bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17658: The Impact of Elective Percutaneous Coronary Intervention on Coronary Microvascular Resistance
Authors: Murai Tadashi , Lee Tetsumin , Suzuki Asami , Kanaji Yoshihisa , Matsuda Junji , Araki Makoto , NIida Takayuki , Isobe Mitsuaki , Kakuta Tsunekazu
Published: July 2021

Background:
The influence of elective percutaneous coronary intervention (PCI) in patients with stable angina pectoris on coronary microvascular function has not been fully elucidated. We performed a prospective study to investigate serial changes of microvascular function in patients undergoing elective PCI.

Methods and Results:
The index of microcirculatory resistance (IMR) and fractional flow reserve (FFR) was measured before, after PCI, and at follow-up (10 months) in 52 patients treated with single vessel uncomplicated elective PCI (male 80.8%, age 66.5 ± 8.3). IMR was calculated by taking collateral flow into account. The median IMR values before, after PCI, and at follow-up were 24.2 (interquartile range (IQR) 13.1-31.3), 15.8 (IQR 11.8-21.6), and 14.7 (IQR 11.3-20.9), respectively. IMR values significantly decreased after PCI (P=0.006), and showed no further significant change at follow-up. There was no significant relationship between delta IMR (post-pre IMR) values and PCI-related cardiac troponin elevations that distributed in the range of (median: 0.50 ng/dL, IQR 0.22-1.02 ng/dL). Pre-PCI IMR was not correlated with pre-PCI FFR values. Post-PCI IMR was significantly correlated with pre-PCI IMR values (P=0.005). Periprocedural IMR decrease (Pre-Post) was inversely associated with pre-PCI FFR (P=0.008) and greater improvement of FFR values by PCI was significantly associated with greater reduction of IMR values at follow-up (P=0.03). Decrease in FFR values from immediately after PCI to follow-up was greater in patients with DM (P=0.01). Furthermore, IMR at follow-up was worse in patients with DM than those without (P=0.009).

Conclusions:
Removal of physiologically significant epicardial stenosis leads to a decrease in microvascular resistance in patients with stable angina undergoing electively performed uncomplicated PCI. The periprocedural decrease in microvascular resistance was influenced by the hemodynamic significance of the epicardial stenosis before PCI. The baseline status of microvascular function is a significant determinant of post-PCI and follow-up microvascular function in these patients, and diabetes has an impact on the serial changes in microvascular function after successful PCI.
Abstract 17667: Local Atrophy of Parahippocampal Gyrus is Prominent in Heart Failure Patients Without Dementia
Authors: Meguro Tomomi
Published: July 2021

Introduction:
The exacerbation of heart failure (HF) induces brain damage and the cognitive impairment that attenuates the effects of treatment. The medial lateral lobe of brain, including parahippocampal gyrus, is known to reduce its volume in patients with cognitive disorder especially in Alzheimer’s disease. The magnetic resonance imaging (MRI) scans identify morphological changes in the brains of patients with HF. Therefore, the Voxel-based morphometry (VBM) of three-dimensional brain MRI may contribute to predict the potential risk of mild cognitive impairment (MCI) of patients with HF.

Hypothesis:
The severity of local atrophy of parahippocampal gyrus, a potential risk of MCI, is prominent in heart failure patients without dementia.

Methods:
Ten HF patients (age 72+/-15 years, NYHA class II, EF43+/-15 %) and 9 control (age 76+/- 8 years) were enrolled. Patients with dementia were excluded from this study. Three dimensional T1 weighted sagittal images of whole brain were taken using 1.5T MRI. Image analysis was performed to evaluate the severity of local brain atrophy of gray matter using 2mm VBM by the software based on statistical parametric mapping. The Z-score value of volume of interest (VOI) was calculated to evaluate the severity of atrophy in parahippocampal gyrus.

Results:
The severity of total brain atrophy was similar between HF (8.3+/-3.4%) and control (8.0+/-4.1%). However, as shown in the figure of representative cases, the Z-score value of VOI (pink circle), reflecting the severity of atrophy in parahippocampal gyrus (white arrows), was larger in HF patients group (1.4+/-0.7) in comparison with control group (0.8+/-0.4, P=0.034). The Z-score value was not correlated with age, ejection fraction, left atrial dimension, left ventricular dimensions, or BNP in HF group.

Conclusions:
In patients with HF, atrophy in parahippocampal gyrus was prominent in comparison with control. Patients with heart failure have potential risk of MCI and dementia.
Abstract 17699: Inositol-1,4,5-Trisphosphate-Mediated Pacemaker Activity in NCX KO Mouse Sinoatrial Nodal Cells
Authors: Kapoor Nidhi , Tran Andrew , Zhang Rui , Kang Jeanney , Goldhaber Joshua I
Published: July 2021

