bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13183: A Novel Model of in vivo Platelet Thrombus Imaging Using CD41-ZsGreen1 Transgenic Rats
Authors: Mizuno Makoto , Tomizawa Atsuyuki , Ohno Kousaku , Jakubowski Joseph A. , Sugidachi Atsuhiro
Published: July 2021

Introduction:
Platelets play important roles in both hemostasis and thrombotic diseases including myocardial and cerebral infarction, and stent thrombosis. While mice models of in vivo fluorescence imaging have been described, there are few suitable in vivo models for platelet imaging in rats which are commonly used as thrombosis models. The objective of this study was to generate fluorescent platelets and assess their dynamics in injured arteries in rats.

Methods:
We generated CD41-ZsGreen1 transgenic (TG) rats, in which the green fluorescence protein ZsGreen1 was expressed specifically in megakaryocytes and thus platelets, and evaluated platelet dynamics in in vivo thrombus imaging experiments. Hematological, including platelet aggregation and blood clotting time, and biochemical parameters were analysed. In the imaging experiments, saphenous arteries of TG rats were injured with 10% FeCl
3
, and thrombus formation was evaluated as fluorescence accumulation using confocal microscopy. The effect of prasugrel, a thienopyridine ADP receptor antagonist, on thrombus formation was also evaluated.

Results:
The CD41-ZsGreen1 TG rats exhibited normal hematological and biochemical values with the exception of body weight and erythroid parameters, which were significantly lower than those in wild type (WT) rats. Platelet aggregation, induced by 20 μM ADP or 10 μg/mL collagen, and blood clotting times (APTT and PT) were not significantly different between TG and WT rats. In thrombus formation experiments, FeCl
3
application caused a time-dependent increase in fluorescence intensity in the injured artery in vehicle-treated rats. Prasugrel at an oral dose of 3 mg/kg, treated 2 h before the FeCl
3
application, significantly inhibited fluorescence accumulation compared to the vehicle-treatment group (14.9±2.4 vs 5.4±0.4 arbitrary fluorescence unit at 30 min for vehicle and prasugrel groups, respectively, n=8, p=0.0037).

Conclusions:
CD41-ZsGreen1 TG rats represent a useful animal for the in vivo imaging of platelet participation in thrombus formation and the evaluation of antithrombotic agents.
Abstract 13192: Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, Ameliorates Endothelial Dysfunction and Atherogenesis in Apolipoprotein-e Deficient Mice Through GLP-1 Dependent and Independent Manners
Authors: Salim Hotimah M , Fukuda Daiju , Higashikuni Yasutomi , Tanaka Kimie , Hirata Yoichira , Yagi Shusuke , Soeki Takeshi , Shimabukuro Michio , Sata Masataka
Published: July 2021

Background:
The dipeptidyl peptidase-4 (DDP-4) inhibitors are a novel class of drug for the treatment of diabetes mellitus. Several studies suggested that their anti-inflammatory effects contribute to the prevention of cardiovascular complication of diabetes. This study aimed to investigate whether linagliptin, a xanthine-based DPP-4 inhibitor, attenuates endothelial dysfunction and prevents subsequent atherogenesis in non-diabetic apolipoprotein-E deficient (ApoE KO) mice.

Methods and Results:
Linagliptin (10 mg/kg/day) was administered orally to 8-week-old ApoE KO mice for 20 weeks. Linagliptin administration reduced atherosclerotic lesion progression in the aortic arch as determined by en-face Sudan IV staining compared with the control group (P<0.05) without the alteration of metabolic parameters including blood glucose level. Plasma active GLP-1 was significantly higher in the treated group. Histological and quantitative RT-PCR analyses demonstrated that linagliptin decreased macrophages accumulation and the expression of inflammatory molecules (e.g; MCP-1 and VCAM-1) in atherosclerotic aorta (P<0.05, respectively). Furthermore, linagliptin significantly attenuated the impairment of endothelial function in ApoE KO mice, as determined by acetylcholine-dependent vasodilation. These vasoprotective effects of linagliptin were associated with the decreased ROS generation as determined by urinary 8-OHdG level and the expression of NOX-2, in the abdominal aorta. Incubation of aortic segments from C57BL/6 mice with exendin-4 (Ex-4), a GLP-1 analogue, ameliorated palmitic acid (PA)-induced impairment of endothelium-dependent vasodilation. Ex-4 ameliorated impaired phosphorylation of Akt and eNOSSer1177 caused by PA in human umbilical vein endothelial cells (HUVECs). In addition, linagliptin directly attenuated PA-induced and eNOSSer1177 phosphorylation in HUVECs.

Conclusion:
Linagliptin inhibited the development of atherogenesis in non-diabetic ApoE KO mice. Our results suggested that linagliptin ameliorated endothelial dysfunction and oxidative stress through GLP-1 dependent and independent manners
Abstract 13252: High-sensitivity Troponin T is a Useful Biomarker of Hemodynamics Response After Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Kimura Mai , Kohno Takashi , Kawakami Takashi , Inohara Taku , Takei Makoto , Tsugu Toshimitsu , Kataoka Masaharu , Murata Mitsushige , Maekawa Yuichiro , Fukuda Keiichi
Published: July 2021

Introduction:
Balloon pulmonary angioplasty (BPA) improves hemodynamics in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Cardiac troponin is a marker of ongoing myocardial damage, and reflects hemodynamics in patients with left-heart failure. However, the clinical significance of cardiac troponin in CTEPH patients treated with BPA was unknown. We hypothesized that cardiac troponin is a surrogate marker of hemodynamic response in CTEPH patients who underwent BPA.

