bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12808: Mechanism of Chronic Ranolazine Caused Regression of Cardiac Dysfunction in a Murine of Diabetic Cardiomyopathy: Beneficial Effects on Cardiomyocyte Contractile Function, [Ca
2+
]
i
Regulation and Beta-Adrenergic Modulation
Authors: Sun Xiaoqiang , Cao Jing , Cheng Heng-Jie , Liu Yixi , Chen Zhe , Kitzman Dalane , Zhao David , McClain Donald A , Cheng Che
Published: May 2021

Background:
Diabetic cardiomyopathy (DCM) increases the risk of heart failure. As yet, no effective therapeutic strategies exist. Recent evidence indicates that intracellular Na
+
concentration ([Na
+
]
i
) is augmented in the myocytes from diabetic hearts, where it causes oxidative stress, augments the sarcoplasmic reticulum Ca
2+
leak and contributes to electrical, structural and functional remodeling. Ranolazine (RAN), inhibiting persistent or late inward Na
+
current has been proposed to be a therapeutic choice for DCM. However, the role and mechanism of chronic RAN in DCM are unclear. We assessed the hypothesis that RAN improves myocyte function, [Ca
2+
]
i
regulation, and β-adrenergic receptor (AR) signaling effectiveness, thus limiting DCM.

Methods:
We compared LV myocyte function, [Ca
2+
]
i
transient ([Ca
2+
]
iT
) and responses to the stimulation of β-AR in 3 groups wild-type (WT) female mice over 10 weeks (W):1)
DM
(n=8), 10 W after receiving streptozotocin (STZ, 200 mg/kg, ip); 2)
DM/RAN
(n=6), 6 W after STZ, RAN (10
-5
M/kg/day, mini-pump) was initiated and was given for 4 W; and 3)
Sham controls (C)
(n=8).

Results:
Versus control, STZ-treated WT mice had DM with significantly elevated blood glucose levels (410 vs 128mg/dl) followed by LV myocyte dysfunction with decreases in myocyte contractility (dL/dt
max
) (75.0 vs 140.1 μm/s), relengthening (dR/dt
max
) (62.5 vs 116.6 μm/s) and [Ca
2+
]
iT
(0.15 vs 0.22). In DM myocytes, the ability of β-AR agonist, isoproterenol (ISO, 10
-8
M) to increase cell contractility was blunted. Versus control, in DM myocytes, ISO-induced increases in dL/dt
max
(31% vs 60%), dR/dt
max
(23% vs 50%) and [Ca
2+
]
iT
(15% vs 30%) were significantly reduced. By contrary, versus DM alone, DM/RAN myocytes showed normal basal cell contraction (137.8 μm/s), relaxation (117.2 μm/s) and [Ca
2+
]
iT
(0.22) with preserved ISO-stimulated positive inotropic effect. Compared control, in DM/RAN, ISO caused similar increases in dL/dt
max
(62% vs 60%), dR/dt
max
(52% vs 50%) and [Ca
2+
]
iT
(32% vs 30%).

Conclusion:
Chronic ranolazine leads to the preservation of myocyte function, [Ca
2+
]
iT
and β-AR responsiveness in DCM. Thus, antagonizing myocyte [Na
+
]
i
dysregulation might provide a new therapeutic strategy for DM-related decline in myocardial function.
Abstract 12907: Treatment of Anomalous Left Coronary Artery From the Pulmonary Artery in a 60-year-old Patient With Primary Re-implantation
Authors: Beschta Sam , Boyd Christopher
Published: May 2021

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart defect accounting for 0.26% - 0.46% of congenital anomalies. Most (85%) cases are diagnosed in the first month of life with only 18-25% of patients reaching adulthood. Patients diagnosed in adulthood typically have collaterals from the right coronary artery (RCA) which provide blood flow to the left coronary artery (LCA) system. They can present with heart failure, mitral insufficiency, arrhythmias, and/or sudden cardiac death. An otherwise healthy 60 y/o female presented to an outside hospital after a witnessed cardiac arrest when leaving the gym. Bystander CPR was started, and she received 2 shocks from an automated external defibrillator for ventricular tachycardia/ventricular fibrillation (VT/VF) with return of spontaneous circulation and taken to the local ED. A CTPE showed no acute PE and a possible ALCAPA. She was transferred to our institution for further assessment by adult congenital cardiology. TTE was performed on arrival which showed a global cardiomyopathy with color flow in the myocardium consistent with extensive collateralization. CT coronary artery was performed which confirmed ALCAPA anatomy without significant CAD. The case was discussed with CT surgery, interventional cardiology and adult congenital cardiology. The decision was made for a right and left heart catheterization and cardiac MRI to plan for possible surgery. Angiography showed a large RCA with extensive collaterals filling the left coronary system and no significant disease. RHC showed a normal cardiac output with a large left to right shunt and moderate pulmonary hypertension. MRI showed a mild diffuse subendocardial ischemia with high viability of the entire left ventricle and a pulmonary to systemic flow ratio (Qp:Qs) of 2.1. The decision was made to go ahead with primary re-implantation of the LCA to the aorta, the preferred method. Ligation of the anomalous coronary artery and coronary artery bypass grafting can also be used. She was taken for surgery and tolerated the procedure well. Follow up echo is pending, but she has had no further VT/VF episodes. This case demonstrates successful re-implantation of an ALCAPA in a symptomatic adult.
Abstract 12913: Trabectedin Related Reversible Cardiogenic Shock: A Rare Side Effect of Anti-neoplastic Drug
Authors: Jha Samir , Wang Jimmy , Jha Roshan , Zoltick Jerel M
Published: May 2021

Trabectedin, an alkylating agent, is used as palliative chemotherapy of soft-tissue sarcoma after failure of first-line treatment. It is labeled as a low cardiac risk profile. We present a case of a lady with metastatic synovial sarcoma with a pre-treatment normal echocardiography, who received 3 cycles of Trabectedin, and presented in cardiogenic shock which reversed back to normal function with vasopressor, diuresis and inotrope support.