Sinoatrial node (SAN) automaticity is due to the interplay of several membrane currents, including the current produced by Na-Ca exchanger (NCX) in response to Ca cycling. Several lines of evidence suggest that inositol-1,4,5-triphosphate receptors (IP
3
Rs) that mobilize [Ca]
i
are implicated in generation of automaticity in embryonic and adult cardiomyocytes. Increased IP
3
R expression observed in failing heart may predispose to arrhythmias and could contribute to the elevated heart rates associated with systolic heart failure. However, whether IP
3
R signaling influences SAN pacemaking is still controversial, in part due to the confounding influence of periodic Ca flux through the sarcolemma during every beat. To address this concern, we used NCX knockout (KO) SAN cells to study the role of IP
3
signaling on pacemaker activity. In these cells Ca flux across the sarcolemmal membrane is practically eliminated due to NCX ablation and no Ca flux through L-type Ca channels due to lack of action potentials, yet periodic spontaneous waves are still generated by the localized Ca releases (LCRs) of the “Ca clock”. Thus these waves are “uncoupled” from the membrane because there is no NCX to contribute to the diastolic depolarization in response to the release of [Ca]
i
. We recorded spontaneous Ca oscillations using line scan confocal microscopy in WT and NCX KO SAN cells in the presence of an IP
3
R blocker or during inhibition of phospholipase C (PLC). We found that superfusion with the IP
3
R blocker, 2-APB (2 μm) decreased the frequency of Ca transients in WT SAN cells by 82.6% (n=9, p<0.05) and Ca waves in NCX KO cells by 66% (n=10, p<0.05). Similar results were also obtained on superfusion with the PLC antagonist, U73122 (1 μm). Alternatively, an increase in IP
3
production using the α-1 adrenergic receptor agonist phenylephrine (10 μm) led to an increase in the frequency of Ca transients in WT SAN cells (n=8. P< 0.05) and Ca waves in NCX KO cells (n=9, p <0.05). This effect was blocked on the subsequent additional application of 2-APB. In summary our results indicate that Ca release from IP
3
Rs can modulate Ca oscillation frequency in NCX KO SAN cells and support our hypothesis that IP
3
signaling modulates the Ca cycling processes that regulate pacemaker frequency in the SAN.
Abstract 17712: Comparison of Three-Dimensional and Two-Dimensional Quantitative Coronary Angiography and Intravascular Ultrasound for the Functional Assessment of Coronary Lesions
Authors: Nishi Takeshi , Nakayama Takashi , Fujimoto Yoshihide , Kobayashi Yoshio
Published: July 2021

Introduction:
Three-dimensional (3-D) quantitative coronary angiography (QCA) reportedly allows a more accurate depiction of true vessel geometry when compared with standard two-dimensional (2-D) QCA and has been validated by intravascular ultrasound (IVUS). Although IVUS is currently thought to provide the most accurate measurements of vessel geometry and lesion severity, 3-D QCA measurements can be performed on existing standard coronary angiography images without the need for additional time or equipment during the procedure.

Hypothesis:
We assessed the hypothesis that 3-D QCA measurements and IVUS are comparable in accuracy in predicting physiologically significant stenosis assessed by fractional flow reserve (FFR).

Methods:
Forty lesions in 38 patients were assessed by FFR, IVUS, and 2-D and 3-D QCA. Correlations between anatomical data and FFR were analyzed. The area under the receiver-operating characteristic (ROC) curve (AUC) was calculated to identify the accuracy of predicting FFR ≤0.80.

Results:
Mean FFR value was 0.75 ± 0.13. FFR ≤0.80 was observed in 26 lesions (65%). Of all measurements of lesion severity obtained by IVUS, minimum lumen diameter (MLD) (r = 0.80, p <0.001) and minimum lumen area (MLA) (r = 0.72, p <0.001) were well correlated with FFR values. Of all 3-D QCA measurements, MLA correlated best with FFR values (r = 0.75, p <0.001). Of all 2-D QCA measurements, MLD correlated best with FFR values (r = 0.58, p <0.001). The AUC were 0.95 for MLA by IVUS, 0.93 for MLD by IVUS, 0.93 for MLA by 3-D QCA, and 0.78 for MLD by 2-D QCA (Figure).

Conclusions:
Anatomical parameters obtained by 3-D QCA and IVUS correlate better with FFR values than those obtained by 2-D QCA. The predictive value of 3-D QCA for reduced FFR is comparable to IVUS measurements.
Abstract 17736: Cardiomyocyte Specific Loss of Diacylglycerol Acyl Transferase 1 (Dgat1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure
Authors: Trent Chad M , Liu Li , Fang Xiang , Son Ni-Huiping , Jiang Hongfeng , Blaner William S , Yin Yu-Xin , Farese Robert V , Homma Shunichi , Turnbull Andrew V , Eriksson Jan W , Hu Shi-Lian , Ginsberg Henry N , Huang Li-Shin , Goldberg Ira J
Published: July 2021

Diacylglycerol acyl transferase 1 (DGAT1) catalyzes the final step in triglyceride (TG) synthesis, the conversion of diacylglycerol (DAG) to TG. Dgat1-/- mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function we created cardiomyocyte specific DGAT1 knockout (hDgat1-/-) mice. hDgat1-/- mice hearts had 95% increased DAG and 85% increased ceramides compared to floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide (Bnp) increased 5-fold in hDgat1-/- hearts and fractional shortening (FS) was reduced. This was associated with a 30% increase in PPARalpha and a 40% increase in Cd36. We crossed hDgat1-/- mice with previously described enterocyte-specific Dgat1 knockout mice (hiDgat1-/-). This corrected the early mortality, improved FS 40%, and reduced cardiac ceramide and DAG content. Treatment of hDgat1-/- mice with GLP-1 receptor agonist exenatide for 1 week reduced Bnp mRNA by 50%, improved FS, and reduced heart DAG and ceramide content by 30-40%. Increased fatty acid uptake into hDgat1-/- hearts was normalized by exenatide. Reduced activity of protein kinase Cα (PKCα), which is known to be increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.
Abstract 17746: Telecinobufagin, a Novel Cardiotonic Steroid, Promotes Myocardial and Renal Fibrosis via Na/K-ATPase Profibrotic Signalling Pathways
Authors: Kennedy David J , Weber Malory E , Guggilam Anuradha , Westfall Kristen M , Agatisa-Boyle Brendan , Bucur Philip , Lingrel Jerry B , Tang W. H. Wilson
Published: July 2021

