bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P296: Effective Arterial Elastance and Hypertensive Response to Stress
Authors: Kieu Andy , Widlansky Michael 
Published: June 2021

Effective arterial elastance (Ea) has shown to be of importance in resting hypertension, though its role is unclear in hypertensive response to exercise or dobutamine. Prior studies have shown that individuals with hypertensive response to exercise (HRE) have diastolic dysfunction as shown on echocardiogram, but there are limited data to show if there are any correlations with Ea.
In this retrospective cohort study, we reviewed 415 stress echocardiograms (treadmill and dobutamine) that were performed between 2009 and 2011 that were completed on the same day as a full resting TTE at our institution. Following exclusion of subjects with coronary artery disease, resting LV ejection fraction less than 50%, resting regional wall motion abnormalities and inducible ischemia, 182 subjects who underwent treadmill stress echocardiogram (TSE) and 149 subjects who underwent dobutamine stress echocardiogram (DSE) were left for analysis. We determined univariate and multivariate predictors of a HTN response to each type of stress test by logistical regression. Covariates included age, sex, resting systolic pressure, resting diastolic pressure, resting hypertension, pulse pressure, Ea, septal e’, septal a’, mitral E/e’, mitral inflow E/A ratio, LV mass index, and left atrial size.
In the TSE group, 26 subjects had hypertensive responses compared to 11 in the DSE group. Resting hypertension was predictive of HRE in both groups. Ea was not predictive of HRE in the TSE group, but was predictive for those in the DSE group (OR 5.91, p=0.03).
Increasing resting Ea predicts hypertensive responses to dobutamine, but not exercise. Traditional diastolic Doppler parameters are not significantly associated with hypertensive responses to either stressor.
Abstract P314: Urinary Renin and Kidney RAS Activation in Mice with Diabetic Kidney Disease
Authors: Rein Johannes , Valles Patricia , Wysocki Jan , Ye Minghao , Afkarian Mariam , Batlle Daniel 
Published: June 2021

RAS is overactive in kidneys from patients with diabetic nephropathy (DN), but circulating plasma renin activity (PRA) is usually low. This is known as the renin-paradox. We evaluated juxtaglomerular (JGA), tubular and urinary renin, as a potential source of local RAS activation, to gain some understanding of this paradox.
Mice with STZ induced diabetes were used which had mild albuminuria and glomerular mesangial expansion consistent with early DN. Renin expression in the JGA and in the collecting tubule (CT) was evaluated by immunohistochemistry. IF was used to localize renin within CT cells. Proximal tubular renin was evaluated by RT-real time PCR in microdissected proximal tubules (PT). Urinary renin and Ang II were measured by ELISA.
Urinary Ang II was increased (37.8±11.4 vs. 99.0±21.6 pg/mg creat, p<0.05) reflecting an active kidney RAS. Urinary renin was also increased in STZ-treated as compared to controls (Table). In microdissected PTs there were no significant differences in renin mRNA between control and STZ-mice. By immunostaining, renin was localized to principal cells in the CT and the number of renin stained CTs was higher in STZ than in control mice. In sharp contrast, renin staining of the JGA of STZ-mice was significantly reduced as compared to controls.
We conclude that in DN renin expression in the JGA, the physiologic site of renin secretion into the circulation is suppressed, whereas in the CT it is increased. Activation of the kidney RAS, as inferred from increased urinary Ang II, likely occurs as a result of renin of tubular origin rather than from JGA renin. Since PT renin is not increased, the CT may provide the source of tubular renin for RAS activation.
Combined Therapy With Polyethylene Glycol‐20k and MCC950 Preserves Post‐Resuscitated Myocardial Function in a Rat Model of Cardiac Arrest and Cardiopulmonary Resuscitation
Authors: Liang Lian , Zhang Guozhen , Li Hui , Cheng Cheng , Jin Tao , Su Chenglei , Xiao Yan , Bradley Jennifer , Peberdy Mary A. , Ornato Joseph P. , Mangino Martin J. , Tang Wanchun 
Published: June 2021

