bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 14035: Autophagy is Regulated by mir-106b in the Heart
Authors: Kuhn Christian , Boeck Lisa , Hille Susanne , Dierck Franziska , Eschenhagen Thomas , Frey Norbert 
Published: July 2021

Autophagy is a lysosome-dependent degradation mechanism. In the heart the autophagic flux is induced by starvation and by specific cardiac disorders ranging from pressure overload to myocardial infarction. Recently, microRNAs have been implicated in the control of cardiac autophagy.
We found a significant induction of miR-106b in the heart of mice that had been starved for 48h (1.6±0.2-fold, n=11, p<0.05). Moreover, miR-106b is upregulated in cardiac tissue of patients with dilated cardiomyopathy (14.4±4.4-fold, n=3, p<0.05). Interestingly, miR-106b is induced in failing hearts of MLP knockout mice (11.5±2.6 fold, n=5, p<0.05), an established DCM model, as well.
Using four different target predictions algorithms (DIANA microT v4.0, miRDB, microRNA.org, TargetScan) we reduced the number of potential targets of miR-106b. Among the genes we found Fyco1. Fyco1 is predominantly expressed in striated muscle and interacts with LC3, a key player in autophagy. We have shown before that Fyco1 is sufficient to induce autophagy in cardiomyocytes. Conversely, Fyco1 deficient mice are protected from increased autophagy by starvation or transverse aortic constriction, but suffer from contractile dysfunction after cardiac stress.
Using the mirSVR tool we identified two potential binding sites in the 3’-UTR of murine Fyco1. We inserted each of the predicted binding sites into a luciferase gene based reporter system. Overexpression of miR-106b with either one of the predicted binding sites caused a significant loss of luciferase activity compared to cells that overexpressed a control microRNA or carried a mutated binding site. Interestingly, a fragment that included both target sites reduced the luciferase activity to the same extent (-32%, p<0.001). Overexpression of miR-106b in neonatal rat cardiomyocytes (NRCM) caused a reduction of Fyco1 protein by 72%. Consistently, the overexpression of miR-106b in NRCM prevented the induction of autophagy measured by LC3-II levels after glucose deprivation for 24h.
Taken together our data identify a miR-106b/FYCO1-dependent pathway regulating autophagy in the heart. It will be interesting to see whether experimental manipulation of this axis may alter the progression of cardiomyopathy and heart failure.
Abstract 15155: Supracardiac Type (1a) Total Anomalous Pulmonary Venous Return with Right to Left Shunt Atrial Septal Defect Diagnosed by 320 Slice CT
Authors: Funabashi Nobusada , Takaoka Hiroyuki , Ozawa Koya , Kobayashi Yoshio 
Published: July 2021

The first choice of imaging modality to evaluate complex congenital heart disease, especially in infants, is transthoracic echocardiogram (TTE) and magnetic resonance imaging. But to evaluate anatomic details of the heart, including coronary arteries with surrounding structures, CT is most useful.
We experienced a patient who was diagnosed as having supracardiac type total anomalous pulmonary venous return (TAPVR) with a right to left shunt atrial septal defect (ASD) by 320 slice CT.
A 63-year-old female who had palpitations and dizziness was referred to our hospital because of cardiac enlargement shown on chest X ray in a health examination. On chest X ray, enlargement of protrusion of the right first and left first aortic arches was observed. ECG revealed ectopic low part atrial rhythm, right axis deviation of the QRS wave, and incomplete right bundle branch block.
On TTE, ASD with right to left shunt was observed, presence of Eisenmenger syndrome was suspected and there seemed to be no surgical indication. But on TTE, right heart configuration seemed not due to pressure load but volume load, which is not indicative of Eisenmenger syndrome.
To evaluate the presence of other complications of anatomical cardiovascular heart disease, ECG-gated 320 slice CT (Aquilion ONE, Toshiba Medical) was performed. On CT, supracardiac type TAPVR with right to left shunt ASD could be accurately diagnosed. She then underwent TAPVR surgical repair from the superior approach in which total PV connected to the LA and ligated innominate vein and ASD pericardial patch closure. By this procedure, there was no blood flow from PV to the right heart, with blood from the PV flowing into the LA directly. Hemodynamics was normalized.
In summary, this patient had remarkable cardiac enlargement on chest X-ray, and on TTE ASD with right-to-left shunt was detected. 320 slice CT can evaluate complex congenital heart disease as well as coronary arteries accurately and provide information on blood flow.
Abstract 15657: Regulation of Cardiac Regeneration by Hippo Pathway and Dystrophin Glycoprotein Complex
Authors: Morikawa Yuka , Martin James F 
Published: July 2021