Case report:
A 66-year-old female with metastatic synovial sarcoma of lungs (post right upper lobectomy and chemotherapy), with positive mediastinal and hilar nodes improvement, was transferred in with hypotension and respiratory distress. She was recently started on trabectedin as palliative chemotherapy, about 2 months prior to this admission, received 3 cycles, the last cycle was 4 days prior to admission. There was an elevation of high-sensitivity troponin (peaked to 2000) which trended down. With metastatic disease and ongoing thrombocytopenia (post-chemotherapy), cardiac catheterization was not deemed appropriate, managed medically with inotrope, and pressor support for cardiogenic shock. A nuclear stress test done after weaning off all intravenous medicine showed an LVEF of 55% without any area of ischemic defect. As no other precipitants were identified and with reversibility of cardiac function over time, we considered these events were related to trabectedin toxicity.

Discussion:
For the use of Trabectedin, there is no specific caution for patients with cardiac disease or risk factors hence labeled as low cardiac risk profile by comprehensive analysis. This case highlights a rare but life-threatening side effect of this drug. It is important to balance the potential of an increase in progression-free survival with chemotherapy versus a life-threatening adverse effect which may counter-effect the mortality benefit and highlights a need for close serial monitoring.
Abstract 12923: Development of a Novel Biomarker-based Risk Score for Heart Failure in Patients With Diabetes
Authors: Berg David D , Wiviott Stephen D , Scirica Benjamin M , Goodrich Erica , Bhatt Deepak L , Leiter Lawrence A , McGuire Darren K , WILDING JOHN , Johanson Per , Langkilde Anna Maria , Braunwald Eugene , Sabatine Marc S , Morrow David A
Published: May 2021

Introduction:
Heart failure (HF) is a prognostically important complication of T2DM, the risk of which can be reduced by SGLT2 inhibitors. Clinical factors and circulating biomarkers of myocardial injury and hemodynamic stress predict risk of hosp for HF (HHF) in pts with T2DM.

Aim:
We aimed to develop and validate a biomarker-based risk score for HHF in pts with T2DM and to assess whether this score can identify high-risk pts with T2DM who have the greatest reduction in HHF risk with SGLT2 inhibition.

Methods:
Blood samples were prospectively collected from pts enrolled in SAVOR-TIMI 53 and DECLARE-TIMI 58 at randomization; high-sensitivity troponin T (hsTnT) and N-terminal B-type natriuretic peptide (NT-proBNP) were measured. We derived a risk score in 6106 pts with T2DM in the placebo arm of SAVOR-TIMI 53. Candidate variables (n=27) were assessed using Cox regression. The strongest indicators of HHF risk (based on Wald χ;2 values) were selected for inclusion and assigned integer weights. We externally validated the score in 7251 T2DM pts in the placebo arm of DECLARE-TIMI 58. Hazard ratios (HR) and absolute risk reductions (ARR) in HHF with the SGLT2 inhibitor dapagliflozin were assessed by baseline risk group.

Results:
The strongest independent indicators of HHF risk were NT-proBNP and hsTnT concentrations, and prior HF (each p<0.001). A risk score using these 3 variables identified a strong gradient of HHF risk (p-trend <0.001) in both the derivation and validation cohorts, with c-indices of 0.87 and 0.84, respectively. HRs with dapagliflozin were similar across risk groups (p-int = 0.64); however, ARRs were greater in those at higher baseline risk (p-trend <0.001), with high- (10-13 points) and very high-risk (14+ points) pts having 3.2% and 4.4% ARRs in KM estimates of HHF at 4 yrs, respectively (
Fig
).

Conclusions:
A novel biomarker-based risk score for HHF in pts with T2DM identifies pts at higher risk of HHF who derive greater absolute benefit from SGLT2 inhibitors.
Abstract 12928: Vascular Complications in Covid-19 and Role of Zinc in Viral Inhibition
Authors: Zhu Donghui , Zhao Zhen
Published: May 2021

Although COVID-19 is associated with severe respiratory dysfunctions, conspicuous vascular complications and neurological manifestations have been reported worldwide. Of note, two distinctive features have been noticed in severe patients, progressive increase of inflammation and an unusual trend of hypercoagulation. Interestingly, evidence is mounting that healthy blood vessels protect children from serious effects of COVID-19, such as stroke. These findings suggest vascular complications play a key role in the progress of COVID-19, warranting an investigation to its pathophysiology and treatment strategy related to vascular cells. Cell entry of this SARS-CoV-2 virus depends on binding of the viral spike (S) proteins to cellular receptor ACE2, which could be a key target for blocking the viral entry into host cells. ACE2 is a zinc (Zn) binding metallopeptidase while Zn possesses distinct antiviral properties against many human viruses including coronaviruses. Although the mechanistic studies are lacking, Zn appears to inhibit viral protease and polymerase enzymatic processes, and physical processes such as virus attachment, cell entry, and uncoating. In fact, our data showed that ACE2 has multiple affinity binding sites for Zn. Excess bindings of ionic Zn to ACE2 led to its conformational or functional change, therefore, interfering with its ability to metabolize its substrate as well as inhibiting its binding to S protein. Computational modeling also revealed that one critical Zn binding motif is located in ACE2’s binding domain to S protein, and docking affinity of S protein to ACE2 was significantly reduced after Zn binding to this specific site. Moreover, cell and animal studies using pseudo-virus bearing CoV-2-S protein validated that significantly lower infection of vascular cells in the presence of Zn was observed. Thus, targeting vascular complications in COVID-19 may offer strong benefits including the potential therapeutic role of Zn.
Abstract 12948: Low Use of Statins in People With Type 2 Diabetes With or Without Cardiovascular Disease: A Capture Post Hoc Analysis
Authors: Arenas Jose Luis , Byram Fahri , Darmon Patrice , Davis Timothy , Dieuzeide Guillermo , Hong Tianpei , Kaltoft Margit S , Lengyel Csaba , Mosenzon ofri , Rhee Nicolai A , Russo Giuseppina T , Shirabe Shinichiro , Thamattoor Usha K , Urbancova Katerina , Vencio Sergio , Alguwaihes Abdullah
Published: May 2021

Background and aim:
The association between LDL levels, CVD and the benefits of statin use are well established. The CAPTURE study estimated the contemporary (2019) global prevalence of CVD and medication use in adults with type 2 diabetes across 13 countries. This post hoc analysis assessed serum lipid status and statin use in people with type 2 diabetes without CVD (NoCVD), with established CVD, and atherosclerotic CVD (AsCVD, a subgroup of CVD).