Methods and Results:
We analyzed 63 consecutive CTEPH patients who underwent BPA procedures, and measured high-sensitivity troponin T (hsTnT) level using electrochemiluminescence immunoassay before and after BPA from November 2012 to May 2015 (age; 62.8±14.3 years, female; n=41, number of target vessels per patient; 13.3±2.4, total sessions per patient; 5.9±1.9). Elevation of baseline hsTnT was associated with older age (p<0.05). Patients with baseline hsTnT level > median value (0.012 ng/ml) was associated with higher right atrium pressure (7.5±3.8 vs 5.9±2.2 mmHg, p<0.05), mean pulmonary artery pressure (mPAP; 41.4±11.0 vs 34.9±9.6 mmHg, p<0.05), pulmonary vascular resistance (PVR; 926.7±663.3 vs 731.1±931.8 dynes•sec•cm-5, p<0.05) and lower pulmonary capillary wedge pressure (8.2±2.9 vs 10.4±4.9 mmHg, p<0.05) and six-minute walk distance (265.9±98.9 vs 342.0±80.9 m, p<0.05), but not associated with cardiac output. BPA improved mPAP (from 38.1±10.7 to 21.1±5.6 mmHg, p<0.05) and PVR (from 823.6±828.2 to 292.8±129.6 dynes•sec•cm-5, p<0.05). HsTnT significantly decreased after BPA (from 0.015±0.012 to 0.012±0.009 ng/mL; p<0.05). Based on change of HsTnT after BPA, we divided the patients into two groups: HsTnT-decrease group (n=34) and HsTnT-increase or stable group (n=29). HsTnT-decrease group showed greater decreases in mPAP and PVR (delta mPAP 20.1±10.3 vs 13.3±11.3 mmHg, p<0.05, delta PVR 686.4±982.6 vs 352.3±452.5 dynes•sec•cm-5, p<0.05) after BPA.

Conclusions:
HsTnT level is a useful biomarker of hemodynamics severity, and change of hsTnT reflected improvement of hemodynamics in CTEPH patients who underwent BPA. Serial measurements of hsTnT could be a less-invasive and useful strategy to monitor therapeutic impact of BPA.
Abstract 13297: Short-Term Mortality in Patients With Myocardial Injury and Myocardial Infarction Type 1 and Type 2
Authors: Sarkisian Laura , Saaby Lotte , Poulsen Tina S , Gerke Oke , Diederichsen Axel C , Jangaard Nikolaj , Hosbond Susanne , Thygesen Kristian , Mickley Hans
Published: July 2021

Introduction:
Troponin elevations occur in a myriad of clinical conditions other than myocardial infarction (MI) and imply a poor prognosis. So far, data comparing the short-term outcome in patients with myocardial injury vs. patients with type 1 or type 2 MI are not available.

Methods:
Over a 1-year period we prospectively studied hospitalized patients having cardiac troponin I (cTnI) measured on clinical indication. The diagnosis of type 1 and type 2 MI was according to the universal definition involving a rising and/or falling pattern of cTnI values above the decision limit of 30 ng/L. cTnI elevations above this limit in patients without overt myocardial ischemia were defined as myocardial injury. A 1-month follow-up was done with mortality as endpoint.

Results:
The study covered 1577 consecutive patients with cTnI values >30 ng/L, of whom 360 had a type 1 MI, 119 a type 2 MI and 1089 had myocardial injury. Type 1 MI patients were younger with a median age of 70 (IQR 61-81) yrs, whereas the median ages in type 2 MI and myocardial injury were higher but comparable : 78 (IQR 67-84) vs. 77 (IQR 67-85) yrs. Peak cTnI values, however, were highest in type 1 MI: 3820 (530-19030) ng/L, lower in type 2 MI: 850 (390-3270) ng/L, and smallest in patients with myocardial injury: 90 (50-270) ng/L (p=0.0001). At one-month follow-up 285 patients had died. Mortality in the different subgroups was: 9% (33/360) in type 1 MI, 24% (28/119) in type 2 MI, and 21% (224/1089) in patients with myocardial injury. The results are depicted in the figure (Kaplan-Meier curves, log-rank-test; p-value <0.0001). Multivariate COX regression analysis revealed a Hazard Ratio (95%) of 2.1 (1.2-3.7) for type 2 MI and 1.4 (0.9-2.1) for myocardial injury.

Conclusion:
The short-term mortality in patients with myocardial injury and type 2 MI is almost identical but higher than in patients with type 1 MI. These prognostic findings imply that the clinical distinction between myocardial injury and type 2 MI may be somewhat artificial.
Abstract 13344: Beneficial Effects of Long-acting Nifedipine on Coronary Vasomotion Abnormalities After Drug-Eluting Stent Implantation -The NOVEL Study
Authors: Tsuburaya Ryuji , Takahashi Jun , Nakamura Akihiro , Nozaki Eiji , Sugi Masafumi , Yamamoto Yoshito , Hiramoto Tetsuya , Horiguchi Satoru , Inoue Kanichi , Goto Toshikazu , Kato Atsushi , Shinozaki Tsuyoshi , Shimokawa Hiroaki
Published: July 2021

Introduction:
It is widely known that drug-eluting stents (DES) induce coronary vasomotion abnormalities. We have previously demonstrated that chronic treatment with long-acting nifedipine, which exerts cardiovascular protective effects through inhibition of vascular inflammation, suppresses DES-induced abnormal coronary vasoconstriction in pigs. In order to test whether this is also the case in humans, we performed a prospective, randomized, multicenter trial, termed as the NOVEL Study.

Methods and Results:
We enrolled 146 patients with stable angina pectoris who underwent elective implantation of everolimus-eluting stents (EES) in the left coronary arteries. They were randomly assigned to receive either conventional treatments alone (aspirin, clopidogrel, renin-angiotensin system inhibitor and statin) or additionally long-acting nifedipine (10-60 mg/day) (n=73 each). After 8-10 months, 53 patients in the control and 57 in the nifedipine group were finally examined for coronary reactivity to intracoronary acetylcholine (ACh) by quantitative coronary angiography after 48-hour withdrawal of nifedipine. Baseline patient characteristics and procedural profiles were comparable between the two groups. Coronary vasoconstricting responses to ACh were significantly enhanced at the distal segment adjacent to EES as compared with non-stented vessel (P<0.001) and were significantly inhibited in the nifedipine group (P<0.01) (Figure). Furthermore, the inflammatory profiles, including serum levels of high-sensitivity CRP and adiponectin, were improved only in the nifedipine group (P<0.05) (Figure).