Cardiotonic steroids (CTS) are Na/K-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We recently discovered significantly elevated levels of a novel CTS, telocinobufagin (TCB), in patients with heart failure. We tested the hypothesis that TCB promotes cardiac and renal dysfunction in a process involving signaling through the NKA-α-1 in the following studies. First, we infused TCB (4 weeks at 10 ug/Kg/day) or vehicle into mice expressing wild type NKA-α-1 (WT), as well as mice with a genetic reduction of NKA-α-1 (NKA+/-) or transgenic human NKA-α-1 (NKA-Tg), which renders them more sensitive to CTS. TCB infusion resulted in impairment of cardiac structure (36% increase in heart weight/body weight ratio, 18% increase in diastolic Left Ventricular Internal Dimension vs. vehicle, p<0.05) in WT mice which was significantly attenuated in NKA+/- mice. TCB infusion also resulted increased proteinuria and cystatin C in WT mice which was significantly attenuated in NKA+/- mice (all p<0.05) despite similar increases in blood pressure. In NKA-Tg mice, TCB infusion resulted in increased myocardial (Fig 1A) and renal (Fig 1B) fibrosis vs. WT (all p<0.05). In a series of in vitro experiments, 24 hour treatment of HK2 renal proximal tubular cells with TCB resulted in significant dose dependent increases in both Collagen 1 and 3 mRNA (2 fold increases at 10 nM, 5 fold increases at 100 nM, p<0.05). TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc resulted in a 1.5 fold increase in Collagen 1 and 3 mRNA (p<0.05) as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p<0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p<0.05), while these effects were absent in SYF cells without Src kinase. These studies suggest that the pro-fibrotic effects of TCB are mediated though the NKA-Src kinase signaling pathway.
Abstract 17763: Inhibition of Bone Morphogenetic Protein Signaling Reduces Endothelial-Mesenchymal Transition and Vascular Smooth Muscle Cell Calcification Associated with Matrix Gla Protein Deficiency
Authors: Burke Megan F , O’Rourke Caitlin , Martyn Trejeeve , Shakartzi Hannah R , Thayer Timothy E , Li Pingcheng , Derwall Matthias , Spagnolli Ester , Kolodziej Starsha A , Mayeur Claire , Jiramongkolchai Pawina , Bloch Donald B , Buys Emmanuel S , Yu Paul B , Bloch Kenneth D , Malhotra Rajeev
Published: July 2021

Background:
Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency.

Methods and Results:
Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P<0.01 for all). Aortic expression of markers of VSMC differentiation (α-smooth muscle actin, transgelin, and calponin) was less in MGP-/- than in wild-type mice (P<0.001 for all). Treatment of MGP-/- mice with the BMP signaling inhibitor, LDN-193189, reduced expression of both osteogenic and EndMT markers (P<0.05 for all) but did not prevent VSMC de-differentiation. Depletion of MGP in cultured wild-type VSMCs with siRNA specific for MGP (siMGP) was associated with a 30-40% reduction in levels of mRNAs encoding markers of VSMC differentiation (P<0.05 for all), an effect that was not prevented by LDN-193189. Incubation in phosphate-containing media induced greater calcification in siMGP-treated VSMCs than in cells treated with control siRNA (P<0.0001). Treatment with LDN-193189 reduced calcification in siMGP-treated VSMCs (50%, P=0.0003). Conversely, infection of MGP-/- VSMCs with adenovirus specifying MGP increased expression of markers of VSMC differentiation by 60-80% (P<0.01 for all) and decreased calcification by 74% (P=0.03).

Conclusions:
Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.
Abstract 17765: Mild Preoperative Anemia is an Independent Predictor of Mortality and Cardiovascular Events in Patients Undergoing Elective Major Noncardiac Surgery
Authors: álvarez-García Jesús , Vives-Borrás Miquel , Llao Joan I , Ferrero-Gregori Andreu , Bausili Marc , Díaz Rubén , Gil María A , Moral Victoria , Paniagua Pilar , Rodriguez Mireia , Urrutia Mónica C , Sionis Alessandro , Pelaez Xavier
Published: July 2021

Background:
Preoperative anemia has been recognized as an important risk factor for perioperative red blood cell transfusions and adverse events in patients undergoing noncardiac surgery. Mild anemia has not unequivocally shown to be a risk factor for death, unless cardiac disease is present or major blood loss occurs.

Objective:
To evaluate the prevalence of preoperative anemia and its effect on 30-day postoperative outcome in subjects undergoing elective major noncardiac surgery.

Methods:
A retrospective cohort study was performed in 1630 patients, 40 years and older, who underwent major noncardiac surgery.Based on preoperative hemoglobin levels and gender, we stratified patients into the next categories of anemia: mild (11-12 g/dl), moderate (10-11 g/dl) and severe (<10 g/dl) for female; mild (12-13 g/dl), moderate (11-12 g/dl) and severe (<11 g/dl) for male. Age, risk factors, previous chronic heart or lung disease, renal function and concomitant treatment were used in a binary logistic regression to determine the impact of anemia in prognosis. The primary outcome measure was a composite of 30-day postoperative mortality or cardiovascular events (cardiac arrest, myocardial infarction, stroke or pulmonary embolism).

Results:
The overall prevalence of anemia was 18.8%. Thirty-day mortality and cardiac event rate increased with the presence of anemia (table). Mild, moderate and severe anemia were associated with a two-fold (OR 2.07; CI 95%: 1.04-4.11), three-fold (OR 2.93; CI 95%: 1.45-5.94) and four-fold (OR 4.09; CI 95%:1.87-8.95) increases in the risk of MACCE respectively.