BackgroundTo investigate the therapeutic potential of combined therapy with polyethylene glycol‐20k (PEG‐20k) and MCC950 on post‐resuscitation myocardial function in a rat model of cardiac arrest.Methods and ResultsThirty rats were randomized into 5 groups: Sham, Control, PEG‐20k, MCC950, PEG‐20k+ MCC950. Except for sham, animals were subjected to 6 minutes of ventricular fibrillation followed by 8 minutes cardiopulmonary resuscitation. Two milliliters PEG‐20k was administered by intravenous injection coincident with the start of cardiopulmonary resuscitation; MCC950 (10 mg/kg), a highly selective NLRP3 inflammasome inhibitor, was delivered immediately after restoration of spontaneous circulation. Myocardial function, sublingual microcirculation, mitochondrial function, plasma cardiac troponin I, and interleukin‐1β, expression of proteins in SIRT1 (sirtuin 1)/PGC‐1α (peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha) and NLRP3 (the NOD‐like receptor family protein 3) inflammasome pathways were evaluated. Following cardiopulmonary resuscitation, myocardial function was compromised with a significantly decreased cardiac output, ejection fraction, and increased myocardial performance index, cardiac troponin I. Sublingual microcirculation was disturbed with impaired perfused vessel density and microvascular flow index. Cardiac arrest reduced mitochondrial routine respiration, Complex I‐linked respiration, respiratory control rates and oxidative phosphorylation coupling efficiency. PEG‐20k or MCC950 alone restored mitochondrial respiratory function, restituted sublingual microcirculation, and preserved myocardial function, whereas a combination of PEG‐20k and MCC950 further improved these aspects. PEG‐20k restored the expression of SIRT1 and PGC‐1α, and blunted activation of NLRP3 inflammasomes. MCC950 suppressed expression of cleaved‐caspase‐1/pro‐caspase‐1, ASC (apoptosis‐associated speck‐like protein), GSDMD [gasdermin d], and interleukin‐1β.ConclusionsCombined therapy with PEG‐20k and MCC950 is superior to either therapy alone for preserving post‐resuscitated myocardial function, restituting sublingual microcirculation at restoration of spontaneous circulation at 6 hours. The responsible mechanisms involve upregulated expression of SIRT1/PGC1‐α in tandem with inhibition of NLRP3 inflammasomes.
Associations of Skeletal Muscle Mass and Fat Mass With Incident Cardiovascular Disease and All‐Cause Mortality: A Prospective Cohort Study of UK Biobank Participants
Authors: Knowles Rebecca , Carter Jennifer , Jebb Susan A. , Bennett Derrick , Lewington Sarah , Piernas Carmen 
Published: June 2021

Background
There is debate whether body mass index is a good predictor of health outcomes because different tissues, namely skeletal muscle mass (SMM) and fat mass (FM), may be differentially associated with risk. We investigated the association of appendicular SMM (aSMM) and FM with fatal and nonfatal cardiovascular disease (CVD) and all‐cause mortality. We compared their prognostic value to that of body mass index.

Methods and Results
We studied 356 590 UK Biobank participants aged 40 to 69 years with bioimpedance analysis data for whole‐body FM and predicted limb muscle mass (to calculate aSMM). Associations between aSMM and FM with CVD and all‐cause mortality were examined using multivariable Cox proportional hazards models. Over 3 749 501 person‐years of follow‐up, there were 27 784 CVD events and 15 844 all‐cause deaths. In men, aSMM was positively associated with CVD incidence (hazard ratio [HR] per 1 SD 1.07; 95% CI, 1.06–1.09) and there was a curvilinear association in women. There were stronger positive associations between FM and CVD with HRs per SD of 1.20 (95% CI, 1.19–1.22) and 1.25 (95% CI, 1.23–1.27) in men and women respectively. Within FM tertiles, the associations between aSMM and CVD risk largely persisted. There were J‐shaped associations between aSMM and FM with all‐cause mortality in both sexes. Body mass index was modestly better at discriminating CVD risk.