Methods:
CAPTURE was a multinational, cross-sectional and non-interventional study. Participant information on CVD status, serum lipid profiles, and medication use were ascertained during single routine clinical visit in primary or specialist setting. This analysis included people who had data on serum LDL-C and lipid-lowering therapies. LDL-C targets were set at <100 mg/dL (<2.6 mmol/L) and <70 mg/dL (<1.8 mmol/L) for people without and with CVD/AsCVD, respectively according to the ADA 2019 guidelines. Data were analyzed descriptively.

Results:
The CAPTURE study enrolled 9823 people aimed to be representative of the general type 2 diabetes population. Most (>80%) had blood LDL-C information. Mean serum levels of lipids varied across 3 groups. (Table) The overall use of any statin was 38% in the NoCVD, 53% in CVD, and 55% in AsCVD groups. In those with documented serum LDL-C levels, 48% in the NoCVD, 67% in CVD, and 66% in AsCVD groups were above LDL-C targets with statin use of 34%, 57%, and 60%, respectively in these participants. Overall, the use of ezetimibe was 3-8% in all the groups and usually in combination with a statin. PCSK9 inhibitors use was <0.1% and used only in participants with CVD. (Table)

Conclusion:
In conclusion, this CAPTURE post hoc analysis found that two-thirds of people with CVD and AsCVD had LDL-C levels above recommendations and only around 60% of them were on statins. Intolerability of statins might partly explain this lower than expected statin use.
Abstract 12990: High Fat Diet Delays Reverse Remodeling of Pulmonary Artery in Hypoxia-induced Pulmonary Hypertension Mice
Authors: Sugimoto Koichi , Yokokawa Tetsuro , Misaka Tomofumi , Yokokawa Sayoko , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika
Published: May 2021

Background:
Previous studies suggest the association of metabolic disorder with pulmonary hypertension. Elevated pulmonary artery pressure induced by hypoxia in mice returns to normal when they are placed back in normoxia. In this study, we investigated the effect of high-fat diet (HFD) on pulmonary artery pressure and reverse remodeling of pulmonary artery in mouse model of hypoxia-induced pulmonary hypertension.

Methods:
We used the female C57/Bl6 mice at the age of 8 weeks. After exposed to hypoxia (10% oxygen for 4 weeks) for induction of pulmonary hypertension, mice were returned to normoxic condition and fed HFD or low-fat diet (LFD) for 12 weeks.

Results:
The body weight (BW), glucose, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C), but not triglyceride (TG) were significantly increased in HFD group (36.9±5.1 vs. 24.0±1.4 g [BW], P<0.05; 404.2±55.1 vs. 326.5±8.7 mg/dl [glucose], P<0.05; 10.2±3.6 vs. 7.5±0.9 mg/dl [LDL-C], P<0.05; 47.2±10.0 vs. 30.9±8.7 mg/dl [HDL-C], P<0.05 and 40.0±21.1 vs. 53.4±12.9 mg/dl [TG], P=0.09). The right ventricular systolic pressure (RVSP) measured by a micro-manometer catheter and the Fulton index in HFD group were significantly higher than those in LFD group (23.8±2.3 vs. 19.3±2.9 mmHg [RVSP], P<0.05; 0.30±0.06 vs. 0.25±0.04 [Fulton index], P<0.05, respectively). The medial smooth muscle area (expressed as a percentage of the external area of the vessel) was larger in HFD group (40.1±5.3 vs. 34.5±3.1%, P<0.05). In addition, the levels of active caspase-3 detected by Western blotting was lower in HFD group than in LFD group. TUNEL staining revealed that the apoptosis of pulmonary artery smooth muscle cells was suppressed in HFD group.

Conclusion:
Our results suggest that metabolic disorder attenuates pulmonary artery reverse remodeling, at least in part, by suppressing apoptosis of pulmonary artery smooth muscle cells when hypoxia-induced pulmonary hypertension mice were returned to normoxia.
Abstract 12992: LA Strain Predicts Exercise Capacity in Chronic Kidney Disease
Authors: Gan Gary , Bhat Aditya , Chen Henry H.L. , Gu Kennith , Fernandez Fernando , Byth Karen , Eshoo Suzanne , Kadappu Krishna K , Thomas Liza
Published: May 2021

Background:
Left atrial (LA) function plays a pivotal role in modulating left ventricular performance particularly during exercise. The aim of our study was to evaluate the relationship between resting LA function by strain analysis as a determinant of exercise capacity in chronic kidney disease (CKD) patients, and evaluate its utility compared to exercise E/e’.

Methods:
Consecutive Stage 3 and 4 CKD patients without prior cardiac history were prospectively recruited from outpatient nephrology clinics and underwent clinical evaluation, resting and exercise stress echocardiography. Patients needed to be in sinus rhythm without significant valvular disease or ischaemia on stress testing. Resting echocardiographic parameters including E/e’ and phasic LA strain [LA reservoir (LASr), conduit (LAScd) and contractile (LASct) strain] were measured and compared to exercise E/e’.