Conclusions:
Anemia is a prevalent risk factor in patients undergoing major noncardiac surgery. Even mild degrees of preoperative anemia are associated with an increased risk of 30-day postoperative mortality and cardiovascular events. Further studies are needed in order to evaluate whether treatment of preoperative anemia could reduce postoperative mortality.
Abstract 17822: Cardiac Biomarkers are Elevated in Children During Chemotherapy Regardless of Anthracycline Status
Authors: Lin Kimberly Y , Freedman Jason L , Ginsberg Jill , Goldmuntz Elizabeth , Shaddy Robert E
Published: July 2021

Introduction:
Conflicting evidence exists as to whether measuring cardiac biomarkers can help identify children at risk of developing anthracycline-mediated cardiomyopathy (ACM). The newest generations of assays can detect minute cardiac perturbations.

Hypothesis:
We hypothesized that exposure to anthracyclines in children causes an increase in highly- and ultra-sensitive troponin I (hsTnI and usTnI), B-type natriuretic peptide (BNP), and NT pro-BNP levels during therapy.

Methods:
Cardiac biomarkers were sampled at baseline, early (within 24 hours), and late (3-7 days) after every 100-150 mg/m2 of anthracycline administered, and within 30 days of the end of all chemotherapy. Biomarkers measured include TnI by fourth (“highly-sensitive”) and fifth (“ultra-sensitive”) generation assays, BNP, and NT pro-BNP. Non-parametric testing was performed to determine if peak values of each biomarker vary between anthracycline exposed and non-exposed (control) individuals.

Results:
Twenty-six patients (54% male, mean age 11.2 ± 6.3 yrs) with a variety of malignancies were enrolled and categorized by target cumulative anthracycline dose: Control (0mg/m
2
), low dose (<100mg/m
2
), middle dose (100-299mg/m
2
), high dose (≤300mg/m
2
). Mean peak biomarker levels are presented in Table 1. No significant differences were seen in peak values of hsTnI (p=0.51), usTnI (p=0.24), BNP (p=0.07) or NT pro-BNP (p=0.57) between control subjects and those receiving anthracyclines.

Conclusions:
Next generation cardiac biomarkers did not distinguish anthracycline subjects from controls while on treatment for various malignancies in this small pediatric cohort. Further study is needed to verify this finding in larger numbers of children with an assessment for differences between subgroups with different cumulative anthracycline exposures, and with follow up to determine whether such biomarkers predict long term cardiotoxicity.
Abstract 17859: Gender Difference in Underlying Plaque Morphology of the Culprit Lesion in Patients with Acute Myocardial Infarction: an in vivo Optical Coherence Tomography Study
Authors: Hu Sining , Jia Haibo , Soeda Tsunenari , Minami Yoshiyasu , Vergallo Rocco , Jang Yang-Soo , Park Seung-Jung , Lee Stephen , Lowe Harry , Barlis Peter , Lee Hang , Uemura Shiro , Yu Bo , Jang Ik-Kyung
Published: July 2021

Introduction:
Autopsy studies in sudden cardiac death subjects showed female had higher incidence of erosion. However, the incidence of erosion in patients with acute myocardial infarction (AMI) has not been systematically studied.

Hypothesis:
This study was to study the gender difference in the prevalence and morphological characteristics of the culprit lesion in patients with AMI using intravascular optical coherence tomography (OCT).

Methods:
A total of 79 patients (65 male and 14 female) with AMI who underwent pre-intervention OCT imaging of the culprit lesion were included.

Results:
Baseline characteristics between the two groups were similar. In OCT findings, the incidence of thin-cap fibroatheroma (TCFA) was slightly lower and the fibrous cap thickness was slightly thicker in female than in male, but the differences were not significant. Defining underlying plaque morphology by genders, plaque erosion was more prevalent in female than in male, whereas plaque rupture was more frequent in male (Table).

Conclusions:
Erosion was the most frequent cause of AMI in female patients, whereas plaque rupture is the predominant underlying pathology of AMI in male patients.
Abstract 17876: NT Pro BNP After Surgery for Constrictive Pericarditis: Does It Increase or Decrease?
Authors: Lanjewar Swapnil S , Hanna Mazen , Cho Leslie , Klein Allan
Published: July 2021

Background:
It has been reported that patients with constrictive pericarditis (CP) have disproportionately lower BNP values compared to their clinical symptoms/signs of heart failure. This has been attributed to lesser stretching of the cardiac myocytes due to constriction. Hence, we hypothesized that surgical correction of constriction would cause an increase in ventricular volume and an elevation in NT pro BNP.

Methods:
We retrospectively reviewed charts of 221 patients who underwent surgery for CP. Patients were included if they had an NT pro BNP reported <6 weeks before and between 6-52 weeks after surgery; and excluded if they had BNP before but NT pro BNP after surgery. The NYHA class during the encounter for NT pro BNP was noted to minimize selection bias based on symptoms. The NT pro BNP and its logarithm before and after surgery were compared using the Wilcoxon signed rank test. The left ventricular systolic, diastolic volumes and internal diameters on 2D ECHO were compared before and after surgery at dates closest to the NT pro BNP.

Results:
17 patients with a median age of 61 [range 33-76, 5 males] met inclusion criteria. NT pro BNP was available a mean 146 days after surgery [range 43-351]. There was a significant increase in the NT pro BNP [mean 877.11 ± 191.1 pg/ml to 3332 ± 1249 pg/ml, p= 0.01] as well as log NT pro BNP [mean 2.715 ± 0.134 to 3.152 ± 0.146, p=0.004] after surgery. At the time of NT pro BNP evaluation post-surgery, the NYHA class was improved in 9, unchanged in 5 and worse in 3 patients. The left ventricular end diastolic volumes showed a trend towards increasing after surgery [103.08 ± 17.23 to 124.08 ± 16.28 ml, p=0.15]. Of the 17 patients, 12 before and 15 after surgery were on diuretics.