Conclusions
FM showed a strong positive association with CVD risk. The relationship of aSMM with CVD risk differed between sexes, and potential mechanisms need further investigation. Body fat and SMM bioimpedance measurements were not superior to body mass index in predicting population‐level CVD incidence or all‐cause mortality.
Standardizing the Definition and Analysis Methodology for Complete Coronary Artery Revascularization
Authors: Ali Ziad A. , Horst Jennifer , Gaba Prakriti , Shaw Leslee J. , Bangalore Sripal , Hochman Judith S. , Maron David J. , Moses Jeffrey W. , Alfonso Maria A. , Madhavan Mahesh V. , Dressler Ovidiu , Reynolds Harmony , Stone Gregg W. 
Published: June 2021

Abstract
Guideline‐based medical therapy is the foundation of treatment for individuals with coronary artery disease. However, revascularization with either percutaneous coronary intervention or coronary artery bypass grafting may be beneficial in patients with acute coronary syndromes, refractory symptoms, or in other specific scenarios (eg, left main disease and heart failure). While the goal of percutaneous coronary intervention and coronary artery bypass grafting is to achieve complete revascularization, anatomical and ischemic definitions of complete revascularization and their methodology for assessment remain highly variable. Such lack of consensus invariably contributes to the absence of standardized approaches for invasive treatment of coronary artery disease. Herein, we propose a novel, comprehensive, yet pragmatic algorithm with both anatomical and ischemic parameters that aims to provide a systematic method to assess complete revascularization after percutaneous coronary intervention or coronary artery bypass grafting in both clinical practice and clinical trials.
Electrocardiographic Imaging of Repolarization Abnormalities
Authors: Bear Laura R. , Cluitmans Matthijs , Abell Emma , Rogier Julien , Labrousse Louis , Cheng Leo K. , LeGrice Ian , Lever Nigel , Sands Gregory B. , Smaill Bruce , Haïssaguerre Michel , Bernus Olivier , Coronel Ruben , Dubois Rémi 
Published: June 2021

Background
Dispersion and gradients in repolarization have been associated with life‐threatening arrhythmias, but are difficult to quantify precisely from surface electrocardiography. The objective of this study was to evaluate electrocardiographic imaging (ECGI) to noninvasively detect repolarization‐based abnormalities.

Methods and Results

Ex vivo data were obtained from Langendorff‐perfused pig hearts (n=8) and a human donor heart. Unipolar electrograms were recorded simultaneously during sinus rhythm from an epicardial sock and the torso‐shaped tank within which the heart was suspended. Regional repolarization heterogeneities were introduced through perfusion of dofetilide and pinacidil into separate perfusion beds. In vivo data included torso and epicardial potentials recorded simultaneously in anesthetized, closed‐chest pigs (n=5), during sinus rhythm, and ventricular pacing. For both data sets, ECGI accurately reconstructed T‐wave electrogram morphologies when compared with those recorded by the sock (ex vivo: correlation coefficient, 0.85 [0.52–0.96], in vivo: correlation coefficient, 0.86 [0.52–0.96]) and repolarization time maps (ex‐vivo: correlation coefficient, 0.73 [0.63–0.83], in vivo: correlation coefficient, 0.76 [0.67–0.82]). ECGI‐reconstructed repolarization time distributions were strongly correlated to those measured by the sock (both data sets,
R
2
≥0.92). Although the position of the gradient was slightly shifted by 8.3 (0–13.9) mm, the mean, max, and SD between ECGI and recorded gradient values were highly correlated (
R
2
=0.87, 0.75, and 0.86 respectively). There was no significant difference in ECGI accuracy between ex vivo and in vivo data.

