bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13433: Predictors of Contrast Induced Nephropathy in Patients With Acute Coronary Syndromes and Normal Baseline Glomerular Filtration Rate
Authors: Negreanu Daniel , Gagnon Michael , nguyen anh , Mansour Samer , Nguyen Michel T , Montigny Martine , Lauzon Claude , Eisenberg Mark , Rinfret Stephane , kouz Simon , Afilalo Marc , L'Allier Philippe L , De la Rocheliere Bernard , Cantin Bernard , Tardif Jean-Claude , Huynh Thao
Published: May 2021

Background:
The incidence and predictors of contrast-induced nephropathy (CIN) in patients with normal glomerular filtration rate (GFR) are not well ascertained. We aim to determine the incidence and predictors for CIN after coronary catheterization (CATH) for acute coronary syndromes (ACS).

Methods:
We combined the datasets of two studies. The AMI-QUEBEC was an observational cohort of patients with ST-segment elevation myocardial infarctions in 2003. The AMI-OPTIMA was a study of patients hospitalized with ACS in 2009 and 2012. For this analysis, we retained only patients with GFR > 60 ml/min who underwent CATH. We defined “hyperfiltrators” as patients with GFR above the 95th percentile age and sex-adjusted value. CIN was defined as an increase in serum creatinine >0.5 mg/dL (44.2 μmols/L) or > 50% from baseline serum creatinine.

Results:
There were 3,188 patients with GFR > 60 ml/min : 39 hyperfiltrators and 3,149 without hyperfiltration. The mean age was similar between the two groups of patients (62 years); 21% and 27% females in hyperfiltrators and non-hyperfiltrators (p<0.0001). The prevalences of diabetes mellitus and hypertension were 36% and 64%, respectively in hyperfiltrators compared to 20% and 46%, respectively in non-hyperfiltrators. The mean baseline GFR and creatinine were 112 ml/min and 50 μmols/L, respectively in hyperfiltrators; 84.2 ml/min and 80 μmols/L in non-hyperfiltrators. There were 225 CIN following CATH; 7.1% of the whole cohort with 35.9% in the hyperfiltrators and 6.7% in non-hyperfiltrators. Hyperfiltration was independently associated with a 13-fold increase in the risk of CIN (Table 1). Each year of increase in age was associated with a 5% increase in the risk of CIN. Shock was also associated with an 11-fold increase in the risk of CIN.

Conclusion:
Hyperfiltrators may be at high risk of CIN following CATH in ACS. The risk of CIN associated with hyperfiltration should be evaluated in other populations.
Abstract 13438: The Role and Mechanism of Chronic Beta3-Adrenergic Receptor Blockade on the Progression of Heart Failure in a Rat Model
Authors: Sun Xiaoqiang , Cheng Che , Cao Jing , Zhang Zhi , Li Tiankai , Zhang Xiaowei , Cheng Heng Jie
Published: May 2021

Background:
The negative inotrope and up-regulation of β
3
-adrenergic receptors (AR) in human and animal failing hearts suggest a direct and contributing role of cardiac β
3
-AR activation on the progression of congestive heart failure (CHF). However, its precise role is still being debated. We hypothesize that up-regulation of cardiac β
3
-AR is detrimental and chronic β
3
-AR blockade may prevent CHF-caused intrinsic defects of left ventricular (LV) myocyte force-generating capacity and relaxation and improve β-AR regulation, thereby limiting the progression of CHF.

Methods:
We compared the alterations of LV and myocyte functional responses and [Ca
2+
]
i
transient ([Ca
2+
]
iT
) in SD rats divided into 3 groups (8/group): 1)
CHF
3 months after isoproterenol (ISO) (170 mg/kg, sq, for 2 days); 2)

ISO/β
3
-ANT

, 2 months after receiving ISO, a selective β
3
-AR antagonist (ANT), L-748,337, was initiated (10
-7
M/kg/day, sq. by mini-pump) and was given for 1 month; and 3)
Sham controls
.

Results:
Compared with controls, the animals that received ISO treatment had CHF onset at 1 month and progressed to severe HF at 3 months after ISO. Plasma norepinephrine (NE) (1295 vs 259 pg/ml) increased 5-fold; whereas, stroke volume (SV) (39 vs 91 μl) and ejection fraction (EF) (39 vs 62%) significantly decreased, and LV end-diastolic pressure (P
ED
) (13.9 vs 6.0 mmHg) was doubled. These changes were paralleled with about 50% reductions in cell contraction (dL/dt
max
, 93 vs 186 μm/s) and relaxation (dR/dt
max
, 96 vs 159 μm/s) associated with a significant decrease in the peak systolic [Ca
2+
]
iT
, (0.17 vs 0.26). In addition, superfusion of ISO (10
-8
M) caused much less increases in dL/dt
max
(39 vs 68%), dR/dt
max
(23 vs 54%), and [Ca
2+
]
IT
(14 vs 28%). Treatment with β
3
-ANT increased SV (89 μl) and EF (60%), decreased P
ED
more than 90% from ISO-treated values, and corrected the elevation of plasma NE (301 pg/ml), dL/dt
max
(184 μm/s), dR/dt
max
(152 μm/s), and [Ca
2+
]
iT
(0.24). ISO-induced increase in dL/dt
max
and [Ca
2+
]
iT
also returned close to control levels.

Conclusion:
Chronic β
3
-ANT treatment after CHF significantly improves LV and myocyte contractile function and [Ca
2+
]
i
regulation and limits the development of CHF. Thus, β
3
-AR blocker may provide a new therapeutic strategy for the treatment of CHF.
Abstract 13448: Impact of Diabetes on Growth Differentiation Factor 15 and Mortality in Patients With Stable Coronary Artery Disease: The ANOX Study
Authors: Wada Hiromichi , Unoki Takashi , suzuki masahiro , Matsuda Morihiro , Ajiro Yoichi , Shinozaki Tsuyoshi , Sakagami Satoru , Yonezawa Kazuya , shimizu masatoshi , FUNADA JUNICHI , Takenaka Takashi , Morita Yukiko , Nakamura Toshihiro , Fujimoto Kazuteru , Matsubara Hiromi , Kato Toru , Takagi Daisuke , Wada Kyohma , Wada Miyaka , Iguchi Moritake , Masunaga Nobutoyo , ISHII MITSURU , Kotani Kazuhiko , Abe Mitsuru , Akao Masaharu , Hasegawa Koji
Published: May 2021

Background:
Diabetes mellitus (DM) is still significantly associated with the risk of mortality in the general population. Higher circulating growth differentiation factor 15 (GDF-15) levels are associated with the risk of mortality in the general population, in patients with DM, and in those with coronary artery disease (CAD). However, whether GDF-15 levels differ according to the diabetic status and whether DM modifies the relationship between GDF-15 and mortality in patients with stable CAD are unclear.