Regeneration of the mammalian heart is limited in adults. In rodents, endogenous regenerative capacity exists during development and in neonate but is rapidly repressed after birth. We are elucidating the mechanisms responsible for regenerative repression and applying this knowledge to reactivate cardiac regeneration in adult hearts. We have previously shown that the Hippo pathway is responsive for regenerative repression, however, the molecular and cellular mechanism responsible remain unclear.
The Hippo pathway controls heart size by repressing myocardial cell proliferation during development. By deleting Salv, a modulator of Hippo pathway, we found myocardial damage in the postnatal and adult heart was repaired anatomically and functionally. This heart repair occurred primarily through proliferation of preexisting cardiomyocyte. We observed that cardiomyocytes in border the zone protrude and fill the damage area during Hippo-mediated cardiac regeneration and thus preventing formation of fibrotic scars. The molecular analysis identified components of dystrophin glycoprotein complex (DGC) as downstream targets of Hippo pathway. The DGC anchors the cytoskeleton and extracellular matrix and is involved in cell migration. The studies using the muscular dystrophy mouse model, mdx, reveals that DGC is required for endogenous cardiac regeneration and cardiomyocyte protrusion. Taken together, we show that cardiomyocyte protrusion is an essential process for cardiac regeneration and the Hippo pathway regulates it through regulating DGC. Our studies provide insights into the mechanisms leading to repair of damaged hearts from endogenous cardiomyocytes and novel information into DGC function.
Abstract 16189: Lineage Tracing of Postnatal Cardiomyogenic Progenitor Cells
Authors: Liu Yuan-Hung , Huang Shih-Yun , Lin Yi-Shuan , Huang Hsing-Yu 
Published: July 2021

Recent studies report that postnatal mammalian hearts undergo cardiomyocyte refreshment. While the exact origin of the cells involved in postnatal cardiomyogenesis remains unclear.
Here, we identified a pool of Nkx2.5 enhancer expressing cells in the postnatal mouse heart with cardiomyogenic differentiation potential in vitro. We tracked the expression of a cardiac-specific enhancer of Nkx2.5 using inducible Nkx2.5 enhancer-Cre mice from embryonic development to adulthood and post-myocardial infarction (MI) and documented the Nkx2.5 enhancer expressing cells directly contribute to postnatal cardiomyogenesis in vivo. Upon genetic ablation of these activated progenitors after myocardial injury, the cardiac function deteriorated. Transcriptomic analysis of Nkx2.5 enhancer expressing cells showed high expression of heart development genes.
To trace the developmental origin of the activated Nkx2.5 cardiomyogenic progenitor cells, we created different lineage-Cre/Nkx2.5 enh-eGFP/ROSA26 reporter triple transgenic mice. Post-MI Nkx2.5 cardiomyogenic progenitor cells originated from the embryonic epicardial cells, not from the pre-existing cardiomyocytes, endothelial cells, cardiac neural crest cells, or perinatal/postnatal epicardial cells.
Together, this study confirmed that cardiac lineage-specific progenitor cells, which originate from embryonic epicardium-derived cells, contribute to postnatal mammalian cardiomyogenesis.
Abstract 16593: Endocytosis Pathway of Kv1.5 Channels in Atrial Cardiomyocytes
Authors: Barbier Camille , Eichel Catherine , Louault Florent , Rucker-Martin Catherine , Coulombe Alain , Hatem Stéphane , Balse Elise 
Published: July 2021