Conclusions
ECGI reliably and accurately maps potentially critical repolarization abnormalities. This noninvasive approach allows imaging and quantifying individual parameters of abnormal repolarization‐based substrates in patients with arrhythmogenesis, to improve diagnosis and risk stratification.
Abstract 234: Physiological Toxicity Assessment of Tyrosine Kinase Inhibitors with Human Induced Pluripotent Stem Cell Cardiomyocytes
Authors: Stohlman Jayna , Schocken Derek , Vicente Jose , Chan Dulciana , Johannesen Lars , Zhang Xiaoyu , Abassi Yama , Strauss David , Blinova Ksenia 
Published: June 2021

Tyrosine kinase inhibitors (TKIs) have improved targeted therapeutics for cancer management despite possible cardiac side effects, including decreased contractility. A combination microelectrode and impedance platform was used to assess field potential (FP) electrical activity and contractility, respectively, after acute and chronic exposure of six TKIs on human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). Four non-TKI drugs were tested to confirm assay sensitivity.
hERG current inhibitors dofetilide and pentamidine increased beat rate (BR) corrected FP duration (FPDc). Dofetilide (6μM) induced transient early afterdepolarizations (EADs), characterized as ectopic beats/notching in the FP signal, and decreased impedance amplitude (BAmp) at 48hrs. Multi-channel blocker amiodarone (2μM) acutely decreased FPDc, with quiescence up to 1hr, and increased BAmp after 24hrs. Doxorubicin decreased BAmp, inducing quiescence starting at 48hrs (5μM and 10μM). Nilotinib, sorafenib and sunitinib, which have varying documented risks of clinical QT prolongation and/or cardiotoxicity, increased FPDc. With highest tested doses, nilotinib (6μM) generated persistent EADs and increased BR, sunitinib (2.5μM) produced tachyarrhythmias with minimal impedance-evident contractions that recovered by 24hrs, and sorafenib (10μM) induced quiescence that recovered by 3hrs. Imatinib, erlotinib and lapatinib, which have fewer clinical cardtiotoxic effects, did not cause rhythm disturbances. Erlotinib and lapatinib had no significant effect on FPDc, lapatinib (2.5μM and 5μM) decreased BR, while imatinib (15μM) acutely increased FPDc and increased BR after 48hrs.
Tandem electrical and impedance screening in hiPSC-CMs for drug cardiotoxicity was consistent with the clinical experience for TKIs, suggesting its potential utility for preclinical cardiotoxicity assessment for proarrhythmia and decreased contractility.
Abstract 251: Mixed Lineage Kinase 3 Functions as a Protein Kinase G I Alpha Antiremodeling Substrate in the Heart
Authors: Calamaras Timothy D , Baumgartner Robert A , Wang Guang-rong , Lane Angela M , Aronovitz Mark , Davis Roger J , Karas Richard H , Blanton Robert M 
Published: June 2021

Background:
cGMP-dependent protein kinase G I α (PKGIα) via its leucine zipper (LZ) domain prevents adverse cardiac remodeling. Identifying and characterizing PKGIα-LZ dependent substrates may reveal novel therapeutic targets in the myocardium. We previously identified the LZ-containing Mixed Lineage Kinase 3 (MLK3) as a potential PKGIα substrate. Further, MLK3 whole body knockout mice had increased LV hypertrophy and dysfunction after pressure overload. In this study we sought to further explore the PKGIα-MLK3 interaction, and to investigate MLK3 in human cardiomyopathy.

Results:
We first tested for a direct interaction between PKGIα and MLK3. Using affinity purified recombinant proteins we observed co-precipitation of PKGIα and MLK3 that was disrupted by mutation of the PKGIα LZ domain (LZ mutation: MLK3 binding decreased by 61.61% ±13.6, n=4). In mouse heart the interaction between native MLK3 and PKGIα was observed by co-immunoprecipitation (n=3). PKGIα phosphorylated MLK3 at the activation loop in vitro, which was attenuated by inhibiting PKGIα kinase function (n=3).