Methods:
Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between diabetic status and GDF-15 and the impact of DM on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 797 DM and 663 non-DM patients enrolled in the ANOX Study.

Results:
The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with DM exhibited significantly higher levels of GDF-15 compared to those without DM (median [interquartile range], 1472 [1049-2258] vs. 1274 [868-1874] pg/mL, respectively;
P
<0.001). Stepwise multiple linear regression analysis revealed that the log-transformed (Ln-) GDF-15 level was independently associated with higher age, DM, current smoking, lower estimated glomerular filtration rate, anemia, no use of aspirin, Ln-N-terminal pro-natriuretic peptide, and Ln-high-sensitivity C-reactive protein (
P
<0.005 for all). In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders (hazard ratio per 1-SD increase [HR], 1.51; 95% confidence interval [CI], 1.33-1.71). This association was still significant in patients with DM (HR, 1.52; 95% CI, 1.30-1.79) and in those without DM (HR, 1.57; 95% CI, 1.25-1.96). However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in the entire cohort and in patients with DM, but not in those without DM.

Conclusions:
Higher levels of GDF-15 were independently associated with DM in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with DM.
Abstract 13454: Relationship Between Brain-type Natriuretic Peptide and Serum Growth Factors in Infants With Single Ventricle Heart Disease and Shunt- or Ductal-dependent Pulmonary Blood Flow
Authors: Gardner Monique M , Faerber Jen , Preminger Tamar J , Avitabile Catherine M , Shankar Somya , Schachtner Susan , Glatz Andrew C , Ravishankar Chitra , Goldberg David J
Published: May 2021

Introduction:
For infants with shunt- or ductal-dependent single-ventricle heart disease (SD-SVHD), poor growth is common and associated with morbidity and impaired neurodevelopmental outcome. While attention has focused on nutrition to promote weight gain, little is known about the contribution of heart failure to diminished growth.

Methods:
A prospective observational pilot study was performed to assess the relationship between heart failure, assessed by brain natriuretic peptide (BNP), and growth factors [insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3)] at 4 visits: 1) prior to discharge from neonatal intervention, 2) immediately prior to stage 2 palliation, 3) prior to discharge after stage 2 palliation, and 4) 3-6 months after stage 2 discharge. IGF-1 Z-scores were generated by the analysis lab using reference data. The relationship between log-transformed BNP and growth factors was analyzed using pairwise correlations at each visit and modeled over time with a linear mixed-effects model. Correlations were considered statistically significant using a p-value <0.10, given the exploratory nature of the study.

Results:
The study included 38 infants (66% male, 68% hypoplastic left heart syndrome). Median BNP was elevated at Visit 1 and decreased over time [287 pg/dL (IQR 147, 794), 85 pg/dL (52, 183), 90 pg/dL (70, 138), and 47 pg/dL (43, 135)]. Median IGF Z-score was <0 at each visit but increased over time [-0.9 (IQR -1.1, 0.1), -0.7 (-1.2, 0.1), -0.5 (-1.2, 0), and -0.2 (-0.8, 0)]. Inverse correlations were noted between log BNP and IGF-1 Z-score at Visit 1 (r = -0.45, p=0.06) and Visit 3 (r = -0.50, p=0.02), and between log BNP and IFGBP-3 at Visit 1 (r = -0.44, p=0.06) and Visit 2 (r = -0.34, p=0.08). There was a small effect of log BNP on IGF-1 Z-score over all time periods (coefficient: -0.23, 95% CI: -0.49, 0.024, p=0.07).

Conclusions:
This pilot study demonstrates an inverse correlation between BNP and growth factors, suggesting that the heart failure state associated with this physiology may play a mechanistic role in impaired growth. Further work directed at therapies that target the underlying heart failure state might help to optimize the potential for growth in this vulnerable patient population.
Abstract 13462: 6-minute Walk Test Variability May be Reduced by a Structured Training and Monitoring Program, Potentially Facilitating Detection of Treatment Effects
Authors: Hsia Judith A , Bonaca Marc P , White Robin , Anderson Victoria , Hiatt William R
Published: May 2021

Background:
The 6-minute walk test (6MWT) is well established for evaluation of functional exercise capacity in patients with conditions such as pulmonary hypertension, peripheral arterial disease and heart failure. Its popularity as an endpoint in heart failure trials has increased in parallel with health authority acceptance of the test as a measure of patients' function. Minimizing variability is key to the successful conduct and outcome of trials with 6MWT endpoints. We assessed the impact on walking distance variability of a structured training and monitoring program

Methods:
After systematically observing conduct of 6MWT worldwide, our core lab developed a multifaceted approach including inspection and standardization of the walking course, standardized training, review of the first 3 tests for each test administrator and random tests thereafter, standardized data collection methods, and assessment of intra-test inconsistencies with feedback. Variability of walking distance using this structured approach is descriptively compared with 6MWT data from the literature.

Results:
In a multicenter trial which used the structured program, the standard deviation (SD) of distance walked was 21.7% of the mean at baseline and 22.6% at Week 4 (Table). For comparison, we reviewed 2018-19 reports of 6MWT not utilizing this structured approach and identified 5 multicenter studies of patients with heart failure which reported mean and SD of distance walked (Table). Baseline distance walked ranged from 104 to 385 m (weighted mean 220.4 m); SD of distance walked ranged from 28% to 135% of distance walked (weighted mean 70.9%).