Conclusions:
The NT Pro BNP increases after surgery for CP. This is despite the fact that the NYHA class may remain stable or in fact improve after surgery. This increase in NT pro BNP can likely be explained by the increased cardiac volumes after surgery for CP. Thus post-surgery, an elevation in NT pro BNP can be expected without actual clinical deterioration. The use of diuretic therapy should still be guided by the NYHA class and symptoms. However, the increasing biomarker may reflect ongoing remodeling of the left ventricle after surgery.
Abstract 17911: Acute Cardiac Dysfunction by Adult-onset Cardiac Myosin Light Chain Kinase Ablation
Authors: Massengill Michael , Chang Eileen , Ashraf Hasssan , Chrzanowski Stephen , Chowdhury Rajib , Kar Jeena , Warren Sonisha , walter Glenn , Zeng Huadong , Kang Byung-Ho , Kasahara Hideko
Published: July 2021

Introduction:
Under sustained pressure overload, myocytes that initially remodel to become short and thick, eventually become elongated and maladaptive with little force for contraction. Mechanisms underlying this transition are largely unknown. We previously demonstrated that 1 week of transverse aortic constriction in wild-type mice reduced cardiac myosin light chain kinase (cMLCK) levels by ~85%. In cultured cardiomyocytes, cMLCK knockdown led to sarcomere disorganization. Germline Mylk3 (encoding cMLCK) knockout mice demonstrated moderate heart failure.

Hypothesis:
Acute cMLCK reduction is causative for reduced contractility and remodeling of cardiomyocytes during the transition from compensated to decompensated hypertrophy.

Methods:
To mimic acute cMLCK reduction, adult inducible Mylk3 gene knockout mice, Mylk3flox/flox/merCremer, were generated and compared to 2 control mice (Mylk3flox/flox and Mylk3+/+/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). We assessed cardiac function (MRI, echocardiogram) in addition to histopathologic (tissue sectioning, immunostaining, and EM), cellular (cell size and cell shortening and intracellular free Ca2+) and molecular analyses.

Results:
Reduction of cMLCK proteins was evident at day 4 following tamoxifen-injection in inducible Mylk3 knockout mice. At day 7, inducible Mylk3 knockout but not control mice demonstrated heart failure [%FS, 28.0% in flox/flox (n=6), 27.7% in +/+/merCremer (n=6), 19.8% in flox/flox/merCremer (n=8)]. Analysis of inducible Mylk3 knockout mice revealed unique, severely convoluted cell morphology; isolated cardiomyocytes were elongated and thinner with disorganized sarcomere and reduced contractility (%FS in sarcomere length, control 5.1% vs. inducible knockout 2.4%). Adenovirus encoding cMLCK enhanced organized sarcomere structures; this was not prevented by co-infection of adenovirus unphosphorylatable MLC2v(Ser14/15Ala) mutants incorporated into sarcomere.

Conclusion:
Results of acute cMLCK reduction in a novel mouse model suggest that cMLCK plays a pivotal role in transition from compensated to decompensated hypertrophy via sarcomere disorganization likely independent of MLC2 phosphorylation.
Abstract 17940: PDEV Inhibition + BNP Administration Enhanced the Cardiac but not the Renal Response to Acute Volume Overload in Human Preclinical Diastolic Dysfunction as Compared to PDEV Inhibition Alone
Authors: Torres-Courchoud Isabel , Mckie Paul M , Benike Sherry , Schirger John A , Redfield Margaret M , Burnett John C , Chen Horng H
Published: July 2021

Background:
Preclinical diastolic dysfunction (PDD) is defined as subjects with normal systolic function, moderate or severe diastolic dysfunction determined by Doppler criteria but with no symptoms of heart failure (HF). We have previously demonstrated that an impaired cardiorenal endocrine response to stress by acute volume loading (AVL) exists in PDD and that is corrected by acute administration of sq B-type natriuretic peptide (BNP). Type V phosphodiesterase (PDEV) metabolizes cGMP, second messenger of BNP. The objective of the current study is to determine if the combination of PDEV inhibitor (PDEVI) and BNP will result in a greater enhancement of the cardiorenal response to AVL as compared to PDEVI alone in PDD.

Methods:
Randomized double-blind single placebo-controlled cross-over study in 20 PSD subjects. We determined cardiorenal effects of PDEVI with Tadalafil (T) 5 mg alone and in combination with acute sq BNP (Nesiritide 10 μg/Kg), in response to AVL (normal saline 0.25 ml/kg/min for 1 hour). Each subject had 2 study visits, separated by at least 1 week. At each visit, echocardiogram and renal clearance studies with iothalmate and PAH to measure GFR and renal plasma flow (RPF) were done before and after AVL. Each patient was randomized to receive T at both visits and either placebo or sq-BNP one visit and crossover to the other on the next visit.

Results:
T+BNP resulted in smaller LA volume index (-4±10 vs 3±7 ml/m
2
, p< 0.05) and lower right ventricular systolic pressure (-4±3 vs 2±6 mmHg, p< 0.05) in response to AVL as compared to T alone. Moreover, T+ BNP resulted in a significant reduction of plasma ANP and LV end-systolic volume in response to AVL while T alone did not. However, the combination to T+BNP did not enhance the renal response to AVL as compared to T alone. Both the change in urine flow (1.7±5 vs 2.4±5 ml/min, p> 0.05) and sodium excretion (129±200 vs 124±270 mEq/min, p>0.05) in response to AVL were similar between T+BNP and T alone.