Conclusions:
These results indicate that DES-induced coronary vasomotion abnormalities still remain an important clinical issue even with the second-generation of DES, for which long-acting nifedipine exerts beneficial effects associated with its anti-inflammatory effects.
Abstract 13449: Cd40 Contributes to Renal Fibrosis in Experimental Renal Ischemia
Authors: Haller Steven T , Folt David A , Kumarasamy Sivarajan , Upadhyaya Siddhi , Shapiro Joseph I , Joe Bina , Cooper Christopher J
Published: July 2021

Introduction:
Cd40 has been implicated in renal injury following activation by its ligand (sCD40L), which is released from activated platelets. Previously we have shown that patients with renal ischemia have elevated levels of sCD40L and circulating levels of CD40 predict changes in renal function. We created a novel Cd40 mutant on the background of the genetically hypertensive Dahl S rat (S rat), which is prone to the development of renal disease, in order to determine the role of Cd40 in ischemic renal disease.

Hypothesis:
Cd40 induces renal fibrosis in renal ischemia.

Methods:
A novel Cd40 mutant, with targeted disruption of Cd40, was created in the S rat using the zinc-finger nuclease method. Male Cd40 mutant rats weighing between 250-300 g were used (n=8). Eight S rats were used as age-matched controls. Western blot analysis, trichrome staining, and immunohistochemistry were performed on kidney tissue derived from Cd40 mutants and S rats four weeks following two-kidney one clip (2K1C) surgery. Renal function was determined by urinary protein excretion (UPE), and creatinine measurements.

Results:
The Cd40 mutants when compared to S rats exhibited significantly lower systolic blood pressure four weeks following 2K1C surgery (130 ± 6 vs. 155 ± 4 mmHg, p<0.01). Kidney tissue derived from the clipped ischemic kidneys showed a substantial decrease in fibrosis in the Cd40 mutants compared to S rat controls as assessed by trichrome staining (p<0.01), which was confirmed by collagen-1 expression. The Cd40 mutants also exhibited a significant decrease in UPE (173.2 ± 18.8 vs. 230.6 ± 17.4 mg/24hrs, p<0.05) and creatinine (0.85 ± 0.03 vs. 1.00 ± 0.06 mg/dL, p<0.05) compared to S rat controls.

Conclusions:
Mutation of the Cd40 gene decreases renal fibrosis and improves renal function following renal ischemia. Our results indicate that Cd40 contributes to ischemic renal fibrosis and provides a mechanistic rationale for the development of renal dysfunction in ischemic renal disease.
Abstract 13457: ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk: Implications for US Hispanics/Latino Based on fFndings From the HCHS-SOL
Authors: Qureshi Waqas , Kaplan Robert C , Swett Katrina , Burke Gregory , Davilgus Martha , Jung Molly , Talavera Gregory A , Chirinos Diana A , Reina Samantha A , Davis Sonia , Rodriguez Carlos
Published: July 2021

Introduction:
Hispanic/Latinos are the largest ethnic minority in United States with significant cultural and racial heterogeneity. The recent cholesterol treatment guidelines are mainly based on estimates from non-Hispanic white and black cohorts.

Aim:
To estimate the proportion of US Hispanic adults potentially affected by recent changes in recommendations for statin therapy eligibility under the 3rd National Cholesterol Education Program Adult Treatment Panel (NCEP/ATP III) and the new 2013 ACC/AHA cholesterol treatment guidelines.

Methods:
HCHS/SOL is a large multi-center study of Hispanics/Latinos in US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA) (n=16,415; mean age 41 years, 40% males) . We evaluated weighted prevalence of statin-treated individuals and the proportion of target population that met the eligibility criteria for statin therapy under NCEP/ATP III versus 2013 ACC/AHA cholesterol treatment guidelines.

Results:
A total of 1,716 (10.4%) were treated with statins in HCHS/SOL cohort. However, 3,366 (20.5%) and 5,268 (32.1%) were eligible for statin therapy under NCEP/ATP III and 2013 ACC/AHA guidelines respectively. The proportion of statin-eligible adults increased primarily among older adults from 44% to 87% and males from 19% to 39% under NCEP/ATP III guidelines and 2013 ACC/AHA guidelines respectively (Figure 1). There was also an increase in eligibility for statin therapy in middle aged adults (44% to 65%).

Conclusions:
Regardless of the definition for statin eligibility, Hispanics are grossly undertreated (only half and only a third of those statin-eligible under the ATP III or the new ACC/AHA guidelines respectively are receiving treatment). The eligibility of statin therapy almost doubles consistently across all Hispanic/Latinos subgroups of under the new 2013 ACC/AHA guidelines.
Abstract 13504: RV Cardiac Output Calculated From an Implantable Hemodynamic Device: A Correlative Approach Using CMR in PAH Patients
Authors: Biederman Robert W , Doyle Mark , Rayarao Geetha , White Jason , Thompson Diane , Yamrozik June , Williams Ronald , Correa-Jaque Priscilla , Benza Raymond
Published: July 2021

Introduction:
The CardioMEMS™ HF System (CMHFS)(St. Jude) is used for wireless monitoring of pulmonary artery (PA) pressure. Pulmonary flow is difficult to model due to prominent reflected waves and McDonald
et al
have shown that the temporal differential of the initial positive pressure pulse effectively provides the flow driving force for cardiac output (CO), with mean pressure indicating resistance. However, the response of this model to stress conditions
in vivo
is unknown.