We next tested if MLK3 regulates hypertrophy of cultured cardiomyocytes. Adult rat ventricular cardiomyocytes treated with the MLK3 inhibitor URMC-099 (100 nM, 48 hrs) exhibited increased cell size compared to vehicle treated cells (23.3% increase ± 3.64 SEM vs DMSO vehicle, n=3, 50 cells per treatment).
Finally, we examined MLK3 expression in hearts from human patients with non-ischemic or hypertrophic cardiomyopathy. Compared to normal LV samples (NDRI, n=4), MLK3 expression was markedly elevated in both non-ischemic and hypertrophic cardiomyopathy LV samples (MLK3/GAPDH: non-ischemic: 6.26 ADU ± 0.85, n=9, hypertrophic: 6.97 ADU ± 1.42, n=8).

Conclusion:
These data support a model in which PKGIa directly binds and activates MLK3, leading in the cardiomyocyte to repression of cellular hypertrophy. Our findings in tissue from human failing hearts further suggest that MLK3 upregulation may act as a compensatory anti-remodeling signal in the setting of cardiac dysfunction, which ultimately becomes overwhelmed by pro-remodeling signals. More broadly our findings support that identifying PKGIa LZ-dependent substrates can reveal novel anti-remodeling molecules.
Abstract 382: Cell Type-specific Fibroblast Growth Factor Receptors That are Regulated in Human Heart Disease
Authors: Peter Angela K , Bugg Darrian N , Ozeroff Christopher D , Chonchol Michel , Ambardekar Amrut V , Kakkar Rahul , Leinwand Leslie A 
Published: June 2021

Chronic kidney disease (CKD) is characterized by increased serum levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23), the development of left ventricular hypertrophy, and increased risk of mortality due to cardiovascular disease. The FGF receptors (FGFRs) responsible for facilitating the effect of FGF23 on the heart and the expression patterns of FGFRs in the different cell types in the heart remain largely uncharacterized. We hypothesized that cardiomyocytes express a different FGFR profile than cardiac fibroblasts and that this differential expression profile could contribute to cell type-specific responses to FGF23. We measured FGFR mRNA levels at baseline and following pro-hypertrophic growth factor stimulation in isolated adult rat ventricular cardiomyocytes (ARVMs), neonatal rat ventricular cardiomyocytes (NRVMs), and neonatal rat ventricular fibroblasts (NRVFs). At baseline, NRVMs expressed predominantly FGFR1 but also expressed FGFRs 2 and 3. In ARVMs, FGFRs 1 and 3 predominated while FGFRs 2 and 4 were expressed at very low levels. FGFRs in ARVMs and NRVMs were unchanged by growthfactor stimulation. At baseline, NRVFs expressed equal amounts of FGFRs 1, 2 and 3 which were all downregulated with FGF23 stimulation.
To determine whether these results translated to human hearts, we examined the FGFR profile in a cohort of non-failing, hypertrophic cardiomyopathy (HCM), and ischemic cardiomyopathy (ICM) human patient samples. Compared to non-failing patients, we found FGFR2 was significantly increased in HCM patients and trended towards an increase in ICM patients. The cardiac FGFR2 profile matched the FGF23 profile. In addition, we found that FGFR4 was significantly down regulated in both ICM and HCM compared to non-failing patients.
In conclusion, different cell types in the heart differ in their FGFR profiles at baseline. The FGFR profile does not change in NRVMs or ARVMs in response to FGF23 treatment, but the expression of FGFRs 1, 2, and 3 decrease in NRVFs in response to FGF23. HCM and ICM in humans is characterized by an increase in FGFR2 and FGF23 expression accompanied with a downregulation of FGFR4 expression. Modulating FGFRs in the myocardium may provide a novel therapeutic target in CKD patients.
Abstract 398: Alternative Splicing of Titin Restores Diastolic Function and Improves HFpEF Associated Symptoms
Authors: Bull Mathew , Methawasin Mei , Strom Joshua , Nair Pooja , Hutchinson Kirk , Granzier Henk 
Published: June 2021