Conclusion:
In PDD, the combination of PDEVI and BNP reduced LV filling pressure in response to AVL as compared to PDEVI alone. However, it did not enhance the renal response to AVL. This suggests a differential cardiac versus renal response to the maximization of cGMP system with PDEVI and BNP.
Abstract 17953: A Novel Biodegradable Cardiac Support Device for Treating Ischemic Cardiomyopathy in Canine Heart
Authors: Kitahara Mutsunori , Miyagawa Shigeru , Fukushima Satsuki , Harada Akima , Saito Atsuhiro , Ueno Takayoshi , Toda Koichi , Kuratani Toru , Sawa Yoshiki
Published: July 2021

Introduction:
The non-biodegradable material-made “Corecap” type cardiac support device reportedly reduces diastolic wall stress and consequently improves systolic cardiac function. However, the efficacy was inconsistent in the clinical studies possibly due to device-related impairment of diastolic cardiac function. We herein hypothesized that use of biodegradable material for the cardiac support device may contribute to improvement in both systolic and diastolic function of the failing heart.

Methods:
Polyglycolic acid and Polyethyleneterephtalate were used to prepare biodegradable (n=6) and non-biodegradable (n=5) cardiac support device, respectively. Both cardiac support devices were structurally designed to cover the entire ventricles of the 12-month-aged Beagle canine heart that was subjected to anterior coronary artery ligation at 1 week prior to the implantation. Sham operation was performed in coronary artery-ligated canines for control (n=7).

Results:
At 12 weeks after coronary artery ligation, the biodegradable group showed a greater recovery of ejection fraction than the non-biodegradable and the control group (39 ± 4% vs. 31 ± 4% vs. 30± 3, respectively, P <0.05), assessed by multi-detector computed tomography. Echocardiographically, diastolic function evaluated by Doppler-derived mitral deceleration time at 12 weeks was significantly greater in the biodegradable group (108 ± 18 msec) than the non-biogradable group (70 ± 13 msec, P<0.05). Thickness of connective tissues around the epicardium was significantly less in the biodegradable groups than the non-biodegradable group at 12 weeks. Histologically, fibrosis in the infarct area was significantly less in the treatment groups than the control group.

Conclusions:
Implantation of cardiac support device made of biodegradable material was effective in improvement of both systolic and diastolic function of the canine infarct heart for 12 weeks, compared with that of non-biodegradable material, warranting clinical studies using biodegradable cardiac support device.
Abstract 17956: External Validation of a Prediction Model for the Development of Atrial Fibrillation in a Repository of Electronic Medical Records
Authors: Kolek Matthew J , Graves Amy J , Bian Aihua , Teixeira Pedro L , Shoemaker Moore B , Parvez Babar , Xu Hua , Heckbert Susan R , Ellinor Patrick T , Benjamin Emelia J , Alonso Alvaro , Denny Joshua C , Moons Karel G , Shintani Ayumi K , Roden Dan M , Darbar Dawood
Published: July 2021

Background:
Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and healthcare costs. Accurate prediction of incident AF might enhance patient care and improve outcomes. We aimed to externally validate the AF risk model developed by the CHARGE-AF investigators utilizing a large repository of electronic medical records (EMR).

Methods:
Using a database of de-identified EMRs, we conducted a retrospective cohort study of subjects serially followed in internal medicine clinics at our institution (minimum 3 visits in a 24 month window). Subjects were followed for incident AF from 2005 until 2010. We applied the published CHARGE-AF Cox proportional hazards model beta coefficients to our cohort. Predictors included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. Calibration and discrimination were assessed by generating calibration plots and calculating C-statistics.

Results:
The study included 33,494 subjects with median age 57 years (25th to 75th percentile: 49 - 67), 57% women, 86% whites, and 14% African Americans. During the mean follow-up period of 4.8 ± 0.85 years, 2455 (7.3%) subjects developed AF. After correcting for baseline hazard, the CHARGE-AF model over-predicted AF at the highest risk deciles but was otherwise well-calibrated (Figure) and showed good discrimination, with a C-statistic of 0.746 (95% confidence interval: 0.738 to 0.754).

Conclusion:
From clinical factors readily accessible in a large de-identified EMR repository, we externally validated the CHARGE-AF risk prediction model to identify individuals at risk for developing AF in an ambulatory setting. These data not only provide strong validation for the CHARGE-AF risk prediction tool, but also indicate that the tool, and thus primary prevention strategies, can be implemented in an EMR context.
Abstract 17963: Cardioprotective Effects of Ecklonia Cava Polyphenol on Doxorubicin-induced Cardiomyopathy in Rats
Authors: Ahn Hyo-Suk , Jeon Hui-Kyung , Kim Ki Tae , Youn Ho-Joong
Published: July 2021

Introduction:
Long-term therapy with doxorubicin is associated with a high incidence of a cumulative and irreversible dilated cardiomyopathy, despite of its broad anti-neoplastic effectiveness. The goal of this study was to evaluate the cardioprotective effects and safety of seapolyphenol (polyphenol purified from Ecklonia cava) against doxorubicin-induced cardiotoxicity in an animal rat model.

Methods and Results:
In total 28 rats including doxorubicin and control groups, baseline and 6 weeks follow up echocardiography were practiced. Left ventricular ejection fraction significantly decreased and the left ventricular end diastolic/systolic dimension and LV mass index significantly increased in single doxorubicin group compared to high dose seapolynol plus doxorubicin group. Also, electron microscopic finding showed less impaired myofiber and mitochondria in high dose seapolynol plus doxorubicin group than in single doxorubicin group.

Conclusions:
Our data showed that high dose seapolynol had cardioprotective effects against doxorubicin-induced cardiotoxicity in an animal rat model with the evidence of electron microscopic finding in addition to echocardiographic results..
Abstract 17983: Ankle-Brachial Index Predicts Progression of Aortic Stiffeness
Authors: Ye Zi , Thais Coutinho , Kullo Iftikhar
Published: July 2021

Background:
Arterial stiffness is associated with increased risk for adverse cardiovascular outcome. Ankle-brachial index (ABI) is a measure reflective of systemic atherosclerosis. Whether it can predict central aortic stiffness and its progression is unknown. As such, we investigated the impact of ABI on carotid-femoral pulse wave velocity (cfPWV) and aortic characteristic impedance (Z
c
) in apparently healthy adults from the community.