Results:
218 (63.9±11.7yrs, 64% men) CKD patients were recruited. Independent clinical predictors of exercise capacity were age, eGFR, body mass index and gender (p<0.01 for all) while independent resting echocardiographic predictors included E/e’, LASr and LASct (p<0.01 for all). Amongst independent resting echocardiographic predictors, LASr (
r
=0.70,p<0.01) demonstrated the strongest correlation to METs achieved. Receiver operating characteristic curves (Figure 1) demonstrated that LASr (AUC 0.83,) had similar predictive value as exercise E/e’ (AUC 0.79; AUC difference of 0.05, p=0.20 on DeLong test). A model combining LASr and clinical metrics showed robust predictive capacity for METs achieved in CKD patients.

Conclusions:
LASr, a marker of decreased LA compliance is an independent predictor of exercise capacity in Stage 3 and 4 CKD patients, with similar predictive value to exercise E/e’. The use of LASr may serve as a resting biomarker of functional capacity in this population.
Abstract 13004: Spelunking for a Cause of Heart Failure: A Fungus Amongst Us
Authors: Hendren Nicholas S , Berlacher Mark , De Lemos James A
Published: May 2021

Two months prior to presenting to our facility, a 63-year-old man was diagnosed with acute pericarditis and treated with colchicine. His chest pain resolved, but he was readmitted a few weeks later with tamponade due to a large exudative pericardial effusion requiring percutaneous drainage. He was discharged on colchicine and furosemide; however, he presented to our institution two weeks later with persisting dyspnea and edema. His blood pressure was 114/84 mmHg without a pulsus paradoxus. Jugular venous pressure was 13 cm H
2
O with a prominent Kussmaul’s sign and 3+ bilateral leg edema. Further evaluation with a transthoracic echocardiogram, cardiac MRI and cardiac catheterization were all consistent with effusive-constrictive pericarditis (Fig A-F). 8-months prior to admission a mediastinal lymph node biopsy noted histoplasma. During admission, chronic histoplasmosis was suspected and a serum histoplasma antigen was reactive (1:256). He was initiated on 12 weeks of itraconazole; however, despite anti-inflammatory therapies, he had refractory congestion. Cardiothoracic surgery was consulted and he underwent pericardial stripping (Fig. G). Pericardial fungal cultures were negative and histopathology noted acute and chronic fibrinous pericarditis without fungal organisms (Fig. H-I). He had an uncomplicated recovery with symptom resolution.
Histoplasma capsulatum
is endemic to the United States and despite >80% of individuals in endemic areas demonstrating exposure, cases of pericarditis, tamponade or pericardial constriction are rare. Pericardial inflammation likely reflects an autoimmune reaction to
H. capsulatum
rather than direct pericardial infection and may respond to anti-inflammatories. In sum, we describe a rare diagnosis of effusive-constrictive pericarditis secondary to chronic histoplasmosis. Our case highlights the salient findings of pericardial constriction and the continued importance of a detailed clinical history.
Abstract 13007: Myocardial Ischemia in Anomalous Aortic Origin of a Right Coronary Artery: Medium-term Follow-up in a Large Prospective Cohort
Authors: Doan Tam T , Bonilla-Ramirez Carlos , Sachdeva Shagun , Wilkes J. Kevin , Reaves-O’neal Dana L , Noel Cory V , Masand Prakash , Mery Carlos M , Binsalamah Ziyad , Caldarone Christopher A , McKenzie E Dean , Molossi Silvana M
Published: May 2021

Introduction:
Anomalous aortic origin of a right coronary artery (AAORCA) may lead to myocardial ischemia (ISCH) and sudden death in the young. Current guidelines deem asymptomatic patients (pts) low-risk if normal exercise stress test (EST).

Hypothesis:
The frequency of ISCH in AAORCA pts is seen more commonly on stress perfusion imaging (sPI) compared to EST.

Method:
Pts <21 yrs with AAORCA were prospectively enrolled and managed following a standardized approach (12/2012-04/2020). Coronary CTA was used to define details of AAORCA. EST and sPI were performed in pts >7 yrs and in younger pts if concern for ISCH. sPI included nuclear imaging initially and dobutamine stress cardiac MRI since 06/2014. High-risk features included intramural length (IML), abnormal ostium, symptoms or evidence of myocardial ISCH. Shared decision-making directed medical/surgical management.

Results:
Of 220 pts (male 135, 61%) enrolled at median age of 12 [IQR 6-15] yrs, 168 (76%) had no/non-exertional symptoms (Group-1) and 52 (24%) had exertional chest pain/syncope (Group-2). Coronary CTA was available in 180 and EST in 164 pts. EST was positive in 2/164 (1%), both had positive sPI. Of 162 negative EST, inducible ISCH was seen in 10/96 (10%) in Group-1 and 8/42 (19%) in Group-2. No difference in IML was noted between pts with/without ISCH (5.7±2.4 vs 6.0±2.1 mm, p=0.6). Surgery was indicated in 67 (30%) pts with high-risk features, not indicated in 143 (65%), and 10 (5%) are undergoing evaluation. In 51 operated pts (38 unroofing; 13 translocation), 3 await post-operative assessment, 48 on normal physical activities; median follow-up of 4.6 [IQR 2.3-6.3] yrs. All patients were alive at last follow-up; median of 2.9 [IQR 1.2-5.1] yrs.

Conclusions:
AAORCA pts can present with reversible ISCH on sPI regardless of symptoms or IML. EST may be a poor predictor of ISCH and caution should be given to determine low-risk. Most high-risk patients return to exercise and remain well at medium-term follow-up.
Abstract 13008: Combined Assessment of American Heart Association Get With the Guidelines-heart Failure Risk Score With Plasma D-dimer and N-terminal Pro-b-type Natriuretic Peptide Levels Improves Prediction of Mortality in Patients Hospitalized for Worsening Heart Failure
Authors: Naruse Hiroyuki , Ishii Junichi , Nishimura Hideto , ohta masaya , Kawai Hideki , Muramatsu Takashi , Harada Masahide , Hayashi Mutsuharu , Yamada Akira , Motoyama Sadako , Sarai Masayoshi , Watanabe Eiichi , Ozaki Yukio , Izawa Hideo
Published: May 2021

American Heart Association Get With the Guidelines-Heart Failure (GWTG-HF) risk score is a useful multivariable score model to predict mortality in patients with acutely decompensated heart failure. We prospectively investigated the prognostic value of combined assessment of GWTG-HF risk score with D-dimer and N-terminal pro-B-type natriuretic peptide (NT-proBNP).