Greater than half of all heart failure (HF) patients suffer from increased diastolic stiffness and impaired relaxation of the left ventricle while their ejection fraction (EF) is preserved (HFpEF). HFpEF is a complex disease characterized by diastolic dysfunction, exercise intolerance, and concentric hypertrophic remodeling. No effective therapy exists for treating this pervasive disease due in part to our limited understanding of the underlying pathophysiology. Titin, the largest known protein and molecular spring in the heart, has emerged as a prime candidate for therapeutic targets aimed at restoring compliance to the sarcomere in order to improve diastolic function.
Titin has two main cardiac isoforms; the smaller N2B isoform (~3.0 MDa) and the larger more compliant N2BA isoform (~3.3 MDa). Diastolic stiffness of the left ventricle is in large part dependent upon the N2BA:N2B isoform ratio. Modification of these two primary isoforms can be achieved post-transcriptionally through inhibiting the known titin splicing factor Rbm20. Alternative splicing of messenger RNA occurs primarily in the spring region of titin and therefore regulates the elastic property of titin through changes in contour length of the spring.

The current study evaluates whether reduction of titin splicing factor Rbm20 has a beneficial effect on the diastolic function of mice with restrictive cardiomyopathy. A previously published mouse model deficient in titin’s IA junction (

Ttn
ΔIAjxn

) places increased strain on the spring region of titin and acts as a mechanical analogue of the titin-based increase in passive myocardial stiffness found in HFpEF patients. This model exhibits a HFpEF-like phenotype apparent as early as 3 months in the adult mouse that becomes exaggerated with age apart from pharmacological or surgical intervention. We report for the first time a rescue of HFpEF in the mouse through inhibiting Rbm20. We demonstrate that Rbm20 reduction restores diastolic function, improves exercise tolerance and attenuates afterload induced pathologic remodeling of the left ventricle. No specific FDA approved therapies exist to treat the pathologically stiff left ventricle, therefore our findings on Rbm20 inhibition are clinically significant.
Abstract 425: Doxorubicin Upregulation of the Fibrotic Transforming Growth Factor-beta Pathway
Authors: Ramirez Trevi A , Aune Greg 
Published: June 2021

Childhood cancer survivors are at an increased risk of heart disease as a result of their cancer treatments. Drugs like doxorubicin (DOX) are an effective part of treatment regimens, but have been proven to cause acute and chronic cardiotoxicity (DOX tox). An under-investigated aspect of DOX tox is the interstitial fibrosis that the majority of patients develop. This project aims to better understand the pathology of DOX-induced cardiac fibrosis and the role of the pro-fibrotic transforming growth factor-beta (TGFb) signaling pathway. Research in the area of fibrosis and the effect of DOX on cardiac fibroblasts will increase our understanding of DOX tox. This understanding will allow for improved treatment of pediatric cancer patients by reducing the cardiotoxic sequelae of many standard chemotherapy regimens.
Cardiac fibroblasts, isolated from 3 week old mice and treated with 5 μM DOX, showed an increase in nuclear pSMAD compared to control cells via fluorescent immunocytology (2.06 ± 0.26 vs 1.13 ± 0.15, p<0.05). Mice treated with 3 mg/kg DOX injections from 2 weeks to 6 weeks of age showed increased TGFb staining in the left ventricle (1.83 ± 0.34 vs 0.87 ± 0.28, p<0.05) a week after treatment ceased. A subset of mice were followed into old age and sacrificed at 80 weeks. A clear increase in TGFb was seen with age. However, 80 week mice that were exposed to DOX early in life showed a greater increase in TGFb staining compared to untreated 80 week old mice (44.50 ± 2.48 vs 30.93 ± 2.30, p<0.001).
Early DOX exposure causes chronic molecular changes as evidenced by acute and chronic changes in signaling molecules in cardiac tissue. Changes in collagen seen in earlier studies and increases in MMP-2 from the literature suggest a cardiac remodeling phenotype in DOX-exposed animals. This project demonstrates that DOX initiates changes to pro-fibrotic pathways, seemingly driven by the TGFb signaling pathway.