) were assessed in the MESA at Exam 1. Participants were followed for a mean (standard deviation) 9.1 (2.8) years for development of CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of chronic asthma and CVD.

Results:
The 6792 MESA participants were 62.2 (10.2) years old: 47% male, 28% African-American, 22% Hispanic and 2% Chinese. The 156 asthmatics that were on CM were compared with the 511 who were asthmatic but not on CM and the 6125 non-asthmatics. Asthmatics on CM, compared to those not on CM and non-asthmatics, respectively had higher age-adjusted levels of C-reactive protein (1.2 [1.2] vs 0.9 [1.2] vs 0.6 [1.2] mg/L) and fibrinogen (379 [88] vs 356 [80] vs 345 [73] mg/dL) (both p<0.006). Asthmatics on CM had the lowest 10-year unadjusted CVD free survival rate of 84.1%, (95% confidence interval [CI] 78.9-90.3%) compared with asthmatics not on CM 91.1%, [95% CI 88.5-93.8%] and non-asthmatics 90.2%, [95% CI 89.4-91%] (p=0.028). After adjustment for age, sex, race, smoking, total and high-density lipoprotein cholesterol, systolic blood pressure, body-mass index, family history, income, anti-hypertensive and lipid medication use, asthmatics on CM had higher risk of CVD events than non-asthmatics (HR 1.6 [95% 1.01-2.5, p=0.040]). CVD-free survival was similar among asthmatics on or not on CM (p=0.155).

Discussion:
In this large multi-ethnic cohort, asthmatics on CM had a higher CVD event rate compared to non-asthmatics. Increased CVD risk among asthmatics may be related to increased inflammatory stress.
Abstract 16030: Heterogeneity of Electrocardiographic Findings in Cardiac Transthyretin (ATTR) Amyloidosis and Impact on Survival
Authors: Patel Ketna S , Fontana Marianna , Sachchithanantham Sajitha , Sayed Rabya , Wechalekar Ashutosh D , Lachmann Helen J , Hawkins Philip N , Whelan Carol J , Gillmore Julian D
Published: July 2021

Introduction:
Cardiac transthyretin (ATTR) amyloidosis is an increasingly diagnosed cause of heart failure. Wild-type ATTR amyloidosis (ATTRwt) is a disease of older Caucasian men. Hereditary (mutant) cardiac ATTR amyloidosis (ATTRm) is most commonly associated with the V122I transthyretin (TTR) variant carried by 3-4% of African Americans or the T60A TTR variant in patients of Irish ancestry, the latter presenting with a mixed cardiac and neurologic phenotype. Most published data consider electrocardiographic (ECG) findings in ATTR amyloidosis as a single entity. Prognostic factors for survival in cardiac ATTR amyloidosis are poorly defined.

Methods and Results:
We analysed ECGs from 158 patients with cardiac ATTR amyloidosis (ATTRwt=75; V122I=49; T60A=34) in a longitudinal retrospective study.

Results are shown in Table 1.

63 patients died; 29 ATTRwt, 24 V122I, 10 T60A, during follow-up of 22.7±14.6, 23.8±12.8, and 31.3±20.4 months respectively. Overall median survival: ATTRwt 3.1yr (95%CI:2.2-4.0); V122I 2.6 yr (95%CI:2.2-3.0); T60A not reached. In ATTRwt, broad QRS (≥120ms) was associated with worse survival (1.6yr; 95%CI:1.3-1.9 vs not reached). No other ECG parameter in ATTRwt, and none in either ATTRm group affected survival. On univariate analysis of the ATTRwt cohort, broad QRS, age, systolic BP, TropT and NTproBNP were significant variables at the <1% level, and eGFR at the 5% level; LVEF, septal S’ TDI and global longitudinal strain were not significant. On multivariate analysis only broad QRS (HR: 3.0, CI 1.2-7.5; P=0.024) and NTproBNP (HR: 3.0, CI 1.1-7.4; P=0.026) predicted mortality. Among ATTRwt patients, there were no significant differences of other characteristics between those with narrow and those with broad QRS complexes.

Conclusions:
The ECG in cardiac ATTR amyloidosis is heterogeneous, greater awareness of which might help prevent diagnostic delays. Broad QRS complexes and NTproBNP are independent predictors of mortality in ATTRwt.
Abstract 16049: A Comparison of Short- and Medium-Term Outcomes Between Men and Women Undergoing Percutaneous Coronary Intervention in a Chinese Population During the Contemporary Era of Drug-Eluting Stents
Authors: He Peiyuan , Yang Yuejin , Qiao Shubin , Xu Bo , Wu Yongjian , Yuan Jinqing , Liu Haibo , Dai Jun , Tang Xinran , Wang Yang , Li Wei , Gao Runlin
Published: July 2021

Background:
Very few studies have compared the percutaneous coronary intervention (PCI) outcomes between men and women among Asian population in the era of drug-eluting stents (DES). We aimed to evaluate the sex-specific disparities in a Chinese population.

Methods:
From June 1, 2006 to April 30, 2011, a total of 21,964 coronary artery disease patients who have undergone PCI with stents implantation were included from one single Chinese heart center. Among them, 17209 were males, and 4755 were females. The primary endpoint was defined as major cardiovascular events (MACE) during hospitalization and at 1 year follow-up, which included cardiac death, myocardial infarction (MI), and target vessel revascularization (TVR). The secondary endpoint was defined as each component of MACE. Major bleeding after the procedure was recognized as the safety endpoint.