Trafficking of ion channels in cardiomyocytes is a highly dynamic process which is determinant for shaping action potential (AP). In this study, we focused on the dynamic of Kv1.5 channel which carry the atria-specific potassium outward current involved in the repolarisation of the AP.
We first investigated the endocytosis pathway for Kv1.5 channels in the atria.
High resolution 3-D microscopy revealed that Kv1.5 channels are associated with clathrin vesicles in atrial myocytes but not with caveolin. Electron microscopy showed that vesicles are found both at the lateral sarcolemma and at the intercalated disc. Blockade of the clathrin pathway using sucrose or SiRNA induced an increase in IKur recorded by whole-cell patch-clamp and an accumulation of Kv1.5 channels at the sarcolemma as shown by biotinylation assay. Clathrin blockade also increased fluorescence recovery after photo bleaching of Kv1.5 channels. Altogether, these data show that Kv1.5 channels are internalized through the clathrin pathway.
TIRF microscopy approach was used to follow eGFPKv1.5-Kv1.5 channels in living cells and to establish their dynamic in control and clathrin-blocked myocytes. Blockade of the clathrin pathway leads to a global increase of Kv1.5 channels at the membrane. Particle analysis revealed an accumulation of the channels into clusters and their stabilisation at the membrane.
Our objective now is to investigate the involvement of the cytoskeleton in Kv1.5 channels endocytosis by using dyes staining tubulin or actin in live cells; and the fate of internalized channels at different time points by co-immunostainings with antibodies directed against the different endosomes.
In conclusion, we have identified the clathrin pathway as the internalization route for Kv1.5 channel, in atrial myocytes. The blockade of this pathway modifies Kv1.5 channels dynamic at the membrane. Future work will be conducted to further investigate dynamic and fate of this atria-specific channel. This study should help understanding the constitution of the sub-membrane reservoir of repolarization that we previously described (Balse E., et al. 2009, PNAS).
Abstract 16698: Comparison of Hospital Length of Stay Between Hospitalized Non-Valvular Atrial Fibrillation Patients Treated With Either Apixaban or Warfarin
Authors: Farr Amanda , Jing Yonghua , Johnston Stephen , Trocio Jeffrey , Singhal Shalabh , Graham John 
Published: July 2021

Hospital length of stay (LOS) is an important cost driver for hospitals and payers alike. Hospitalized non-valvular atrial fibrillation (NVAF) patients treated with apixaban may have shorter LOS than those treated with warfarin because of the absence of need for INR monitoring in apixaban. Thus, this study compared LOS between hospitalized NVAF patients treated with either apixaban or warfarin.
This was a retrospective, observational cohort study based on a large U.S. database including diagnosis, procedure, and drug administration information from over 600 acute-care hospitals. Patients selected for study were aged ≥18 years and had a hospitalization record with an ICD-9-CM diagnosis code for atrial fibrillation (AF) in any position from Jan-1-2013 to Feb-28-2014 (index hospitalization). Patients with diagnoses indicative of rheumatic mitral valvular heart disease or a valve replacement procedure during index hospitalization were excluded. Patients were required to have been treated with either apixaban or warfarin, and not treated with rivaroxaban or dabigatran, during index hospitalization. Apixaban patients were propensity score (PS) matched to warfarin patients at a 1:1 ratio, using patient demographic/clinical and hospital characteristics. Study outcome was LOS, calculated as discharge date minus admission date; a sensitivity analysis calculated LOS as discharge date minus first anticoagulant administration date. Subanalyses were conducted among patients with a primary diagnosis of AF.
The study included 832 apixaban patients matched to 832 warfarin patients. Patients had a mean age of 74 years and 46% were female. Mean [standard deviation (SD)] and median LOS was significantly (P<0.001) shorter in apixaban patients (4.5 [4.2] and 3 days) than in warfarin patients (5.4 [5.0] and 4); results were consistent in sensitivity analyses of LOS after first anticoagulant administration date (2.8 [3.5] and 2 days for apixaban vs. 3.9 [3.9] and 3 for warfarin, P<0.001). Subanalyses yielded very similar results.
Among NVAF patients, apixaban treatment was associated with shorter hospital LOS when compared with warfarin treatment. These findings may have important clinical and economic implications for hospitals, payers, and patients.
Abstract 16709: Contrasting Influences of Renal Function on Blood Pressure and HbA1c Reductions With Empagliflozin in Patients With Type 2 Diabetes and Hypertension
Authors: Cherney David , Cooper Mark , Tikkanen Ilkka , Crowe Susanne , Johansen Odd Erik , Lund Søren S , Woerle Hans J , Broedl Uli C , Hach Thomas 
Published: July 2021