Hypothesis:
We hypothesize that the temporal differentiation of pressure model of CO applied to the CMHRS data at baseline and during stress provides an accurate calculation of noninvasive CO in PAH.

Methods:
10 pts with PAH were implanted with the CMHFS to measure PA pressure, HR, and CO longitudinally. Cardiovascular Magnetic Resonance (CMR) was performed at baseline, and after 1) inhalation of nitric oxide (20 ppm), 2) dobutamine (20 μcg/kg/min), and 3) volumetric challenge (500ml NaCl). Flow through the MPA was measured using phase velocity mapping. The mean pressure and area of the temporal differential of the initial positive pressure pulse from the CMHFS device were measured (Fig 1A) to calculate CO. In each case the calibrating constant to relate to CMR CO was calculated at baseline and then applied during stress.

Results:
The pressure derived CO correlated with CMR CO via a linear relationship for 32 comparison measures according to the following equation: Pressure CO = 1.1 CMR CO + 0.8Bland-Altman analysis has an offset bias of 0.2, a four standard deviation range of ±3.1 l/m and a correlation of 0.9. (Fig 1B).

Conclusions:
The temporal differential of the initial positive pressure pulse forms the effective driving force for pulmonary blood supply. This formulation overcomes the difficulties in identifying reflected waves and is highly responsive to stress conditions and may advance current prototypes. This approach may provide additional value once validated for implantable PA manometers.
Abstract 13532: Diastolic Function at Presentation Has Independent Prognostic Value in Patients With Peripartum Cardiomyopathy
Authors: Delgado-Montero Antonia , McNamara Dennis , Damp Julie B , Drazner Mark , Hsich Eileen , Mather Paul J , Rajagopalan Navin , Gorcsan John
Published: July 2021

Background:
Peripartum cardiomyopathy (PPCM) is a rare disease with variable but potentially devastating consequences. The prognostic importance of alterations in LV diastolic function is unclear.

Methods:
Pregnancy Associated Cardiomyopathy cohort was a prospective study of 100 PPCM women from 30 centers presenting with LV ejection fraction (EF) < 45% within 2 months of delivery. Baseline data were mitral inflow E-wave, A-wave, E/A ratio, E deceleration time (DT), tissue Doppler septal and lateral annular velocities and biplane LA volume index. There were 90 PPCM patients and 21 female controls (8 healthy postpartum and 13 non-pregnant) with diastolic data. LV recovery was defined as LVEF ≥ 50% at 1 year. Outcome events were predefined as death, heart transplant or LV assist device (LVAD).

Results:
PPCM patients were aged 30±6 years with EF 35±9% at presentation. At 1 year, 84 patients had follow-up data: 63 patients (75%) had LV recovery (EF ≥50%) and 11 patients (13%) had either LVEF ≤35% or a major event (4 LVADs and 2 deaths). Elevated filling pressures (E/A≥2 and DT<150ms) were present in 57% at baseline and persisted in 11% at last echo, p<0.0001. Abnormalities in baseline diastolic function were associated with clinical outcomes and lack of LV recovery: area under the ROC curve (AUC) for E/A 0.78, p=0.0002, AUC for DT 0.82, p<0.0001, AUC for LA volume index 0.79, p<0.0001. Diastolic measures were also predictive of persistent severe LV dysfunction (EF ≤35%) or unfavorable events: E/A, p<0.0001; DT, p<0.0001, and LA volume index, p=0.0001. By multivariate analysis, baseline diastolic function was independently associated with subsequent lack of LV recovery or unfavorable events (Table).

Conclusions:
In PPCM patients, echo-Doppler measures of diastolic function at presentation provide important prognostic information regarding LV recovery and clinical outcomes.
Abstract 13536: Vascular Function is Predictive of Functional Outcomes in Adolescent and Young Adult Fontan Survivors
Authors: Goldstein Bryan H , Urbina Elaine M , Khoury Philip R , Gao Zhiqian , Amos Michelle A , Mays Wayne A , Redington Andrew , Marino Bradley S
Published: July 2021

Introduction:
Fontan survivors demonstrate diminished vascular function and functional outcomes. The relationships between measures of vascular function and functional outcomes have not been established.

Methods:
Cross-sectional single-institution study of Fontan survivors ages 8-25 years. Multimodality assessment of endothelial function (reactive hyperemia index [RHI] and flow mediated dilation [FMD]) and arterial stiffness (augmentation index [AI] and baseline pulse amplitude [BPA]) was performed with peripheral arterial tonometry (PAT), brachial FMD and pulse wave analysis (PWA). Aerobic capacity was determined using cardiopulmonary exercise testing with cycle ergometry and a ramp protocol. Quality of life (QOL) was assessed using the pediatric QOL inventory (PedsQL) and physical activity (PA) was assessed using the PA Questionnaire (PAQ). Vascular measures served as predictor variables while functional outcome measures served as outcome variables. Bivariate predictors (p<0.1) were candidates for inclusion in multivariable models. Model development utilized linear regression and ordered logistic regression techniques.

Results:
Sixty patients (52% male) completed the protocol with a mean age of 13.9 ± 4.1 years and duration of Fontan circulation of 9.9 ± 4.2 years. Maximal (max) exercise was achieved in 54 subjects with mean peak and %-predicted oxygen consumption (VO
2
) of 27.8 ± 7.6 ml/kg/min and 71.0 ± 21.2%, respectively. FMD-RHI (p<0.05) was associated with VO
2
at anaerobic threshold (AT, R
2
0.33). PAT-BPA (p<0.05) was associated with the ratio of minute ventilation to carbon dioxide at AT (R
2
0.40). FMD-RHI, PAT-AI and PWA-AI (p<0.05) were associated with max VO
2
(R
2
0.36-0.53), %-predicted max VO
2
(R
2
0.40-0.56) and max O
2
pulse (R
2
0.26-0.31). PAT-AI and PAT-BPA (p<0.05) were associated with PedsQL total (R
2
0.19-0.34) and physical heath summary score (R
2
0.36-0.41). FMD max and PAT-BPA (p<0.05) were associated with PAQ score (R
2
0.33-0.38).