Results:
The rates of MACE during hospitalization and at 1 year follow-up were similar between men and women (in-hospital: 1.5% vs. 1.6%, P=0.730, at 1 year follow-up: 4.0% vs. 4.1%, P=0.589). The adjusted rates of the primary endpoint was still similar (in-hospital odds ratio [OR], 0.94; 95% confidence interval [CI], 0.66–1.33, at 1 year follow-up hazard ratio [HR], 1.00; 95% CI, 0.96-1.04). No significant differences were detected in each component of MACE (P all > 0.05). But major bleeding after PCI occurred more in women than in men (1.2% vs. 0.7%, P=0.002), mainly driven by the access site-related major bleeding (0.8% vs. 0.4%, P=0.002). The access site complications were also more frequent in women (2.5% vs. 1.6%, P <0.001).

Conclusions:
In the Chinese population with frequent use of DES, women present similar in-hospital and 1 year major outcomes compared with men. But women have higher risk of major bleeding and access site complications.
Abstract 16064: Effect of Intensive versus Moderate Lipid-Lowering Therapy on the Progression of Coronary Lipid-Rich Plaque: A Prospective, Randomized, Serial Combined Optical Coherence Tomography and Intravascular Ultrasound Study
Authors: Hou Jingbo , Jia Haibo , Hu Sining , Xing Lei , Yang Shuang , Zhang Shaosong , Yu Bo , Jang Ik-Kyung
Published: July 2021

Background:
Despite dramatic improvements in clinical outcome, intravascular ultrasound (IVUS) trials have shown minimal improvement of atheroma volume with statin therapy. Changes in plaque composition rather than plaque volume may contribute to the marked clinical benefit.

Objectives:
To assess the effect of intensive versus moderate lipid-lowering therapy on fibrous cap thickness (FCT) by optical coherence tomography (OCT) and percent atheroma volume (PAV) by IVUS.

Methods:
The patients with ≥1 non-treated lipid-rich plaque (LRP) with moderate stenosis were randomized to receive atorvastatin 60 mg (AT60), or atorvastatin 20 mg (AT20). OCT and IVUS imaging were performed at baseline, 6 months and 12 months. The primary endpoint was the change in FCT. The secondary endpoints were the change in PAV and the percent change in normalized total atheroma volume (%NTAV). Sixty-six LRP in 46 patients defined by OCT were studied.

Results:
Low-density lipoprotein cholesterol (LDL-C) was reduced significantly in both groups at 6 months; however, there was no further reduction at 12 months (Fig A, C). OCT demonstrated a continuous increase in FCT over time in both groups, with greater increase in the AT60 group than the AT20 group at 6 months (139.7±160.9% vs. 68.1±83.9%, p=0.021) and 12 months (211.3±125.4% vs. 120.2±136.9%, p<0.0001) (Fig B, D). IVUS showed no significant changes in PAV and NTAV over time in two groups. The changes in PAV were similar between the two groups at 6 months (-0.48±3.4% in AT60 vs. 0.28±5.2% in AT20, p=0.50) and 12 months (-0.26±4.3% vs. 0.11±4.1%, p=0.73). %NTAV were also comparable between the two groups at 6 months and at 12 months.

Conclusions:
Intensive atorvastatin therapy induces more rapid and effective stabilization of coronary lipid-rich plaques by increasing FCT, as compared with moderate atorvastatin therapy. IVUS analysis did not show significant change in plaque volume over time in both groups.
Abstract 16074: Risk of Blood Transfusion(s) With New Oral Anticoagulants for Short-Term Thromboprophylaxis in Hip and Knee Surgery: Insights From a Meta-Analysis of Fifteen Randomized Trials Including 36,176 Patients
Authors: Krishnamoorthy Parasuram , Chatterjee Saurav , Garg Jalaj , Sardar Partha , Messerli Franz , Mukherjee Debabrata
Published: July 2021

Introduction:
Blood transfusions have been associated with poor outcomes in cardiac patients. The objective of our study was to systematically examine the overall risk of blood transfusion with new oral anticoagulants (NOACs) and individually in thromboprophylaxis for hip and knee surgery.

Hypothesis:
Treatment with NOACs is safe for short-term thromboprophylaxis in patients undergoing hip and knee surgery compared with conventional therapy.

Methods:
PubMed, Cochrane CENTRAL, EMBASE, EBSCO, Web of Science and CINAHL databases were searched from January 01, 2001 through September 30, 2013. Systemic review of randomized controlled trials (RCTs) comparing the use of NOACs (apixaban, dabigatran and rivaroxaban) with conventional therapy was performed. Clinical and outcome data were extracted from individual studies by 2 independent authors. Primary endpoint of interest was transfusion events in the NOAC and comparator arms. Random effects model was used to pool event rates and results were expressed as risk ratios (RR) with 95% confidence intervals (CIs).

Results:
Fifteen randomized controlled trials (RCTs) including a total of 36,176 patients were included for analysis. Transfusion events were not higher with use of NOACs in comparison to all comparators in patients undergoing hip and knee surgery- RR 1.02 (95% CI 0.98-1.06), p=0.40. Statistical heterogeneity was negligible (I2=22%).

Conclusions:
Blood transfusion events with NOAC use were not significantly higher than that with conventional drugs in thromboprophylaxis for hip and knee surgery patients, as noted in evidence from contemporary RCTs.