The sodium glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces HbA1c, weight and blood pressure (BP) in patients with type 2 diabetes (T2D). While glucose lowering with EMPA is dependent on renal function, the impact of chronic kidney disease (CKD) on BP reduction with EMPA is less well understood. Our aim was to determine if impaired renal function attenuates antihypertensive effects of EMPA.
A Phase III randomized placebo (PBO)-controlled trial (EMPA-REG BP™) investigated the efficacy and safety of EMPA in patients with T2D and hypertension (defined as mean seated office systolic BP [SBP] 130-159 mmHg and diastolic BP [DBP] 80-99 mmHg at screening). Patients (mean [SD] age 60.2 [9.0] years, HbA1c 7.90 [0.74] %, 24-hour SBP 131.4 [12.3] and 24-hour DBP 75.0 [7.8] mmHg) received EMPA 10 mg (n=276), EMPA 25 mg (n=276) or PBO (n=271) once daily for 12 weeks. We assessed changes from baseline in mean ambulatory 24-hour SBP and HbA1c in subgroups by baseline eGFR (MDRD equation), adjusting for differences in baseline mean 24-hour SBP (for SBP analyses only), HbA1c, region, number of antihypertensive medications, treatment, eGFR and treatment by eGFR interaction between groups.
In patients with normal renal function, or stage 2 or 3 CKD, EMPA significantly reduced HbA1c and mean 24-hour SBP vs PBO (Table). As expected, PBO-corrected HbA1c reductions with EMPA appeared to decrease with decreasing eGFR (Table). In contrast, PBO-corrected reductions in mean 24-hour SBP with EMPA mostly appeared to increase with decreasing eGFR (Table).
Unlike HbA1c, mean 24-hour SBP reductions with EMPA in patients with T2D and hypertension appear to be greater in patients with lower eGFR, indicating that SBP modulation with EMPA may involve pathways other than urinary glucose excretion such as diuretic effects, weight loss, improved glycemic control, reduced arterial stiffness or direct vascular effects.
Abstract 16714: Real-World Cost of All-Cause Hospitalizations Over a 12-Month Period After Acute Venous Thromboembolism
Authors: Shorr Andrew F , Johnston Stephen , Jing Yonghua , Schaiff Robyn A , Trocio Jeffrey , Thomson Erin , Juneau Paul , Graham John 
Published: July 2021

Recent clinical trial data have shown that newer oral anticoagulants may reduce all-cause hospitalizations in patients with venous thromboembolism (VTE) who complete anticoagulation therapy for 6-12 months. To understand the potential cost implications of such hospitalization reductions, this study sought to quantify the real-world cost of all-cause hospitalizations over a 12-month period after acute VTE.
This was a retrospective cohort study using U.S. health insurance claims data. Patients included in the study were aged ≥18 years, had experienced a non-fatal hospitalization or ED visit with a principal diagnosis of VTE between 1-Jan-2007 and 31-Mar-2013 (first visit=index) and had ≥1 claim for anticoagulation (warfarin, enoxaparin, rivaroxaban) or placement of an inferior vena cava filter ≤30 days after index. For up-to one year after discharge from the hospitalization or ED visit for acute VTE, patients were followed to identify the occurrence and costs of all-cause hospitalizations. Multivariable regressions were used to compare per-patient per-month (PPPM) total healthcare costs between patients with vs. without a hospitalization during follow-up.
The final cohort included 123,665 patients (mean age 59 years, 50% male). During an overall mean follow-up of 284 days after discharge from the acute VTE event, 33,843 patients were hospitalized at least once for any cause within 1 year and 37% of these hospitalized patients had at least one hospitalization for VTE. Among patients who were hospitalized, mean (standard deviation) PPPM hospital length of stay and PPPM costs for hospitalizations were 1.4 (2.8) and $5,800 ($14,723) at 1 year. Adjusted incremental PPPM differences in total healthcare costs between patients with vs. without a hospitalization during the 1-year follow-up were $ $4,808 (P<0.001).