Conclusion:
Standardization of the 6MWT walking course, structured training of test administrators and monitoring of test quality may reduce test variability which could improve accuracy of treatment effect assessment and possibly require smaller sample sizes.
Abstract 13469: Novel Role of Extracellular SOD-derived H
2
O
2
Signaling in Exercise-induced Vascular Adaptation in Type 2 Diabetes
Authors: Varadarajan Sudhahar , Abdelsaid Kareem , McMenamin Malgorzata , Fang Xuexiu , Hou Yali , Ushio-fukai Masuko , Fukai Tohru
Published: May 2021

Background:
Exercise training promotes vascular adaptation (restoration of endothelial function and angiogenesis) in type2 diabetes (T2D). Since eNOS uncoupling/O
2
-
are increased in T2D, exercise may promote vascular adaptation via mechanism other than eNOS-NO axis. Extracellular superoxide dismutase (ecSOD) is a secreted copper (Cu) containing SOD that catalyzes the dismutation of O
2
-
to H
2
O
2
and its full activity requires Cu transporter ATP7A. We reported that ATP7A-ecSOD pathway is reduced in T2D and that ecSOD-derived H
2
O
2
promotes VEGFR2 signaling and angiogenesis in endothelial cells. However, role of ATP7A-ecSOD axis and H
2
O
2
signaling in vascular adaptation to exercise in T2D have not been reported. Oxidation of Cysteine residues of targets proteins to generate cysteine sulfenic acid (Cys-OH) is a key initial event in H
2
O
2
-mediated signaling.

Results:
Here we show that ATP7A protein (49%), ecSOD activity (51%) and extracellular H
2
O
2
levels in blood vessels and skeletal muscles were significantly decreased in high fat diet-induced T2D mice compared to control C57Bl6 mice, which were rescued by volunteer wheel exercise (2 weeks) or in T2D/ATP7A overexpressing mice. In parallel, exercise training restored impaired endothelium-dependent relaxation (EDR) of resistant arteries and angiogenesis (CD31+ capillary, 2.4-fold) in skeletal muscle of T2D mice, which were inhibited by exogenous catalase or in T2D/ecSOD KO mice, but not by L-NAME, suggesting that ecSOD-derived H
2
O
2
, but not eNOS/NO, mediates exercise-induced beneficial effects. Mechanistically, exercise significantly increased Cys-OH formation of PKG1α (2.3-fold), which was shown to induce EDR in H
2
O
2
-, but not NO/cGMP-, dependent manner, in T2D vascular tissues as well as Cys-OH formation of AMPK (3.6-fold) and AMPK downstream angiogenic PGC1α and VEGF protein expression in T2D skeletal muscles. Of note, these exercise-induced Cys oxidation of PKG1α and AMPK were not observed in control or T2D/ecSOD KO mice.

Conclusion:
Exercise-induced ATP7A-ecSOD axis-mediated out-side in H
2
O
2
signaling plays an important role in promoting vascular adaptation in T2D via Cys oxidation of redox-sensitive kinases required for endothelial function and angiogenesis in skeletal muscles.
Abstract 13502: Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in Fuel Study Participants
Authors: Di Maria Michael V , Goldberg David J , Paridon Stephen , Lubert Adam , Dragulescu Andreea , Mackie Andrew S , McCrary Andrew , Weingarten Angela , Parthiban Anitha , GOOT Benjamin , Goldstein Bryan H , taylor carolyn , Lindblade Christopher , Petit Christopher , Spurney Christopher , Harrild David M , Urbina Elaine M , Schuchardt Eleanor , Trachtenberg Felicia , Kim Gi Beom , Yoon Ja Kyoung , Colombo Jamie N , Wang Ke , Files Matthew D , Schoessling Megan , Ermis Peter R , Wong Pierre , Garg Ruchira , Swanson Sara , Menon Shaji C , Srivastava Shubhika , Thorsson Thor , Johnson Tiffanie , Krishnan Usha , Frommelt Peter C
Published: May 2021

Introduction:
The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle (SV) function in this cohort has not been studied.

Methods:
Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline in indices of SV systolic, diastolic and global function, atrioventricular valve (AVV) regurgitation and mean Fontan fenestration gradient in the udenafil cohort vs placebo, controlling for ventricular morphology (LV vs. RV/other). Effects of ventricular morphology on echo measures and its interaction over time was also evaluated. Difficult imaging windows limited consistent capture of all measures.

Results:
The 191 udenafil participants had significantly improved myocardial performance index (p=0.03), AVV inflow peak E and A velocities (p = 0.007 and 0.03), and annular DTI-derived peak e’ velocity (p = 0.008) compared to 195 placebo participants (Table). There were no significant differences in change in SV size, systolic function, AVV regurgitation severity or mean fenestration gradient. Although LV morphology participants had significantly more favorable indices of SV size and function (lower volumes and areas, E/e’ ratio, systolic:diastolic time and AVV regurgitation, and higher annular s’ and e’ velocity) at baseline, there was no differential effect of udenafil by ventricular morphology at 26 weeks.

Conclusions:
FUEL participants who received udenafil demonstrated a significant improvement in global and diastolic echo indices. The changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular relaxation, which may help explain improved exercise performance in that cohort.
Abstract 13531: Coronary Artery Disease Predicts Venous Occlusion in Patients Undergoing Lead Extraction
Authors: Kumar Kris , Howell Stacey , Sanghai Saket , Giraud George , Jessel Peter , Henrikson Charles A
Published: May 2021

Introduction:
Pacemaker and ICD lead failure or vascular occlusion can require lead extraction. Predictors of a need for lead extraction due to venous occlusion are not well characterized.

Hypothesis:
Coronary artery disease (CAD) is an independent predictor of lead extraction due to venous occlusion.

Methods:
We performed a retrospective study of consecutive patients in a prospectively collected registry at a single center undergoing lead extraction due to either venous occlusion or lead failure from 10/2011 to 02/2020. Patients requiring lead extraction due to infection were excluded. Continuous variables are reported as mean ± standard deviation or total number reported as a percentage (%). Chi square test and logistic regression were used to estimate difference in rates and Odds Ratio. Statistically significant findings were identified with a p valve < 0.05.