Methods:
On admission, we measured plasma D-dimer and NT-proBNP levels in 1735 patients (mean age, 75 yrs) hospitalized for worsening heart failure. GWTG-HF risk score, including race, age, systolic blood pressure, heart rate, blood urea nitrogen level, sodium concentration, and presence of chronic obstructive pulmonary disease, was calculated at admission.

Results:
During a follow-up period of 12 month after admission, 371 (21%) deaths occurred. Patients who died were older (mean: 78 vs. 74 years; P<0.001), had a higher frequency of NYHA functional class IV (63 vs. 49%; P<0.001), higher values of GWTG-HF risk score (43 vs. 38; P<0.001), D-dimer (2.90 vs. 1.30 μg/mL; P<0.001), and NT-proBNP (7202 vs. 3689 pg/mL; P<0.001) than survivors. In the multivariate logistic analysis, elevation (more than the highest tertile value) in D-dimer (>2.5 μg/mL; P<0.001), NT-proBNP (>7399 pg/mL; P<0.001), and GWTG-HF risk score (>42 point; P<0.001) were independently associated with mortality within 12 months. Furthermore, adding D-dimer and NT-proBNP to the GWTG-HF risk score improved the C-index (P<0.01), net reclassification improvement (P<0.001), and integrated discrimination improvement (P<0.001) greater than GWTG-HF risk score alone. The number of elevation in GWTG-HF risk score, D-dimer, and NT-proBNP was strongly associated with a higher risk of mortality within 12 months (
Figure
).

Conclusion:
The combined assessment of GWTG-HF risk score with D-dimer and NT-proBNP facilitates the risk stratification for mortality within 12 months in patients hospitalized for worsening heart failure.
Abstract 13023: Incremental Diagnostic Accuracy of Hybrid Single Photon Emission Computed Tomography Coronary Angiography in Suspected Coronary Artery Disease
Authors: Hachiya Shoko , Kosuge Hisanori , Fujita Yasuhiro , Hida Satoshi , Chikamori Taishiro
Published: May 2021

Background:
Single-photon emission computed tomography (SPECT) and computed tomography coronary angiography (CTCA) are often undertaken independently in patients with suspected coronary artery disease (CAD).

Hypothesis:
We assessed the hypothesis that hybrid SPECT/CTCA imaging results in higher diagnostic accuracy than either method alone, allowing some false positives to be ruled out in the non-invasive testing phase.

Methods:
A total of 129 vessels (43 patients) were screened by SPECT with cadmium-zinc-telluride semiconductors and CTCA with a 256-detector row CT of the right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex (LCX) segments. Patients who were diagnosed with myocardial ischemia then went on to undertake CAG. A diameter stenosis > 50% and any non-diagnostic segment in CTCA were considered abnormal. CAG results were classified as positive for stenosis when either a diameter stenosis was over 75% or fractional flow reserve was under 0.8. These were then compared to an image fusion of SPECT and CTCA data sets performed on a dedicated workstation. The results were categorised as a match or a mismatch (same as or different to the CAG, respectively).

Results:
Matched findings at SPECT, CTCA, and hybrid imaging were found in vessels of 75%, 67%, and 92%, respectively. Compared to the individual diagnostic performance of SPECT or CTCA in detecting significant CAD, hybrid imaging exhibited greater results in all of sensitivity, specificity, and accuracy (Fig 1). Segmental reclassification of perfusion abnormalities by hybrid imaging occurred at 10% for LAD, 56% for LCX, and 5% for RCA. Moreover, hybrid imaging allowed for accurate diagnosis of 22 vessels with severe calcification which CTCA alone could hardly evaluate correctly (Fig 2).

Conclusions:
Hybrid imaging showed higher diagnostic accuracy compared to single modalities, enabling physicians to make better decisions about the necessity for invasive CAG procedure.
Abstract 13025: Methotrexate Carried in Lipid Core Nanoparticles Prevented the Dilation and Dissection of the Aortic Arch in Mice With Marfan Syndrome by Increasing the Bioavailability of Intracellular Adenosine
Authors: Guido Maria Carolina , Lopes Natalia M , Albuquerque Camila I , Tavares Elaine R , Jensen Leonardo , Pereira Lygia V , Laurindo Francisco R , Maranhao Raul C
Published: May 2021

Introduction:
Mutations in the fibrillin-1 gene result in aneurysms and rupture of the aorta, the main cause of mortality in patients with Marfan syndrome (MFS). Inflammation is associated with dissection and rupture of the aorta. We showed that methotrexate (MTX) carried in lipid core nanoparticles (LDE) had powerful anti-inflammatory effects on atherosclerotic lesions and myocardial infarction.

Hypothesis:
To investigate whether treatment with LDE-MTX can prevent the development of aortic arch lesions in MFS.

Methods:
mgΔloxPneo MFS murine model and wild-type mice were allocated in 3 groups of treatment: LDE only; MTX in commercial formulation; LDE-MTX. The treatment occurred weekly at a dose of 1mg/kg ip, between the 3rd and 6th month of life, period in which both dilation and dissection of the aortic arch are observed. After 12 weeks, animals were submitted to analysis of the aortic arch.

Results:
Compared to LDE and MTX groups, LDE-MTX treatment showed smaller lumen area of ascending and descending aorta and aortic arch segments in MFS mice. LDE-MTX also decreased collagen volume fraction and the amount of aortic dissections, but did not affect the thickness of the vessel wall and the number of elastic fiber ruptures. Protein expression of the inflammatory markers CD68 (macrophages), CD3 (lymphocytes) and tumor necrosis factor alpha, of the apoptotic marker caspase 3 and of type 1 collagen were lower in LDE-MTX group when compared to LDE and MTX. Moreover, treatment with LDE-MTX reduced TGF-β, ERK and SMAD3 protein expression. Of note, CD68 and CD3 protein expression were positively correlated with the lumen area of the aortic arch (r2=0.36; p<0.001), indicating the importance of inflammation for the aortic dilation. The increase in bioavailability of intracellular adenosine was suggested by higher expression of A2a adenosine receptor and lower levels of adenosine deaminase in the aortic arch.