Conclusion:
Hospitalizations within 1 year after acute VTE are common and costly. VTE treatments which reduce hospitalizations after acute VTE may confer substantial cost offsets.
Abstract 17155: Complications with Cardiac Perforation and Lead Dislodgement of the 5086 MRI Pacing Lead
Authors: Choi Jin Hee , Kim Jun , Jo Uk , Kwon Chang Hee , Lee Woo Seok , Kim Yoo Ri , Nam Gi-Byoung , Choi Kee-Joon , Kim You-Ho 
Published: July 2021

As the MR-conditional Medtronic 5086 lead has been implanted, there were some reports that the 5086 lead demonstrated higher lead dislodgement and cardiac perforation compared with the 5076 lead. However, little is known regarding the rates of complications between the 5086 lead and the 5076 lead especially in asian populations.
The purpose of this study was to describe the incidence of lead-related complications including cardiac perforation and lead dislodgement of the 5086 lead compared to the 5076 lead and to investigate the clinical factors associated with development of cardiac perforation or lead dislodgement.
This study was a retrospective single center study. Consecutive 292 patients who underwent dual chamber pacemaker implantation using either 5076 (N=121) or 5086 lead (N=171) between January 2008 and March 2014 were enrolled in this study. Primary endpoint was incidence of cardiac perforation with pericardial effusion or cardiac tamponade within 30 days of implant. Secondary endpoint was combined incidence of cardiac perforation or lead dislodgement.
Primary outcome occurred in 3 patients with the 5806 lead (1.8%) and no patient with the 5076 lead (0.0%) (p=0.269). Lead dislodgement occurred in 9 patients with the 5806 lead (5.3%) and 5 patient with the 5076 lead (4.1%) (p=0.784) (Table1). There was no difference in the incidence of secondary endpoint between groups (7.0 vs 4.1%, p=0.447). On logistic regression analysis after multivariate adjustment, factors associated with an increased risk for dislodgement and cardiac perforation included heart failure, taking a rivaroxaban, and location of atrial lead other than right atrial appendage (Table2).
Compared with the 5076 lead, the rate of cardiac perforation and lead dislodgement was not significantly higher with the 5086 MRI lead in asian population. Cardiac perforation and lead dislodgements occured more often in patient with heart failure, taking a rivaroxaban, and unusual location of atrial lead.
Abstract 18092: Nitroxyl (HNO) Improves Ventricular Relaxation and Ca2+-Handling in Rats with Induced Chronic Diastolic Dysfunction
Authors: Roof Steve R , Hartman Craig , Reardon John , del Rio Carlos , Ziolo Mark , Hamlin Robert 
Published: July 2021

Despite the morbidity and clinical burden of primary diastolic cardiac dysfunction, effective therapies for patients presenting with heart failure with preserved ejection fraction (HFpEF) are limited. Nitroxyl (HNO) produces cAMP-independent functional support, in part by improving myocardial calcium-handling. We hypothesize that HNO can rescue lusitropic function when acutely administered to rats with chronic diastolic dysfunction, mimicking HFpEF.
Diastolic dysfunction, as demonstrated by decreased E/A ratios via echocardiography, was induced by either 4 weeks of chronic isoproterenol administration (via a mini-osmotic pump; ISO) or by renoprival hypertension (secondary to renal wrapping; RW) for 5 weeks. In vivo left-ventricular hemodynamics/pressure-volume relationships were assessed before/during a 30 minute IV administration of a HNO pro-drug (CXL-1020, 100 μg/kg/min). Ca2+ handling in isolated cardiomyocytes was also studied (CXL-1020, at 50 μM). In both cases, milrinone (mil) was used as a cAMP-dependent positive control (at a matched-efficacy in healthy rats, i.e., 10 μg/kg/min and 0.5 μM)
In the setting of chronic diastolic dysfunction, HNO lowered the LV filling pressures in both models by a combined average of 46 ± 8% versus baseline, accelerated the time-constant (tau) of relaxation (-26 ± 3%) and improved compliance (flattened the end-diastolic PV relationship) (-61 ±3%). In myocytes isolated from dysfunctional hearts, HNO accelerated the time for Ca2+ to decline to 50% of its max amplitude (RT50) by -10 ± 2% and myocyte relengthening by -12 ± 3% in ISO rats. Despite eliciting comparable responses in healthy animals/myocytes, the HNO-mediated effects on both tau (in vivo) (-33 ± 3% vs mil -25 ± 2%) and Ca2+ decline (myocyte) (-10 ± 2% vs mil -6 ± 1%) were greater than those of milrinone in the ISO rats, which had greater impairment at baseline compared to RW rats.
In conclusion, acute-therapy with HNO improved ventricular relaxation, compliance and Ca2+ handling, in the setting of chronic diastolic dysfunction. Moreover, these effects were greater than observed with the cAMP-dependent agent milrinone.