Conclusions:
Increased arterial stiffness and decreased endothelial function are associated with lower aerobic capacity, QOL and physical activity in adolescent and young adult Fontan survivors. Vascular dysfunction may be an important target for future therapeutic trials.
Abstract 13604: Physical and Affective Symptom Clusters Are Strongly Associated in Heart Failure
Authors: Denfeld Quin E , Gelow Jill M , Hiatt Shirin O , Mudd James O , Chien Christopher V , Lee Christopher S
Published: July 2021

Introduction:
The syndrome of heart failure (HF) is a constellation of both physical and affective symptoms. How physical and affective symptom clusters are associated, however, is not well understood.

Hypothesis:
There is a strong association between physical symptom clusters and affective symptom clusters among adults with moderate to advanced HF.

Methods:
This was a secondary analysis of combined data collected during two prospective cohort studies of symptoms among adults with moderate to advanced HF. Physical symptoms of dyspnea and wake disturbances were measured with the Heart Failure Somatic Perception Scale Dyspnea subscale (HFSPS-D) and the Epworth Sleepiness Scale (ESS), respectively. Affective symptoms of depression and anxiety were measured with the Patient Health Questionnaire-9 (PHQ-9) and the Brief Symptom Inventory Anxiety subscale (BSIANX), respectively. Physical and affective symptoms were clustered separately using latent mixture modeling and then compared using cross classification modeling and traditional comparative statistics (i.e. student’s t, Kendall’s tau-b and chi-square tests).

Results:
The average age of the sample (n=291) was 56.7±13.3 years, and most were male (61.9%). A majority of subjects were classified as NYHA Class III HF (56.4%), and most had non-ischemic etiology (65.2%). Two physical symptom clusters (severe physical (26.3%) and mild physical (73.7%); dyspnea t=7.35, p<0.001; wake disturbances t=16.80, p<0.001) and two affective symptom clusters (severe affective (21.2%) and mild affective (78.8%); depression t=22.1, p<0.001; anxiety t=7.87, p<0.001) were identified in a model with good fit (entropy=0.80). Subjects with severe physical symptoms were more likely to have severe than mild affective symptoms, and those with mild physical symptoms were more likely to have mild than severe affective symptoms (χ2=106.8, p<0.001; tau b=0.62).

Conclusions:
There is a strong association between physical and affective symptom clusters among adults with moderate to advanced HF that may be helpful in identifying adults with HF at risk for multiple, co-occurring symptoms.
Abstract 13671: GSK-3α Directly Regulates Lipid Metabolism Through Obesity-linked Phosphorylation of PPARα
Authors: Nakamura Michinari , Zhai Peiyong , Liu Tong , Li Hong , Sadoshima Junichi
Published: July 2021

Obesity impairs lipid metabolism and leads to cardiac dysfunction, where peroxisome proliferator-activated receptor α (PPARα) serves as a key regulator of lipid metabolism. Glycogen synthase kinase-3α (GSK-3α), a serine-threonine kinase, is markedly upregulated in the heart of obese mice, suppressing glycogen synthesis. However, the functional significance of upregulated GSK-3α in lipid metabolism remains unknown. Here we show that GSK-3α directly upregulates lipid metabolism and aggravates cardiac lipotoxicity in obesity. GSK-3α activity was enhanced by palmitic acid (PA) in the nucleus in cardiomyocytes (CMs), and knockdown of GSK-3α suppressed PA-induced activation of PPARα. GSK-3α, but not GSK-3β, directly interacted with PPARα. Mass spectrometry analysis revealed that GSK-3α phosphorylates PPARα at Ser280, located in the ligand binding domain. A PPARα phospho-mimicking mutant (PPARα-S280D) exhibited an increase in both the interaction of PPARα with RXR and its DNA binding, enhancing PPARα activity and stimulating expression of lipid metabolism-related genes, including Cpt1b, CD36 and PDHK4, in CMs. High-fat diet (HFD)-fed mice displayed increased GSK-3α activity and PPARα phosphorylation in the heart. Cardiac-specific haploinsufficiency of GSK-3α normalized HFD-induced lipid accumulation (Oil Red O staining), abnormally enhanced palmitate oxidation (0.82 fold, p<0.05), cardiac hypertrophy and diastolic dysfunction (0.36 fold in EDPVR, p<0.05) without affecting body weight gain or food intake. While adenovirus-mediated overexpression of PPARα in the heart exacerbated HFD-induced lipid dysregulation and cardiac dysfunction, that of PPARα phospho-resistant mutant (PPARα-S280A) failed to facilitate lipid metabolism and cardiac dysfunction in the presence of a HFD. Notably, a PPARα ligand, fenofibrate, allosterically inhibited PPARα phosphorylation in obese mice by interfering with the interaction between GSK-3α and PPARα, and improved HFD-induced lipid accumulation and cardiac dysfunction. These data show that GSK-3α directly regulates lipid metabolism through Ser280 phosphorylation of PPARα, and that its phosphorylation could be a novel therapeutic target for obesity-related cardiac dysfunction.
Abstract 13677: Left Atrial Structure and Function in Relation to Incident Stroke/TIA and Dementia: The Multi-ethnic Study of Atherosclerosis
Authors: Habibi Mohammadali , Zareian Mytra , Ambale Venkatesh Bharath , Samiei Sanaz , Chamera Elzbieta , Rezzadeh Kevin , Wu Colin , Launer Lenore J , Diez Roux Ana , Shea Steven , Heckbert Susan R , Bluemke David A , Lima Joao A
Published: July 2021

Introduction:
Increased left atrial (LA) size and reduced LA function are known predictors of atrial fibrillation (AF). Evidence also links increased LA size and stroke. We sought to examine the association of LA function, measured with cardiac magnetic resonance imaging (CMR) and incident stroke/TIA and dementia.