Conclusions:
Possibly by increasing the bioavailability of intracellular adenosine, LDE-MTX treatment had the ability to reduce the processes of inflammation, apoptosis and fibrosis that are consequent to fibrillin-1 mutation. By these means, LDE-MTX may conceivably prevent the development of the dilation and dissection in the aortic arch, the hallmarks of MFS.
Abstract 13026: Homogeneous 2D and 3D Alignment of Cardiomyocytes in Dilated Cardiomyopathy Revealed by Intravital Heart Imaging
Authors: Masuyama Kiyoshi , Higo Tomoaki , Lee Jong-Kook , Miyagawa Shigeru , Sawa Yoshiki , Sakata Yasushi
Published: May 2021

Background:
In contrast to hypertrophic cardiomyopathy, there has been reported no specific pattern of cardiomyocyte array in dilated cardiomyopathy (DCM). This might be because it is assessed only on heart tissue sections two-dimensionally (2D). To address this, we sought to evaluate cardiomyocyte alignment in DCM three-dimensionally (3D) using intravital heart imaging techniques.

Methods and Results:
We observed cardiomyocytes of membrane fluorescent reporter mice up to 100μm depth by an intravital imaging system with two-photon microscopy. On each 2D images taken at 1μm interval, the angles of cardiomyocytes from a vertical line were measured and their distribution was plotted. Then the plots of all layers were merged so that layer-to-layer change of angle distribution can be visualized. In these merged plots, cardiomyocytes exhibited several peaks with a certain spread around each peak, suggesting that cardiomyocytes change their alignments by every layer in 3D and position twistedly even in a single layer (Figure). We next assessed cardiac mutant Troponin T knock-in mice as a DCM model. The angle distribution in these mice was less various within a single layer and between layers as well. These results indicate that cardiomyocytes of DCM model mice align homogeneously both in 2D and in 3D. To determine how homogeneous alignment contributes to cardiomyocyte contractility, we captured the motion of cultured cardiomyocytes and found that cardiomyocytes seeded on the top of linearly aligned fibers show greater motion than those seeded on randomly aligned fibers.

Conclusion:
Using intravital imaging, we have provided a first evidence of cardiomyocyte array in 3D and demonstrated that cardiomyocytes of DCM model mice align homogeneously both in 2D and in 3D. Homogeneous alignment of those mice might be the consequences of impaired cardiac function as a way to increase let ventricular contractility.
Abstract 13027: Differential Direct Effects of Equal Hypotensive Natriuretic Peptides (NPs) of ANP, BNP and CNP on Left Ventricular Contractile Performance in Heart Failure: Assessment by Left Ventricular Pressure-Volume Analysis
Authors: Cheng Che , Zhang Zhi , Li Tiankai , Zhang Xiaowei , Sun Xiaoqiang , Cao Jing , Herrington David M , Zhao David X , Cheng Heng Jie
Published: May 2021

Background:
Natriuretic peptides (NPs) play a crucial role in maintaining cardiovascular homeostasis. NPs stimulate the production and release of cGMP, leading to the vasodilating and natriuretic actions. In heart failure (HF), circulating and cardiac ANP, BNP, and CNP are increased and exhibit a range of actions. However, although they serve as therapeutic agents, their direct cardiac effects in HF are uncertain due to the confounding influence of NPs-produced changes in loading condition on conventional measures of LV function. We test the hypothesis that equal hypotensive 3 NPs may have different inotropic effects on LV contractility and relaxation in HF.

Methods:
We assessed the cardiac effects of intravenous infusion (20 min) of ANP (2 μg/kg plus 0.5 μg/kg/min), BNP (2 μg/kg plus 0.04 μg/kg/min) and CNP (2 μg/kg plus 0.4 μg/kg/min) on different days in 6 instrumented conscious dogs with pacing-induced HF by using pressure (P)-volume (V) analysis, a load-independent measure of LV contractility.

Results:
Versus baselines, 3 NPs produced arterial vasodilation with similar and significant decreases in LV end-systolic pressure (10 to 12 mmHg) with relatively unchanged heart rate. ANP caused significant reductions (13%) of E
ES
(4.2 vs 4.8 mmHg/ml) and M
SW
(54.6 vs 62.8 mmHg). The time constant of LV relaxation (τ, 45.1 vs 37.6 ms) was lengthened. The LV-arterial coupling, E
ES
/ E
A
(arterial elastance) (0.57 vs 0.58) was unaltered. The peak mitral flow, dV/dt
max
was only increased by 7% (178 vs 166 ml/s). With BNP, there were no significant changes in E
ES
(5.1 vs 4.9 mmHg/ml) and M
SW,
but E
ES
/E
A
was improved 30% (0.74 vs 0.57) due to decreased E
A
. τ (33.4 vs 37.9 ms) was significantly shortened and dV/dt
max
increased 15% (189 vs 165 ml/s). In contrast, CNP produced significant increases (~30%) in E
ES
(6.3 vs 4.8 mmHg/ml) and M
SW
(80.5 vs 62.4 mmHg) with enhanced increase in E
ES
/E
A
(50%, 0.87vs 0.58), but decrease in τ (25%, 28.4 vs 38.1 ms) and significantly greater augmented dV/dt
max
(25%, 205 vs 164 ml/s). Similar observations of NPs were made at constant heart rate, or after autonomic blockade.