Results:
Of 384 procedures included in the database, 131 patients met inclusion criteria for venous occlusion (17%) or lead failure (83%) (Table 1). Average age of the cohort was 55.1 ± 16.4 years and 51% were female. Baseline ejection fraction was 44.6 ± 15.5% and 19.7% of patients had NYHA class III or IV symptoms. 29.7% had a history of CAD. Average number of leads extracted was 1.3 ± 0.57 compared to 2.1 ± 0.82 leads in situ. Patients with CAD had a statistically significant increased risk for extraction as a result of venous occlusion Odds Ratio of 6.80, 95% CI 2.47-18.6, p = 0.0001.

Conclusions:
Identification of predictors of venous occlusion and risk stratification of these patients is an important component of procedural planning and shared decision making. CAD is a predictor of venous occlusion in patients undergoing lead extraction and should be assessed as a risk factor for complex lead management decisions. Further study is warranted to identify mechanisms by which this relationship can be used to predict need for extraction due to vascular occlusion.
Abstract 13532: Comparison of Inferior Vena Cava and Subclavian Vein Collapsibility Index by Ultrasound for Determination of Relative Intravascular Volume in Acute Decompensated Heart Failure
Authors: Kaptein Yvonne E , Salinas Pedro D , Sharma Payal , Perez Moreno Ana Christina , Sulemanjee Nasir , Jan M. Fuad
Published: May 2021

Introduction:
Accurate assessment of relative intravascular volume is needed to guide management of acute decompensated heart failure (ADHF). Current assessments include history and physical examination (specific but not sensitive), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (sensitive but not specific).Ultrasound (US) of inferior vena cava (IVC) collapsibility with respiration is commonly used to assess intravascular volume and right atrial pressure (RAP) but may be technically challenging. US of subclavian vein (SCV) collapsibility may provide an alternative assessment.

Hypothesis:
In ADHF, SCV collapsibility index (CI) may correlate with IVC CI and RAP.

Methods:
Prospective study of non-ventilated patients with ADHF who had NT-proBNP within 24 hours of paired IVC and SCV diameter measurements by US.

Results:
Forty-two patients (median age 66.5 years, 45% female, and 64% white) were enrolled, with 52 encounters. Cardiovascular comorbidities included hypertension (93%), chronic kidney disease (64%), coronary artery disease (55%), atrial fibrillation/flutter (55%), and valvular disease (55%). Of 38 patients with known heart failure, 63% had HFrEF, 16% HFmrEF, and 21% HFpEF.Correlation of paired IVC CI and SCV CI with relaxed breathing was R = 0.65 (N = 36). Correlation of paired IVC CI and SCV CI with forced inhalation was R = 0.47 (N = 36). Log
10
NT-proBNP was inversely correlated with IVC CI (R = -0.35; N = 51) and SCV CI (R = -0.33; N = 36). For patients with right heart catheterization within 24 hours of US, correlation of RAP to IVC CI was R = -0.53 (N = 9), and RAP to SCV CI was R = -0.65 (N = 9). Moderate or severe tricuspid regurgitation decreased CI independently of intravascular volume and RAP (figure).

Conclusions:
US measurements of SCV CI correlate well with paired IVC CI in non-ventilated ADHF. RAP by RHC correlated better with SCV CI than with IVC CI. SCV CI may be a reliable alternative to IVC CI in assessing relative intravascular volume.
Abstract 13535: Cardiopulmonary Exercise Testing in Pediatric Patients With Hypertrophic Cardiomyopathy
Authors: Edelson Jonathan B , Burstein Danielle , Stanley Helen , Shah Maully , McBride Michael W , Stephens Paul , Min Jungwon , Griffis Heather M , Wittlieb-Weber Carol , O’Connor Matthew J , Rossano Joseph W , Lin Kimberly Y , Paridon Stephen
Published: May 2021

Introduction:
Data from exercise stress tests (EST) offer novel information about cardiovascular (CV) health of pediatric hypertrophic cardiomyopathy (HCM) patients and may have prognostic utility.

Methods:
A retrospective single center analysis of all HCM patients <21 years old who had EST from 1/1/2000-1/1/2019 was performed. Clinical and demographic characteristics, and exercise capacity data were analyzed. The primary composite endpoint included death/aborted cardiac death, transplant, or internal cardiac defibrillator (ICD) placement, with each patient limited to a single outcome. Outcomes analysis was performed using a multivariate analysis.

Results:
142 patients (53% with a recognized genetic variant) were identified: 70% were white, and 79% male. No tests were aborted due to safety concerns. By echo, the mean ejection fraction was 68.2% (SD 8.7), mean max septal diameter (MSD) was 1.6 cm (SD 0.7) and average peak left ventricular outflow tract (LVOT) gradient at rest was 26.9 mmHg (SD 53.1). The mean age at EST was 15.3 y (SD 3.5). 90% of patients were tested using cycle ergonometry, and 48% of patients were on a beta-blocker. The mean peak oxygen consumption (V02) was 36.0 ml/kg/min (SD 9.5), 79.7% predicted, mean anaerobic threshold (AT) was 22.1 ml (SD 5.8), and mean peak power (P) was 2.4 watts/kg (SD 0.7), 71.5% predicted. 45.5% of patients had ectopy during exercise, and 9% had an abnormal blood pressure response to exercise (ABPR). The primary endpoint was reached in 32 patients (cardiac death/aborted cardiac death/transplant in 5 and ICD placement in 27). Adjusting for clinical and demographic factors, and beta blocker use, low P, MSD
>
1.8 cm, and LVOT gradient > 50 mmhg, but not ABPR were independent predictors of the composite endpoint.