Methods:
This case-cohort study compared LA size and function in 180 MESA participants with incident Stroke/TIA and 95 with incident dementia, over a median follow up of 10.7 years, to 550 participants randomly selected from the whole MESA cohort. All individuals were free of clinical cardiovascular and major valvular heart disease. Phasic LA volumes, LA emptying fractions (LAEF) and peak strain were quantified in sinus rhythm using tissue-tracking CMR. Vascular neurologists adjudicated stroke events by medical record review. Dementia cases were identified using ICD9 codes from hospital records. Modified Cox proportional hazard models weighted for the stratified case-cohort sampling design was used to examine the associations.

Results:
Incident Stroke/TIA (age 67 ± 9 years, 45% male) and dementia cases (age 74 ± 6 years, 58% male) were older than the subcohort population (age: 61 ± 10, 49% male). In multivariable analysis adjusted for standard cardiovascular risk factors and left ventricular ejection fraction, lower peak LA strain and passive LAEF were associated with both incident stroke/TIA and dementia. After further adjustment for incident AF, the associations were attenuated for peak LA strain but remained significant for passive LAEF (HR for incident Stroke/TIA: 0.72 per SD 95% CI: 0.55-0.93, p=0.013 and for incident dementia: 0.59 per SD 95% CI: 0.37-0.95, p=0.031).

Conclusions:
Reduced LA conduit function was associated with incident Stroke/TIA and dementia independent of other cardiovascular risk factors and incident AF. Assessment of LA function may add further information in risk stratifying individuals at risk for stroke and dementia.
Abstract 13700: High Affinity CaM, but Not Normal Affinity CaM Can Prevent Arrhythmias in CPVT Which Mutation is Located at CaM-like Domain of RyR2
Authors: Nishimura Shigehiko , Yamamoto Takeshi , Fukui Go , Maeda Takako , Hino Akihiro , Suetomi Takeshi , Ono Makoto , Mochizuki Mamoru , Oda Tetsuro , Okuda Shinichi , Kobayashi Shigeki , Yano Masafumi
Published: July 2021

Introduction:
We have been previously reported that calmodulin (CaM) binding affinity to RyR2 decreases upon beta stimulation in catecholaminergic polymorphic ventricular tachycardia (CPVT) type knock-in mice with mutation at central domain (R2474S-KI). Meanwhile, amino acid residues from 4026 to 4172 of RyR2 have EF hand motifs and are called CaM-like domain (CaMLD). Some of the human CPVT mutations were reported in this CaMLD. In the present study we investigated the molecular mechanism of arrhythmogenesis of CPVT with mutation at CaMLD using N4103K KI mice.

Methods and Results:
VT and/or Vf were frequently observed after 120 mg/kg caffeine plus 1 mg/kg epinephrine infusion in KI mice, but not in WT mice (WT: 0%, KI: 43%). CaM binding affinity to RyR2 was assessed by incorporation of exogenous CaM labeled with HiLyte Fluor® in isolated saponin-permeabilized cardiomyocytes. The binding affinity of CaM decreased in KI cells (Kd: 161 nM) compared with WT cells (Kd: 89 nM). Addition of 1μM cAMP did not change the affinity of CaM to RyR2 in both KI and WT cells, while it decreased the affinity in R2474S-KI. Frequency of the Ca
2+
sparks was measured in isolated saponin-permeabilized cells. The Ca
2+
spark frequency (SpF: s
-1
100μm
-1
) was much higher in KI than in WT cells {KI (n=79): 21.5±6.3; WT (n=34): 10.6±4.1; p<0.01}. Addition of 100 nM CaM to KI cells did not decrease SpF {(n=87): 22.4±6.5}, however, significant decrease was observed by HA-CaM (modified CaM which has higher affinity to RyR2). Spontaneous Ca
2+
transient (SCaT) was measured during sequential pacing from 1 to 5 Hz in isolated intact cardiomyocytes. The SCaT was rarely observed in WT cells even with 10 nM isoproterenol and 5 Hz pacing, whereas that was observed in 33% of KI cells. Incorporation of CaM to intact KI cells using protein delivery kit (BioPORTER®) did not decrease incidence of SCaT (34% of KI cells), however, significantly decreased by HA-CaM incorporation.

Conclusions:
Different from R2474S-KI mice, CaM binding affinity to RyR2 is decreased without beta stimulation in KI mice with CaMLD mutation. Conformational change of CaMLD might affect CaM-binding domain (CaMBD) and decrease the affinity of CaM to CaMBD. The CaMLD-CaMBD interaction may be a novel therapeutic target of lethal arrhythmias.
Abstract 13750: Cardiac Resynchronization Therapy for Patients With Cardiac Sarcoidosis
Authors: Sairaku Akinori , Yoshida Yukihiko , Nakano Yukiko , Maeda Mayuho , Hashimoto Haruki , Hirayama Haruo , Kihara Yasuki
Published: July 2021

Objective:
Little is known about the clinical features in patients with cardiac sarcoidosis who receive cardiac resynchronization therapy (CRT). We aimed to clarify the clinical response to CRT in patients with cardiac sarcoidosis.

Methods:
We compared the clinical data on CRT between heart failure patients with cardiac sarcoidosis and those with other etiologies at 3 cardiovascular centers. The primary endpoint was composite outcome of cardiovascular death or hospitalization from worsening heart failure within 5 years after the CRT.