Conclusion:
In conscious dogs with HF, equal hypotensive ANP, BNP and CNP have negative, no effect, and positive inotropic effects on LV contractility and relaxation, respectively.
Abstract 13031: Universal Screening for Familial Hypercholesterolemia in Young Adults: The Young FH Study
Authors: Okazaki Sachiko , Takase Satoru , Tanaka Masaki , Kubota Midori , Amiya Eisuke , Takanashi Mikio , Li Chengcheng , Shi Jingxuan , Noto Hiroshi , Iizuka Yoko , Yanagimoto Shintaro , Kadowaki Takashi , Yamauchi Toshimasa , Okazaki Hiroaki
Published: May 2021

Introduction:
Familial hypercholesterolemia (FH) is caused by genetic defects in low-density lipoprotein (LDL) receptor pathway, resulting in a persistent elevation of plasma LDL-cholesterol (LDL-C) levels as well as an increased risk of cardiovascular diseases. Early diagnosis and treatment are imperative for its management. Currently, FH patients are mainly identified by cascade screening. However, FH is underdiagnosed and undertreated, particularly in young adults, which warrants a systematic screening strategy.

Hypothesis:
Considering that the prevalence of FH is high (~0.4% in the general population) and that treatment of FH should be initiated earlier at the latest in young adults, we hypothesized that the universal screening of LDL-C in young adults is beneficial for early diagnosis and treatment of FH.

Methods:
At the University of Tokyo, plasma LDL-C levels have been measured at heath checkups for employees as well as new students. Young adults (18-30 years old) with hypercholesterolemia (LDL-C ≥ 160 mg/dL) identified by universal screening and referred to the University of Tokyo Hospital were eligible (the Young FH study). Those who have been identified by cascade screening were excluded. Mutation in FH-causing genes, as well as clinical and biochemical parameters useful for the clinical diagnosis of FH, were analyzed. The protocol was approved by the human genome, gene analysis research ethics committee of the University of Tokyo.

Results:
Of the total participants (n = 89, mean age 23.4 ± 3.4 years), 36 (40%) had mutations in
LDLR
or
PCSK9
. The prevalence of mutation carriers was higher in non-obese than in obese participants (47% for body mass index (BMI) < 24 kg/m
2
vs. 26% for BMI ≥ 24). The sensitivity and specificity of clinical diagnosis were 28% and 85%, respectively, by Dutch Lipid Clinic Network Criteria (definite + probable FH), or 22% and 98%, respectively, by Japanese diagnostic criteria of FH.

Conclusions:
The universal screening of LDL-C effectively identifies FH high-risk patients in Japanese young adults. This screening may be beneficial in countries with low-prevalence of obesity or in non-obese populations. The use of clinical diagnostic criteria of FH for universal screening may lead to underdiagnosis.
Abstract 13038: Utility of Left Atrial Strain Mechanics and Stiffness in Patients With Hypertrophic Cardiomyopathy
Authors: Saijo Yoshihito , Van Iterson Erik H , Vega Brizneda Maria , Desai Milind Y , Lever Harry M , Smedira Nicholas G , Wierup Per , Thamilarasan Maran , Popovic Zoran B , Grimm Richard A , Griffin Brian P , Xu Bo
Published: May 2021

Introduction:
Llittle is known about the relationship between LA strain mechanics and exercise intolerance in hypertrophic cardiomyopathy (HCM), or whether LA strain mechanics might serve as novel imaging markers in predicting the need for septal myectomy.

Hypothesis:
LA mechanical dysfunction would be associated with impaired exercise capacity and clinical deterioration necessitating septal myectomy in HCM.

Methods:
Consecutive patients with HCM who underwent exercise stress echocardiography and cardiopulmonary exercise testing between October 2015 and April 2019 were enrolled prospectively. LA structure parameters (maximum and minimum LA volume indices) and LA function parameters were measured. LA strain mechanics (reservoir, conduit and contractile strains) were analyzed by speckle tracking echocardiography. LA stiffness was calculated as the ratio of E/e’ to reservoir strain. Based on the quartile of percent-predicted peak VO
2
, the study cohort was divided into four groups. Exercise intolerance was defined as the lowest quartile of percent-predicted peak VO
2
(≤52%).

Results:
Of 536 HCM patients studied (mean age: 51 ± 15 years, 42% female), 212 (40%) demonstrated exercise intolerance. Receiver operating characteristics analysis demonstrated LA contractile strain, using a cut-off of 13.8%, to be optimal for predicting exercise intolerance (AUC: 0.68, p <0.001). On multivariable logistic regression analysis, impaired LA contractile strain was an independent predictor for exercise intolerance (p <0.001). Among 258 patients who were followed up at our center, patients with LA stiffness worse than the median value (≥0.41) had significantly higher probability of requiring myectomy, compared with those with LA stiffness below the median (p = 0.02,
Figure
).

Conclusions:
Impaired LA contractile strain was an independent predictor of exercise intolerance in HCM. Patients with worse LA stiffness were more likely to require septal myectomy.
Abstract 13048: Do Anti-HLA Antibodies Pre-heart Transplant Truly Impact Post-transplant Outcomes?
Authors: Ho Timothy , Patel Jignesh K , Nishihara Keith , Kittleson Michelle M , Chang David H , Kransdorf Evan P , Czer Lawrence S , Zhang Xiaohai , Kobashigawa Jon A
Published: May 2021

Introduction:
Antibody-mediated rejection (AMR) continues to be a major barrier to favorable long-term outcomes and long-term survival. Sensitized pre-heart transplant (HTx) patients, those with anti-HLA antibodies, have previously demonstrated increased post-HTx rejection risk as well as increased mortality. In the current era, there is contention as to whether pre-HTx antibodies result in poor outcome after HTx.

Methods:
Between 2010 and 2015, 580 HTx patients were assessed for pre-HTx panel reactive antibodies (PRA). PRA levels were measured by the Luminex Single Antigen assay. Patients were divided into 5 groups of PRA levels including 0%, n=423 (Control); PRA 1-10%, n= 21; PRA 11-25%, n=24; PRA 26-50%, n=49; PRA 51-75%, n=32; and PRA >75%, n=35. Endpoints included 5-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events (NF-MACE), freedom from donor specific antibody (DSA) development, and freedom from LV dysfunction (LV ejection fraction ≤40%) and 1-year freedom from rejection (any treated rejection (ATR), acute cellular rejection (ACR), AMR).