Conclusion:
Pediatric patients with HCM have impaired CV fitness as measured by EST. EST can be performed safely, and may provide valuable information in the risk stratification in children with HCM.
Abstract 13548: Dicarbonyl Stress, Mitochondrial Impairments, and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension
Authors: Prisco Sasha Z , Hartweck Lynn , Eklund Megan , Thenappan Thenappan , Prins Kurt W
Published: May 2021

Introduction:
Right ventricular dysfunction (RVD) is the leading cause of mortality in pulmonary arterial hypertension (PAH), but the molecular mediators of RVD are incompletely understood. In PAH, RV glucose uptake is inversely proportional to RV function, which is a consequence of increased glycolytic flux due to mitochondrial dysfunction. Methylglyoxal (MG) is a highly reactive dicarbonyl that is generated during glycolysis. MG can deleteriously modulate protein function via post-translational modifications. MG is metabolized by two key enzymes: glyoxalase (Glo) 1 and 2. Finally, DJ-1 is a deglycase enzyme that reverses protein-glycation. The regulation of protein-glycation, the glyoxalase system, and DJ-1 in RVD due to PAH are unexplored.

Methods:
We analyzed protein-glycation, Glo-1/2, and DJ-1 expression in RV extracts from control, monocrotaline (MCT), and pulmonary artery banded (PAB) rats. The effects of protein-glycation on mitochondrial function in H9c2 cardiomyocytes were probed using Seahorse analysis. Finally, we examined the link between protein-glycation and RV function in PAH patients using hemoglobin-A1C as a surrogate measure of protein-glycation.

Results:
In MCT RVs, protein-glycation was increased (3.2±0.9-fold), Glo-1 (48±7%) was decreased, while Glo-2 (1.4±0.1-fold) and DJ-1 (1.5±0.4-fold) were increased. Conversely, in PAB rats, protein-glycation (1.4±0.3-fold) was not as drastically elevated. Moreover, Glo-1 (1.7±0.3-fold), Glo-2 (1.6±0.2-fold change), and DJ-1 (2.3±0.3-fold) levels were all increased. In H9c2 cardiomyocytes, MG treatment induced protein-glycation and impaired mitochondrial function. Finally, hemoglobin-A1C levels were inversely associated with RV contractility in PAH patients.

Conclusions:
Increased protein-glycation results in impaired mitochondrial function in vitro and is associated with more severe RV dysfunction in rodent and human PAH.
Abstract 13571: Association Between Pre-kidney Transplantation Medial Arterial Calcification Andpost-transplant Visit-to-visit Blood Pressure Variability: A Propensity Score Matching Analysis
Authors: Tantisattamo Ekamol , Saowapa Sakditad , Leelaviwat Natnicha , Songtanin Busara , Lopimpisuth Chawit , Vutthikraivit Possawat , Polpichai Natchaya
Published: May 2021

Introduction:
Arterial calcification is associated with vascular stiffness, which manifests with visit-to-visit blood pressure variability (VVBPV). Although media arterial calcification (MAC) is significantly associated with poor cardiovascular outcomes in kidney patients, the association in kidney transplant (KT) patients is unknown.

Hypothesis:
We hypothesize that MAC is associated with VVBPV in long-tern post-KT.

Methods:
Since MAC, which is detected from mammogram (MG) and determined by linear calcified breast arteries, is exclusively medial, female KT patients with ≥1 MG during pre-KT period were included in this study. VVBPV was examined by average successive variability (ASV), which is the average absolute difference between successive BP measured at 4, 12, 24, 36, and 48 weeks post-KT. After balancing patients with and without MAC by using propensity score matching based on age, diabetes, and obesity status, the association between MAC and systolic and diastolic VVBPV (VVSBPV and VVDBPV) at 48 weeks post-KT was tested by multiple linear regression (Figure1A&1B).

Results:
Of 51 patients, mean age±SD is 54±12 years, 21 had diabetes, and 21 were obese. Mean duration of follow-up was 47±9 years. Among 20 patients with MAC, mean VVSBPV was 20±14 mmHg; whereas, VVSBPV in non-MG group was 14±8 mmHg (mean difference -6± 3.0, p 0.06, 95%CI -12.03, 0.15). Mean VVDBPV in MG and non-MG groups were 12±5 and 11±5.6 mmHg, respectively (mean difference -1±1.6, p 0.41, 95%CI -4.44, 1.86). Laboratory-related bone and mineral metabolism were not different between both groups. On average, MG group had 8 mmHg higher VVSBPV compared to non-MG group (Coef. 3.62, p 0.02, 95%CI 1.16, 15.34). The MG group remained having higher VVDBPV but the magnitude of the association decreased and no statistical significance (Coef. 0.58, p 0.83, 95%CI -4.58, 5.73).

Conclusions:
Similar to non-transplant patients, KT recipients with pre-KT MAC had significant higher VVSBPV at the late post-KT.
Abstract 13575: Lack of Both Mitochondrial Proteins Sirt3 and Ucp2 in Mice Recapitulates Many Critical Features of Human Pulmonary Arterial Hypertension (PAH), Including Inflammatory Plexogenic Lesions, Supporting the Metabolic Theory of PAH
Authors: Zhang Yongneng , Zervopoulos Sotirios D , Boukouris Aristeidis E , Saleme Bruno , Liu Yongsheng , Haromy Alois , Webster Linda , Tabatabaei Dakhili Seyed Amirhossein , Ussher John R , Sutendra Gopinath , Michelakis Evangelos D
Published: May 2021

Loss-of function SNPs for Sirt3 (a mitochondrial deacetylase) and Ucp2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with insulin resistance and obesity in humans; and patients with PAH have insulin resistance without being obese. In a cohort of PAH patients (n=60) we found these SNPs often both in the same patient in a homozygous or heterozygous manner and their presence correlated positively with the degree of PAH upon referral, the presence of type II diabetes and outcomes (death, transplantation). We generated and studied double KO mice for
Sirt3
and
Ucp2
using closed-chest right heart catheterization and echocardiography and found increasing severity of pulmonary hypertension (PHT) in

Sirt3
+/-
-Ucp2
+/

-
,

Sirt3
-/-
-Ucp2
+/

-

, Sirt3
+/-
-Ucp2
-/-

and

Sirt3
-/-
-Ucp2
-/-

, associated with decreasing cardiac output and increasing right ventricular hypertrophy, dilatation and dysfunction (TAPSE), compared to wild-type (WT) mice. The LVEDP in all mice was normal. There was increasing severity of vascular remodeling with increasing levels of CD4
+
cell infiltration, while