Methods:
Participants were from the GENOA study without cardiovascular disease at baseline (December 2000 to September 2006) and completed follow-up (September 2009 to December 2012) assessment (n=358, 63%women, 69% hypertensive). ABI was measured by standard protocol at baseline. cfPWV was measured by applanation tonometry. Difference in log-cfPWV between two visits ([[Unable to Display Character: ∆]]log-cfPWV) was used to estimate progression of aortic stiffness. Z
c
was ascertained at 2
nd
visit using carotid tonometry followed by echocardiography (Cardiovascular Engineering Inc., Norwood).

Results:
After a mean follow-up of 8.5±0.9 years, cfPWV increased from 9.3±2.4m/s to 11.1±5.0m/s. After adjusted for age, sex and time-interval between two visits, lower ABI was associated with greater [[Unable to Display Character: ∆]]log-cfPWV (β±SE:-0.41±0.15), and increased risk for higher log-cfPWV (β±SE:-0.38±0.12) and higher log-Z
c
at 2
nd
visit (β±SE:-0.38±0.18) (all P≤0.04). Diabetes and renal function at baseline were predictors for higher cfPWV and Z
c
;

hypertension and metabolic syndrome were only predictors of cfPWV; while age and male gender were major predictors for [[Unable to Display Character: ∆]]log-cfPWV (all P≤0.04). The association of ABI with cfPWV or Z
c
remained significant after adjustment for these covariates (both P<0.05). Greater [[Unable to Display Character: ∆]]log-cfPWV was associated with increased risk for higher log-Z
c
; longer time-interval amplified this effect (both p for [[Unable to Display Character: ∆]]log-cfPWV and [[Unable to Display Character: ∆]]log-cfPWV x time-interval ≤0.03).

Conclusions:
Lower ABI predicts progression of aortic stiffness, leading to both increased aortic wall stiffness (PWV) and greater aortic area-flow mismatch (Z
c
), suggesting the impact of subclinical atherosclerosis on proximal aortic stiffening.
Abstract 17984: Validating the Gold-standard: Steady-State Free Precession Sequence for Assessment of Left Ventricular and Right Ventricular Mass
Authors: Santos-Gallego Carlos G , Njerve Ida U , Ishikawa Kiyotake , Aguero Jaime , Vahl Torsten , Picatoste Belén , Hammoudi Nadjib , Hajjar Roger J , Fuster Valentin , Badimon Juan , Sanz Javier
Published: July 2021

Background:
Left ventricular (LV) mass (LVM) predicts cardiovascular morbidity and mortality, thus accurate quantification of LVM is essential. Cardiac magnetic resonance (CMR) is considered the gold-standard for LVM and right ventricular (RV) mass (RVM) quantification. The steady-state free precession (SSFP) is the most widely used sequence nowadays; however, SSFP-derived LVM/RVM has only been validated in normal animals, while CMR is usually performed under pathological conditions. Therefore, our objective was to validate in vivo SSFP-derived LVM/RVM with the gold-standard autopsy weights of experimental animals with myocardial infarction (MI), LV remodeling, and pulmonary hypertension (PH).

Methods:
MI was induced in 11 pigs by balloon occlusion of the proximal LAD for 60 min, and MRIs were obtained 2 months post-MI. PH was induced in 11 pigs by surgical ligation of three pulmonary veins and animals underwent CMR 4 months post-surgery. Animals were euthanized immediately after CMR. Each ventricle was separately weighted using a high-fidelity scale. MRI studies were performed with a 3.0 Tesla magnet.

Results:
In the MI model, infarct size (IS) was 29±6% of LV, LVEF 34±8%, RVEF 62±149%, mean pulmonary artery pressure (mPAP) 16±4mmHg, and pulmonary vascular resistance (PVR) 2.3±1.1 Wood units. In the PH model, IS was 0%, LVEF 64±5%, RVEF 55±10%, mPAP 36±16mmHg and PVR was 7.2±5.5 Wood units. All animals provided images of diagnostic quality. Excellent correlations were obtained between SSFP-calculated LV mass (86.6±12.9g) and autopsy-measured LV mass (91.1±15.2g, r=0.97, p<0.001). For LV, the correlation was not different in both groups of animals (r=0.98, p=0.01 for post-MI animals; r=0.96, p=0.01 for PH animals). There was also a strong correlation between RV mass obtained from CMR (37.9±14.1g) and from autopsy (41.6±13.1g r=0.9, p=0.01). For RV, the correlation was higher in PH animals (r=0.92, p<0.001) than in post-MI pigs (r=0.8, p=0.01).

Conclusions:
In vivo SSFP-CMR sequences determine LVM and RVM accurately and reliably compared with autopsy. Therefore, our study provides further validation for the clinical use of SSFP sequence derived LVM and RVM.
Abstract 18010: Induced Pluripotent Stem Cell-Based Modeling of Human NOTCH1 Mutations Reveals Novel Pathways Regulating Aortic Valve Disease
Authors: Theodoris Christina V , White Mark P , Li Molong , Liu Lei , He Daniel , Pollard Katherine S , Bruneau Benoit G , Srivastava Deepak
Published: July 2021