Results:
The patients with cardiac sarcoidosis (N=18) were more likely than those without cardiac sarcoidosis (N=141) to be female (83.3% vs. 22.7%; P<0.001), and undergo an upgrade from a pacemaker or implantable cardioverter defibrillator (72.2% vs. 18.4%; P<0.001). The composite outcome occurred with a similar frequency (38.9% vs. 48.2%; P=0.37). The patients with cardiac sarcoidosis were more likely than those without to have sustained ventricular arrhythmias occurring before or after the CRT (66.7% vs. 29.1%; P=0.003). The reduction in the left ventricular end-systolic volume after the CRT was significantly smaller in the patients with cardiac sarcoidosis than in those without (mean±SD, -1.5±28.7 vs. -20.1±33.7%; P=0.03). Patients with an improved clinical composite score were seen with a similar proportion (55.6% vs. 61.7%; P=0.86).

Conclusions:
Outcomes after the CRT may be acceptable in patients with cardiac sarcoidosis. A poor left ventricular reverse remodeling and higher occurrence of ventricular arrhythmias may characterize them.
Abstract 13751: Categorizing the Burden of Arrhythmia in Adults With Congenital Heart Disease
Authors: Peritz David C , Gonzalez Vincent J , Edwards April , Nelson Jennifer E , Ferns Sunita J
Published: July 2021

Introduction:
Advances in surgical and medical therapies have increased the life expectancy for patients with congenital heart disease. Arrhythmias in these patients are common and multi-factorial, often due to a disruption of the hearts’ intrinsic electrical system and degenerative remodeling, secondary to varying pressure and volume loads. The aim of this study is to better characterize the association between type of structural heart disease (SHD) and clinically significant arrhythmias.

Methods:
We identified all adults with diagnosed congenital heart disease seen at a large tertiary care referral center between 2000 and 2014. Patients were categorized based on gender, SHD, and type of arrhythmia. We used the American Thoracic Society guidelines to group SHD into discrete categories and grouped arrhythmias as tachyarrhythmias (atrial/ventricular) and bradyarrhythmias.

Results:
We identified 1355 individuals with at least one congenital structural heart defect and at least one arrhythmia. Of those, the most common structural abnormality was left-sided outflow tract obstruction and the least common was congenitally corrected transposition of the great arteries. The most common category of arrhythmia identified was atrial arrhythmia and the least common was sinoatrial node dysfunction (Figure). The most common association between SHD and arrhythmia was atrial arrhythmia in patients with left-sided outflow tract obstruction.

Conclusions:
This study is one of the largest single-center reports linking specific structural heart defects to type of rhythm disturbance. These data may help providers better anticipate future arrhythmia development based on a patient’s underlying structural defect and offer prognostic information to patients and families. Future studies to more closely evaluate the relationship between arrhythmia patterns and specific risk factors within each category of SHD are needed.
Abstract 13767: Nitric Oxide Plays a Janus Role in the Pathogenesis of Tako-tsubo Cardiomyopathy
Authors: Nguyen Thanh H , Surikow Sven , Raman Betty , Chapman Matthew , Stafford Irene , Horowitz John
Published: July 2021

Introduction:
Tako-tsubo cardiomyopathy (TTC) is fundamentally a catecholamine-stimulated myocardial inflammatory state, initiated by aberrant β2-adrenoceptor signalling in susceptible (usually female) myocardium. We have recently reported that (i) TTC patients exhibit evidence of “supranormal” NO signalling, (ii) at post-mortem, heart of patients dying of TTC have increased content of 3-nitrotyrosine (3NT), a marker of nitrosative stress. Furthermore, in a rat model of TTC, isoproterenol (ISOP) induces increased myocardial expression of both 3NT and thioredoxin-interacting protein (TXNIP), a pro-inflammatory protein normally suppressed by NO. We therefore sought to determine the effects of suppression of NO generation in this rat model.

Methods:
Female Sprague-Dawley rats, aged 4-5 months, were randomly assigned to one of two groups: ISOP (5mg/kg) (n = 11) and L-NAME (50mg/kg) + ISOP (n = 14). Echocardiography was performed at baseline and after 24 hours. Animals were then sacrificed and immunoblotting was performed in both apical and basal samples to determine the extent of activation of both inducible NO synthase (iNOS) and endothelial NOS (eNOS). Expression of 3NT, TXNIP, and PARP1 as marker of DNA damage were also determined.

Results:
The results are summarized in the Table: mean ± SE are shown. Furthermore, L-NAME accentuated falls in LVEF and induced marked increases in intraventricular septal wall thickness (p < 0.05 for both).

Conclusions:
NOS inhibition in this model of TTC limits PARP1 expression and thus potentially conserves energetics, but does not reduce overall nitrosative stress. Moreover, NOS inhibition worsens myocardial inflammation and impairment of LV function. Increased TXNIP expression may reflect withdrawal of NO-mediated inhibition.
Abstract 13841: The Impact of Age on Coronary Perfusion, Cardiac Function and Inflammation in a Rat Model of Ashpyxial Cardiac Arrest
Authors: Secher Niels , Østergaard Leif , Tønnesen Else , Granfeldt Asger
Published: July 2021

Introduction:
Age is an independent predictor of poor outcome after cardiac arrest (CA), and age reduces organ function and increase infarct size, oxidative stress and inflammation in studies of regional ischemia reperfusion injury. Meanwhile, experimental CA studies are mostly performed in young, healthy animals, and our understanding of the CA pathophysiology may therefore fail to address the age-effects inherent to human CA.

Objective:
To investigate whether high age affects the reduction in cardiac function, increased inflammation, and endothelial activation observed after CA.

Method:
Aged (26 months, n=12) and young (5 months, n=10) male Sprague Dawley rats were subjected to 8 min of asphyxia induced CA, resuscitated using adrenalin and mechanical CPR, and observed for 360 min. Coronary perfusion pressure (CPP) was measured during CPR, and left ventricular end diastolic pressure, dP/dtmax, and dP/dtmin were determined at baseline and at the end of follow up. Blood samples at baseline, 120min, and 360min after CA were analysed for IL-6, IL-10, elastase, sE-selectin, and sI-CAM1.