Sirt3
-/-
-Ucp2
+/-
,
Sirt3
+/-
-Ucp2
-/-

and

Sirt3
-/-
-Ucp2
-/-

mice also developed frequent plexogenic lesions. In vivo and in vitro pulmonary artery smooth muscle cells (PASMC) expressed higher levels of Ki67, compared to WT mice. In vitro, the

Sirt3
-/-
-Ucp2
+/-
,
Sirt3
+/-
-Ucp2
-/-

and

Sirt3
-/-
-Ucp2
-/-

PASMC exhibited more apoptosis-resistance, expressed higher nuclear levels of proliferative transcription factors (HIF1, NFATc2), exhibited decreased respiration and higher levels of glycolysis, similarly to previous reports of animal and human PAH PASMC. The

Sirt3
-/-
-Ucp2
-/-

, but not the WT mice, also developed in vivo evidence of insulin resistance. Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PHT (without environmental or chemical triggers) in a gene dose-response dependent manner that mimics human PAH. No other mouse model of PHT has shown frequent and predictable plexogenic lesions. Our study is relevant to the PAH patients that carry loss-of-function SNPs of mitochondrial proteins and offers a new mouse model of PAH, with more features of human PAH than previous mice models.
Abstract 13581: Prognostic Value of the Patterns of Non-adherence to Anti-platelet Regimen in Stented Patients (PARIS) Bleeding Risk Score for Long Term All-cause and Cardiac Mortalities After Percutaneous Coronary Intervention
Authors: Akama Joh , Shimizu Takeshi , Ando Takuya , Anzai Fumiya , Muto Yuuki , Kimishima Yusuke , Kiko Takatoyo , YOSHIHISA Akiomi , Yamaki Takayoshi , Kunii Hiroyuki , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika
Published: May 2021

Background:
The Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) bleeding risk score has been proposed to predict the risk of bleeding events after percutaneous coronary intervention (PCI). However, the prognostic value of the PARIS bleeding risk score for long term all-cause and cardiac mortalities has not been evaluated. Therefore, we aimed to evaluate the predictive value of the PARIS bleeding risk score for all-cause and cardiac mortalities after PCI.

Methods and Results:
Consecutive 1061 patients, who had admitted to our hospital and performed or undergone PCI, were divided into 3 groups based on PARIS bleeding risk score: low (n = 113), intermediate (n = 420) and high risk groups (n = 528). We compared comorbidities and characteristics of patients among 3 groups. Furthermore, we prospectively followed up all-cause and cardiac mortalities. Clinical characteristics of 3 groups were as follows: mean age (low, intermediate and high risk groups; 56.5, 65.6 and 73.9 years, P < 0.001, respectively), prevalence of chronic kidney disease (2.7%, 24.2% and 67.8%, P < 0.001), atrial fibrillation (8.2%, 8.9% and 21.6%, P < 0.001) and peripheral artery disease (3.1%, 9.1% and 22.1%, P < 0.001). During the mean follow-up period of 1809 days, there were 205 deaths and 64 cardiac deaths. The Kaplan-Meier analysis revealed that both all-cause and cardiac mortalities were highest in high risk group among 3 groups (P < 0.001 and P < 0.001, respectively, Figure). In multivariable Cox proportional hazard analysis adjusted for confounding factors, PARIS bleeding score was an independent predictor of both all-cause and cardiac mortalities (adjusted hazard ratio 1.27 and 1.21 per 1 point increase, P < 0.001 and P = 0.004, respectively).

Conclusion:
The PARIS bleeding risk score showed significant prognostic values for all-cause and cardiac mortalities in patients after PCI.
Abstract 13582: The Effect of Time-restricted Feeding on Weight: A Randomized Feeding Trial
Authors: Maruthur Nisa , Pilla Scott , Maw May T , Duan Daisy , Zhao Di , Guallar Eliseo , Turkson Ocran Ruth Alma , White Karen , Wu Beiwen , Charleston Jeanne , Appel Lawrence J , Clark Jeanne M
Published: May 2021

Introduction:
Time-restricted feeding (TRF) may improve cardiometabolic outcomes. Prior studies of TRF in humans were limited by lack of randomization and controlled feeding, inadequate sample size and short duration.

Hypothesis:
Participants following a TRF pattern will lose more weight at 12 weeks than those following a Usual Feeding Pattern (UFP).

Methods:
We randomized 41 adults with BMI 30-49.9 kg/m
2
and HbA1c 5.7-6.9% to either TRF (80% of total calories before 1 pm) or a UFP (50% of calories after 5 pm) for 12 weeks. Dietary caloric requirement for weight maintenance was determined at baseline for each participant and held constant during the intervention. Participants in both arms consumed the same diet with the same nutrient and food content and only consumed food prepared by the study metabolic kitchen. The primary outcome was weight. Weight and office blood pressure were measured at baseline and 4, 8, and 12 weeks and were analyzed using a linear mixed effects model with an unstructured covariance with indicators for visit and intervention interacted with visit.

Results:
All participants completed the study (TRF, n=21; UFP, n=20). Demographics were similar across arms; mean age was 59 years, and over 90% of participants were female and were black. Baseline weight and systolic BP were higher in the UFP than TRF arm (Table). Weight and blood pressure decreased in both arms during the study, but these decreases did not differ by arm.

Conclusions:
In this controlled feeding study, TRF did not reduce weight and blood pressure compared to UFP.
Abstract 13588: Cardiovascular Outcomes in Patients With Established Atherosclerosis and LDLR Loss of Function: Results From the FOURIER Trial
Authors: Marston Nicholas A , Pirruccello James , Melloni Giorgio , Kamanu Frederick , Choi Seung Hoan , Philippakis Anthony A , Sever Peter S , Keech Anthony C , Lira Pineda Armando , Wang Huei , Giugliano Robert , Lubitz Steven A , Ellinor Patrick T , Sabatine Marc S , Ruff Christian T
Published: May 2021

Introduction:
Patients with loss of function (LoF) mutations of the LDL receptor gene (LDLR) have lifelong elevations in LDL-C. We investigated their risk of cardiovascular (CV) events compared with patients with intact LDLR function.