In humans, NOTCH1 mutations result in congenital heart defects including valve malformations and severe valve calcification in adults. Valve calcification typically occurs on the aortic side of the valve leaflets that is not exposed to laminar shear stress, suggesting a protective role of flow sensed by the endothelial lining. To understand the mechanisms by which NOTCH1 mutations in endothelial cells (ECs) cause disease, we generated induced pluripotent stem cell (iPSC) lines from fibroblasts of four individuals from two families affected with aortic valve disease due to heterozygous non-sense mutations in NOTCH1. We differentiated control and mutant iPSC lines into ECs and exposed the ECs to either static or fluid shear stress conditions. NOTCH1 mRNA levels were decreased by ~50% in the NOTCH1+/- ECs under static or shear stress conditions. RNA-seq revealed that 165 genes were differentially expressed in static conditions and 193 genes responded abnormally to shear stress in NOTCH1+/- ECs compared to NOTCH1+/+ ECs. Differentially expressed genes included canonical NOTCH1 targets HRT2 and EFNB2 as well as novel targets involved in vascular development, inflammation, and endochondral ossification. Anti-calcific genes uniquely upregulated in shear stress were dysregulated in NOTCH1+/- ECs, indicating that they were unable to mount the normal protective response induced by shear stress in the valve. Generating isogenic NOTCH1+/+ and NOTCH1+/- cell lines using TALEN genome editing identified genes specifically dysregulated due to NOTCH1 heterozygosity rather than differentially expressed due to genetic background and showed rescue of this dysregulation in TALEN-corrected NOTCH1+/+ ECs. We have mapped the gene networks dysregulated in NOTCH1+/- ECs as determined by NOTCH1 ChIP-seq, differentially methylated regions of DNA, and genome-wide differences in the progression of activating and repressive chromatin states that begin to explain the mechanisms by which heterozygosity of a transcription factor leads to disease-specific changes. Determining the consequence of NOTCH1 heterozygous mutations in human patient-specific ECs will reveal novel mechanisms underlying aortic valve disease, leading to potential targets for intervention.
Abstract 18020: Identifying Hospitalizations Related to Heart Failure in Dronedarone Users Who Are Supplementary Medicare Beneficiaries
Authors: Wu Chuntao , Koren Andrew , Thammakhoune Jane , Wu Jasmanda , Kechemir Hayet , Tcherny-Lessenot Stephanie , Lin Stephen , Juhaeri Juhaeri
Published: July 2021

Background:
When using inpatient claims data to identify hospitalizations in supplemental Medicare beneficiaries, e.g., in the MarketScan database, there is a concern that the coverage of hospitalizations in such inpatient claims may be incomplete. However, whether hospitalizations are covered by inpatient claims or not, they incur professional charges that are recorded in the professional claims data in the MarketScan Medicare database. In the context of identifying hospitalizations that might be related to heart failure (HF) in dronedarone users, we compared different approaches to identify such hospitalizations.

Objective:
To assess the impact of using professional claims in addition to inpatient claims on identifying hospitalizations that might be related to HF.

Methods:
A total of 20,834 dronedarone users who were supplemental Medicare beneficiaries between July 2009 (launch date in US) and December 2012 were identified in the MarketScan database. The hospitalizations that might be related to HF within 30 days prior to initiating dronedarone were identified by searching (1) inpatient claims and (2) both inpatient and professional claims using related ICD-9-CM diagnosis codes for HF and Current Procedural Terminology codes for hospitalizations.

Results:
A total of 1,162 patients who had HF hospitalizations within 30 days prior to initiating dronedarone were identified by searching inpatient claims between July 2009 and December 2012. Supplementing with professional claims identified an additional 177 patients who had HF hospitalizations, increasing the total number to 1,339. Therefore, 13.2% (177/1,399) of the patients who had HF hospitalizations could only be identified in professional claims. Thus, the prevalence of hospitalizations that might be related to HF within 30 days prior to initiating dronedarone was 5.6% (1,162/20,834; 95% confidence interval (CI): 5.3 - 5.9%) when hospitalizations were identified using inpatient claims alone. Adding professional claims in the search algorithm, the prevalence of HF hospitalizations was 6.4% (1,339/20,834, 95% CI: 6.1 - 6.8%).

Conclusions:
Using professional claims, in addition to inpatient claims, can improve the identification of hospitalizations that might be related to HF.
Abstract 18028: Inclusion of B-type Natriuretic Peptide into Existing Atrial Fibrillation (AF) Risk Scores Improves Identification of Patients with Recurrence of Atrial Fibrillation after Pulmonary Vein Isolation
Authors: Shaikh Amir Y , Esa Nada , Kinno Menhel , Martin-Doyle William , Floyd Kevin C , Browning Clifford , Rosenthal Lawrence S , McManus David D
Published: July 2021

AIMS:
Pre-procedural identification of patients with atrial fibrillation (AF) who will remain free from AF after pulmonary vein isolation (PVI) remains challenging. Clinical risk scores, including CHADS2, CHA2DS2-VASc, R2CHADS2, and HATCH scores show modest discriminative ability with respect to AF recurrence. B-type natriuretic peptide (BNP) is associated with risk for AF and AF recurrence but is not currently included in existing AF risk scores. We sought to evaluate the incremental benefit of adding pre-operative BNP to existing risk scores in predicting AF recurrence within 6-months after PVI.

METHODS AND RESULTS:
One hundred and fifty one patients (105 men, age 60 ± 10 years) with paroxysmal or persistent AF underwent an index PVI procedure between 2010-2014. Seventy-seven patients had an AF recurrence (51%) over the 6-month follow-up period. BNP level of >100 units was significantly associated with 6-month AF recurrence in univariate models (p<0.001). A composite risk score including BNP to the existing scores significantly improved their predictive value and net AF recurrence reclassification (net reclassification index, 63.4%; p<0.001) (Table 1).

CONCLUSIONS:
Addition of BNP to existing AF risk scores enhanced their predictive value and discriminative ability in predicting AF recurrence after PVI. Further research is needed including large and diverse cohorts of patients undergoing ablation and monitored for AF recurrence over extended periods to further validate the performance of this composite score.