Results:
We found no difference in CPP (aged: 16 [95%CI 13;20] vs young: 23 [95%CI 12;34]) or rate of ROSC (aged: 9/12 vs. young 9/10) between groups. During the first hour after resuscitation, a hyperperfusion phase was seen in the young group but not in the aged group (MAP aged: 50mmHg [95%CI 38;62] vs MAP young 105 [95%CI 88;123]). Left ventricular end diastolic pressure and dP/dtmax was higher in aged animals at baseline (p<0.02). We observed a significant decrease in dP/dtmax and increase in dP/dtmin after CA, with no group difference. Compared to young rats, aged animals showed a significantly higher increase in plasma elastase and sE-selectin levels after CA. In contrast, plasma IL-6 and IL-10 increased from baseline to end of follow up, but with no difference between the groups. sI-CAM1 showed no difference over time or between groups.

Conclusion:
We found increased endothelial activation and a blunted hyperperfusion in aged compared to young rats after CA. Age did not affect cardiac function and cytokine levels.
Abstract 13850: Severity Assessment of Coronary Artery Aneurysm by Z-score of the Internal Diameter in Kawasaki Disease
Authors: Miura Masaru , Fukushima Naoya , Kaneko Tetsuji , Kobayashi Tohru , Suda Kenji , Yamagishi Hiroyuki , Kato Taichi , Shimoyama Shinya , Kato Hitoshi , Saji Tsutomu , Hamaoka Kenji , Nomura Yuichi , Waki Kenji , Fukazawa Ryuji , Hirono Keiichi , Fuse Shigeto
Published: July 2021

Introduction:
The severity of coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) has been recently classified according to the z-score. However, it is not known whether this classification can predict coronary events such as stenosis, obstruction, and thrombosis.

Methods:
In this multicenter retrospective study, data on height, weight, CAA diameter measured by echocardiography in the acute phase, and the clinical course in KD patients 18 years of age or younger who received a coronary angiography between 1992 and 2011 were collected. Time-dependent occurrence of coronary events was analyzed by Kaplan-Meier method according to small (z-score, < 5.0), medium (≥ 5.0 to < 10.0), and large (≥ 10.0) CAA using a 5 increment scale scheduled to be included in the new American Heart Association criteria. Cox regression analysis was used to identify risk factors for coronary events. The occurrence rate of major cardiac events such as angina pectoris, myocardial infarction, and cardiac death was also analyzed.

Results:
Data were analyzed for 1,002 patients from 44 institutions. Both the body surface area and CAA diameters were available in 741 cases for the right coronary artery (RCA) and 609 cases for the left anterior descending artery (LAD). Coronary events occurred in 83 (11.2%) of the RCA group and 57 (9.4%) of the LAD group, while major events occurred in 30 cases (3.0%). The 10-year event-free survival rate for coronary events for small, medium, and large aneurysms was 100, 95.5, and 64.9% in the RCA group, and 100, 94.4, and 63.5% for aneurysms in the LAD group, respectively. The rate of major cardiac events was 98.5, 98.1, and 87.6% for the RCA group, and 100, 97.5, and 86.8% for the LAD group, respectively. Cox regression analyses showed that the z-score of the CAA diameter was an independent risk factor for coronary events for the RCA [large versus medium aneurysm; hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.5 to 5.3, p = 0.002] and the LAD [HR 3.2, 95% CI 1.6 to 6.5, p = 0.015] groups.

Conclusions:
The severity assessment of CAA using the 5-increment z-score for coronary arterial diameter can predict the time-dependent occurrence of coronary events in patients with KD.
Abstract 13975: Association of In-Hospital Acute Kidney Injury With Long-term Outcomes in Survivors of Acute Myocardial Infarction: Insight From the NCDR
Authors: Mody Purav , Wang Tracy , McNamara Robert , Das Sandeep , Kumbhani Dharam , Roe Matthew , Wiviott Stephen , Tsai Thomas , De Lemos James
Published: July 2021

Background:
Chronic kidney disease (CKD) and acute kidney injury (AKI) have both been associated with adverse short-term outcomes after MI. However, the impact of AKI on long-term outcomes and the interaction of AKI with baseline renal function have not been well described.

Methods:
ACTION Registry®-GWTGTM records from 2008-2012 were linked to Medicare data yielding a population of 76,500 acute MI patients from 581 hospitals who survived to hospital discharge. We excluded patients with cardiogenic shock, cardiac arrest, and those undergoing CABG or currently on dialysis. CKD status was defined using the Kidney Disease Outcome Quality Initiative criteria based on admission GFR estimated using the MDRD equation. No, mild, moderate and severe AKI were defined as changes in creatinine (Cr) from baseline to peak of < 0.3, 0.3 to < 0.5, 0.5 to < 1.0 and ≥ 1.0 mg/dl respectively. Cox proportional hazard modeling was used to examine associations between AKI and 1-year mortality. Covariates for risk adjustment were adapted from the CRUSADE long-term mortality risk model.

Results:
The median age was 77 years, 30% had STEMI and 78% underwent diagnostic angiography.The incidence of mild, moderate and severe AKI was 7.5%, 6.0% and 3.0%. CKD stages 3, 4, and 5 were present in 41.2%, 6.7%, and 1.0% of patients. Both CKD and AKI were significantly associated with 1-year mortality (p< 0.0001 for each). A significant interaction was noted between CKD and AKI with respect to 1-year mortality (p-interaction<0.0001). Adjusted 1-year mortality increased in a dose-dependent manner across increasing severity of AKI, but this association was attenuated among individuals with more severe baseline CKD (Figure).

Conclusion:
One-year mortality increased in proportion to severity of AKI, with even a small increase in Cr associated with worse outcomes. The association of AKI with outcomes was modified by baseline Cr, with a greater impact of AKI observed among patients with higher baseline eGFR.