Methods:
We performed a prospective genetic cohort analysis from the FOURIER trial including all 14,297 patients who consented for genetic testing, passed QC, and were of European ancestry. All patients had established ASCVD and were on moderate or high intensity statin therapy. Whole exome sequencing was performed and LoF mutations in LDLR were identified using LOFTEE, a tool for detecting protein-truncating variants. Polygenic risk for CAD was also calculated for each patient using a previously validated 27-SNP genetic risk score, with high and low risk defined as above and below the median. The primary endpoint was a composite of CV death, myocardial infarction, stroke, unstable angina, or coronary revascularization.

Results:
There were 111 (0.8%) patients identified with an LDLR LoF mutation, representing an approximately 4-fold enrichment compared to the general population. These patients had mean baseline LDL-C levels 62 mg/dl higher than those without an identified LDLR LoF mutation (160 vs. 98 mg/dl, p<0.0001) and a 70% increased risk of CV events (HR 1.70 [1.04-2.79], p=0.03) (
Figure, a
). When polygenic risk for CAD was combined with LDLR mutation status there was a significant gradient of risk identified (p-trend=0.001). Patients without a monogenic LDLR mutation or high polygenic risk had a 2.5-year KM event rate of 8.6%; those with either one had a 10.0-12.9% event rate; those with both had a 17.1% event rate (
Figure, b
).

Conclusion:
ASCVD patients with LDLR LoF mutations have persistently elevated LDL-C and increased CV risk despite intensive statin therapy. The combination of a monogenic LDLR mutation with high polygenic risk for CAD appears additive in this secondary prevention cohort.
Abstract 13593: Global Aortic Stiffness in Bicuspid-associated Aortopathy is Independent of Aortic Dimensions and Similar to Tricuspid Aortic Valve Control Subjects
Authors: Johnson Ethan M , Scott Michael , Jarvis Kelly , Allen Bradley D , Malaisrie S , McCarthy Patrick M , Fedak Paul W , Barker Alexander J , Markl Michael
Published: May 2021

Introduction:
Bicuspid aortic valve (BAV) carries high aortopathy risk, and debate exists about relative contributions of altered wall structure vs. BAV-mediated hemodynamics. Pulse wave velocity (PWV), a surrogate for stiffness, can be quantified from 4D flow MRI. Here we use PWV to study wall stiffness in a large cohort of BAV aortic dilatation patients and two control groups.

Hypotheses:
1. abnormal thoracic aortic (Ao) wall biomechanics for BAV patients result in altered PWV compared to controls and 2. PWV correlates with Ao diameter.

Methods:
This retrospective IRB approved study included 483 subjects: 124 healthy (no known cardiovascular disease), 168 BAV patients with ascending Ao (AAo) dilatation—maximal-area AAo (MAA) or sinus of Valsalva (SOV) diameter ≥4cm—and 191 TAV AAo dilatation (see table). No subjects had valve stenosis or ejection fraction ≤50%. Global PWV was assessed from MRI by cross-correlating flow in 80-100 Ao cutplanes and median AAo diameter by geometric mesh analysis of 3D Ao segmentations.

Results:
In multivariate regression, older age was the most significant predictor of higher PWV (controls: 0.073 m/s / y; TAV: 0.072 m/s / y; BAV: 0.092 m/s / y; all p<1E-4). Increased Ao diameter in controls associated with higher PWV (0.10 m/s / mm, p=0.03). Both BAV and TAV patients had no association between any Ao diameter (MAA, SOV, median) and PWV (p≥0.1 for all metrics). Between subject groups in a given age range, no significant differences of PWV existed except in some younger groups (see image; p≤0.04 in some under-40y).

Conclusion:
Global Ao wall stiffness from PWV in BAV Ao dilatation patients has minimal/no significant difference from non-BAV control PWV, despite genetic factors and different wall structure in BAV patients. This suggests wall tissue differences of BAV patients do not coincide with globally altered Ao stiffness. However, BAV-mediated Ao flow changes manifest regionally, and further study of localized properties would be valuable.
Abstract 13772: Percent Predicted Peak Oxygen Pulse Predicts Vascular Responses to Exercise in HFpEF
Authors: Li Jason P , Sbarbaro John , Schoenike Mark , Nayor Matthew G , Ho Jennifer E , Lewis Gregory D , Malhotra Rajeev
Published: May 2021

Introduction:
Cardiopulmonary exercise testing (CPET) can help identify early stages of heart failure with preserved ejection fraction (HFpEF). We sought to determine if percent predicted peak oxygen pulse (%PredO
2
P, as defined by peak oxygen uptake/heart rate), a noninvasive measure combining stroke volume and peripheral oxygen extraction, could serve as a marker of the hemodynamic response to exercise in HFpEF patients.

Methods:
154 consecutive patients who underwent maximal CPET (RER>1.05) and were diagnosed with HFpEF (defined as LVEF>50% and PCWP/CO >2 mmHg*min/L or supine resting PCWP >15 mmHg) were included. Exclusion criteria included patients who were taking AV nodal agents, were paced, or had atrial fibrillation. Peak O
2
P and percent predicted were calculated using the Wasserman equation for peak VO2 in conjunction with peak predicted heart rate (220-age).