Results:
All groups with PRA >10% had significantly lower 1-year freedom from AMR and 5-year freedom from DSA compared to the control, worsening with higher the PRA group. There was no significant difference in 5-year survival, 5-year freedom from CAV, NF-MACE, or LV dysfunction and 1-year freedom from ATR or ACR.

Conclusions:
Patients with increased anti-HLA antibody levels pre-HTx do not appear to have lower 5-year survival compared to patients without anti-HLA antibody levels. However, the development of 1-year AMR and 5-year DSA increased progressively with higher the PRA group. Further studies and longer follow-up are needed to better understand the effects of elevated pre-HTx PRA, immune therapies (desensitization) and post-HTx outcomes.
Abstract 13050: Acute Alcohol-Induced Enhanced Cardiac Depression in a Canine Model of Chronic Alcohol Consumption: Adverse Effects on Left Ventricle and Myocyte Contraction, [Ca
2+
]
i
Transient and Ca
2+
Current
Authors: Zhang Zhi , Cheng Che , Masutani Satoshi , Li Tiankai , Zhang Xiaowei , Sun Xiaoqiang , Cao Jing , Herrington David M , Cheng Heng Jie
Published: May 2021

Background:
Acute alcohol ingestion produces transient RAS activation. Alcoholics have an enhanced RAS activation after acute ethanol ingestion. Thus, chronic alcohol users may have enhanced cardiac functional responses to acute alcohol intake. However, it is unclear whether and how chronic alcohol intake alters cardiac response to acute alcohol exposure. We tested the hypothesis that acute alcohol may exacerbate cardiac depression and [Ca
2-
]
i
dysregulation, thus play important role in development of irreversible cardiomyopathy in alcoholics.

Methods:
We compared LV and cardiomyocyte response to acute alcohol in 6 chronically-instrumented conscious dogs before and 6 months after the once daily ingestion of alcohol (400 ml, 22% providing 33% of total daily caloric intake).

Results:
In conscious dogs, 6 months of alcohol significantly decreased LV contractility by 48% measured by the slopes of pressure-volume relations (E
ES
, 48%, 4.4 vs 8.4 mmHg/ml and M
SW
, 50.8 vs 98.6 mmHg) and increased the time constant of relaxation (τ, 78%, 47.8 vs 26.9 ms). In the alcoholic animals, when compared with the same animals prior to alcohol, acute alcohol (0.2 g/kg, iv, plasma level 62.3 ± 8 mg/dL) caused a greater decrease in LV contractility (47% vs 23%) and increase in τ (27% vs11%). In isolated myocytes, abrupt exposure to alcohol (250 mM) produced significant decreases in cell contraction, [Ca
2+
]
i
transient ([Ca
2+
]
i
) and Ca
2+
current (I
Ca,L
) in both normal and alcoholic myocytes. However, compared with the isolated cells obtained from LV biopsied tissues of the same animals prior to alcohol, the acute alcohol-induced decrease in I
Ca,L
(alcoholic: 50%, 1.3 vs 2.6; normal: 29%, 4.0 vs 5.6 pA/pF) was much greater in the alcoholic myocytes, the resulting reductions in the cell contractility, dL/dtmax (alcoholic: 46%, 36vs67; normal: 24%, 82vs108 μm/s), the percent shortening (49% vs 24%) and relengthening, dR/dtmax were doubled.

Conclusion:
In chronically alcohol-fed dogs, acute alcohol produces increased direct inhibition in LV and myocyte contractility, relaxation and exacerbates [Ca
2+
]
i
hemostasis. The chronic alcohol-induced increased cardiac sensitivity to acute alcohol may play an important role in the functional impairment in alcoholic cardiomyopathy.
Abstract 13067: When Are 3 ECG Leads Better Than 12? Streamlining and Optimizing ECG Assessment in Sudden Death Prediction
Authors: Ruedisueli Isabelle , Ma Joyce , Lakhani Karishma , Nguyen Randy , Gornbein Jeffrey , Middlekauff Holly R
Published: May 2021

Introduction:
Prolonged Tpeak to Tend (Tp-e) interval, an index of repolarization on the 12-lead ECG, is associated with increased risk for sudden cardiac death. However, there is no current consensus on which of the 12 leads is the most sensitive to measure the longest Tp-e interval.

Aim:
The aim of this study was to measure all 12 ECG leads and to analyze whether there are leads that are most sensitive to detect prolongation of Tp-e in order to optimize methodology for future investigations.

Methods:
Fifteen healthy volunteers (F/M 6/9; mean age 25 yrs) were included in our study. We recorded the 12-lead ECG for 5-minutes. Tp-e was defined as the interval from the peak of the T wave to the end of the T wave. QT is the interval from QRS complex onset to the end of the T wave. Using commercially available software (AdInstruments), three primary outcomes, Tp-e interval, Tp-e/QT, Tp-e/QTc ratios, and two secondary outcomes, QT, QTc intervals, were determined.

Results:
The location of maximum value for primary outcomes (Tp-e, Tp-e/QT, Tp-e/QTc) were not evenly distributed across the 12 leads, but most frequently was located in leads V2, V3 & V4. The maximum Tp-e was located in one of these three leads 79.7% of the time (CI 69.4, 89.9%) vs other leads (p=0.007, Figure). Conversely, maximum values for the secondary outcomes (QT, QTc) were located in AVL, AVR and III (Figure). Two of the leads, V5 and V6, never had a maximum value for any outcomes.

Conclusion:
Preliminary findings in our study suggest that investigators should focus on leads V2, V3 & V4 to detect prolongation of Tp-e intervals and leads AVL, AVR & III for prolongation of QT interval when investigating associations with sudden cardiac death.