Results:
Tertiles of %PredO
2
P were determined with first tertile at 42.1-76.2%, second tertile at 76.2-94.4%, and third tertile at 94.4-139.2%. Baseline parameters differed across %PredO
2
P tertiles (
Table 1
) with BMI increasing (trend p=0.014). Peak cardiac output (1
st
: 10.0±3.0 L/min, 2
nd
: 11.1±2.4, 3
rd
: 11.5±3.5; p=0.038) and peak stroke volume (1
st
: 70.6±20.1 mL, 2
nd
: 83.0±16.6, 3
rd
: 92.7±20.1; p<0.001) were higher across tertiles, whereas peak HR (1
st
: 143±23 bpm, 2
nd
: 135±25, 3
rd
: 123±26; p<0.001) and peak SVR (1
st
: 959±304 dynes*s/cm
5
, 2
nd
: 831±187, 3
rd
: 810±321; p=0.009) were lower. Exercise PAP/CO slope (1
st
: 4.5±2.1 mmHg*min/L, 2
nd
: 3.6±1.6, 3
rd
: 3.3±1.7; p=0.003) and PCWP/CO slope (1
st
: 3.4±1.8 mmHg*min/L, 2
nd
: 2.9±1.4, 3
rd
: 2.8±2.0; p=0.015) were lower across tertiles of %PredO
2
P.

Conclusions:
%PredO
2
P is a noninvasive variable that associates with vascular responses to exercise in HFpEF patients. Higher %PredO
2
P was associated with improved vascular responses to exercise with lower SVR, PAP/CO and PCWP/CO slopes.
Abstract 13788: Acute Administration of Nicotine Induces Transient Elevation of Blood Pressure and Increases Myocardial Infarct Size in an Acute Myocardial Ischemia/reperfusion Rat Model
Authors: Zhao Lifu , Dai Wangde , Carreno Juan , shi jianru , Kleinman Michael , Kloner Robert A
Published: May 2021

Introduction:
Nicotine is a major bioactive component in tobacco cigarettes and electronic cigarettes. Despite the fact that smokers are at higher risk of experiencing an acute myocardial infarction (AMI), there are few studies that have examined the acute effects of nicotine on AMI.To address this issue, our present study was to examine the acute effects of nicotine on myocardial infarct size, no reflow, cardiac hemodynamics and cardiac function in a rat myocardial infarct model.

Methods:
Forty-six female Sprague-Dawley rats were randomly divided into nicotine group and control group (n=23/group) and received an intravenous loading dose of nicotine at 2.0 μg/kg/min or saline for 30 minutes before starting coronary artery occlusion, then followed by a maintenance dose 0.35 μg/kg/min of nicotine to the end of 3.5 hours of occlusion (30 minutes) and reperfusion (3 hours).

Results:
At baseline, there were no difference between the two study groups, in systolic blood pressure (BP in mmHg) (nicotine, 69.0±2.7; control, 69.3±4.4;
p
> 0.05), or diastolic BP (nicotine, 45.7±3.2; control, 48.2±4.2;
p
> 0.05). Nicotine initially increased systolic BP (nicotine, 97.0±8.6; control, 69.2±3.3,
p
<0.05) and diastolic BP (nicotine, 65.6±6.4; control, 47.4±3.1,
p
< 0.01) at 10 minutes after starting injection of the loading dose; pressures dropped to control levels in both groups at 30 minutes. During occlusion/reperfusion, the BP and heart rate were not altered by nicotine. Nicotine significantly increased myocardial infarct size as a percentage of the ischemic risk zone compared to the controls (nicotine, 54.9 ± 1.9 %; control, 48.6 ± 2.7 %,
p
< 0.05), but nicotine did not affect the no-reflow size (nicotine, 34.8 ± 3.10 %; control, 33.7 ± 3.0%,
p
> 0.05). Nicotine did not alter fractional shortening assessed by echocardiography.

Conclusions:
Nicotine infusion can transiently increase blood pressure in anesthetized rats. During coronary occlusion and reperfusion, nicotine increased myocardial infarct size, but did not affect hemodynamics or fractional shortening, suggesting that the increase in infarct size was not simply due to an increase in oxygen demand due to altered afterload, heart rate or contractility, but may reflect a more direct effect on the myocardium.
Abstract 13804: Clinical Profile and Outcomes of Myocardial Infarction With Non-obstructive Coronary Arteries in Older Adults
Authors: Rostomian Ara H , Phan Derek Q , Lee Mingsum , Zadegan Ray X
Published: May 2021

Introduction:
Myocardial Infarction with non-obstructive coronary artery disease (MINOCA) is found in 5%-6% of patients with acute myocardial infarction (AMI). As such, the diagnosis and management of AMI patients with non-obstructive coronary artery disease (NOCAD) poses a challenge as compared to patients with MI with coronary artery disease (MICAD).

Hypothesis:
To evaluate the characteristics and outcomes of MINOCA in older patients as compared with MICAD patients, with and without revascularization.

Methods:
This was a retrospective observational study of patients ≥80 years old who underwent invasive coronary angiography (ICA) for AMI between 2009-2019 at Kaiser Permanente Los Angeles Medical Center. MINOCA was defied as <50% stenosis of coronary arteries on angiography with a troponin level ≥0.05 ng/ml. Patients with MINOCA vs MICAD were compared. Multivariate logistic regression was used to identify independent predictors of MINOCA and Kaplan-Meier survival analysis was used to analyze all-cause mortality between cohorts.

Results:
A total of 259 patients with MINOCA (mean ± SD age 83.8±2.7 years, 68% female) and 687 patients with MICAD (84.7±3.4 years, 40% female) were analyzed. Younger age (odds ratio [OR]=1.11; 95% confidence interval [CI]=1.05-1.18), female sex (OR=3.14; CI=2.20-4.48), black race (OR=2.53; CI=1.61-3.98), no history of prior stroke (OR=1.56; CI=1.06-2.33), atrial fibrillation or flutter (OR=2.04; CI:1.38-3.02), lower troponin levels (OR=1.08; CI:1.03-1.11), and lower triglyceride levels per 10 mg/dl increments (OR=1.06; CI:1.03-1.11) increased the odds of having MINCOA as compared to MICAD. At median follow-up of 2.4 years, MINOCA was associated with a lower rate of death (44.8% vs 55.2%, p<0.01) compared to un-revascularized MICAD, but no difference (31.3% vs 40.4%, p=0.68) when compared to re-vascularized MICAD.

Conclusions:
Patients age ≥80 years with MINOCA have fewer traditional risk factors compared to their counterparts with MICAD and fewer deaths compared to un-revascularized MICAD, but similar mortality compared to revascularized MICAD