bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time Trends in Simple Congenital Heart Disease Over 39 Years: A Danish Nationwide Study
Authors: El‐Chouli Mohamad , Mohr Grímur Høgnason , Bang Casper N. , Malmborg Morten , Ahlehoff Ole , Torp‐Pedersen Christian , Gerds Thomas A. , Idorn Lars , Raunsø Jakob , Gislason Gunnar 
Published: July 2021

Background
We describe calendar time trends of patients with simple congenital heart disease.

Methods and Results
Using the nationwide Danish registries, we identified individuals diagnosed with isolated ventricular septal defect, atrial septal defect, patent ductus arteriosus, or pulmonary stenosis during 1977 to 2015, who were alive at 5 years of age. We reported incidence per 1 000 000 person‐years with 95% CIs, 1‐year invasive cardiac procedure probability and age at time of diagnosis stratified by diagnosis age (children ≤18 years, adults >18 years), and 1‐year all‐cause mortality stratified by diagnosis age groups (5–30, 30–60, 60+ years). We identified 15 900 individuals with simple congenital heart disease (ventricular septal defect, 35.2%; atrial septal defect, 35.0%; patent ductus arteriosus, 25.2%; pulmonary stenosis, 4.6%), of which 75.7% were children. From 1977 to 1986 and 2007 to 2015, the incidence rates increased for atrial septal defect in adults (8.8 [95% CI, 7.1–10.5] to 31.8 [95% CI, 29.2–34.5]) and in children (26.6 [95% CI, 20.9–32.3] to 150.8 [95% CI, 126.5–175.0]). An increase was only observed in children for ventricular septal defect (72.1 [95% CI, 60.3–83.9] to 115.4 [95% CI, 109.1–121.6]), patent ductus arteriosus (49.2 [95% CI, 39.8–58.5] to 102.2 [95% CI, 86.7–117.6]) and pulmonary stenosis (5.7 [95% CI, 3.0–8.3] to 21.5 [95% CI, 17.2–25.7]) while the incidence rates remained unchanged for adults. From 1977–1986 to 2007–2015, 1‐year mortality decreased for all age groups (>60 years, 30.1%–9.6%; 30–60 years, 9.5%–1.0%; 5–30 years, 1.9%–0.0%), and 1‐year procedure probability decreased for children (13.8%–6.6%) but increased for adults (13.3%–29.6%) were observed.

Conclusions
Increasing incidence and treatment and decreasing mortality among individuals with simple congenital heart disease point toward an aging and growing population. Broader screening methods for asymptomatic congenital heart disease are needed to initiate timely treatment and follow‐up.
Association of Psychological Distress, Contextual Factors, and Individual Differences Among Citizen Responders
Authors: Ries Emma Slebsager , Kragh Astrid Rolin , Dammeyer Jesper , Folke Fredrik , Andelius Linn , Malta Hansen Carolina 
Published: July 2021

Background
Little is known about the psychological risks of dispatched citizen responders who have participated in resuscitation attempts.

Methods and Results
A cross‐sectional survey study was performed with 102 citizen responders who participated in a resuscitation attempt from July 23, 2018, to August 22, 2018, in the Capital Region of Denmark. Psychological distress, defined as symptoms of posttraumatic stress disorder, was assessed 3 weeks after the resuscitation attempt and measured with the Impact of Event Scale‐Revised. Perceived stress was measured with the Perceived Stress Scale. Individual differences were assessed as the personality traits of agreeableness, conscientiousness, extraversion, neuroticism, and openness to experience with the Big Five Inventory, general self‐efficacy, and coping mechanisms (Brief Coping Orientation to Problems Experienced Inventory). Associations between continuous variables were examined with the Pearson correlation. The associations between psychological distress levels and contextual factors and individual differences were analyzed in multivariable linear regression models to determine factors independently associated with psychological distress levels. The mean overall posttraumatic stress disorder score was 0.65 of 12; the mean perceived stress score was 7.61 of 40. The most common coping mechanisms were acceptance and emotional support. Low perceived stress was significantly associated with high general self‐efficacy, and high perceived stress was significantly associated with high scores on neuroticism and openness to experience. Non–healthcare professionals were less likely to report symptoms of posttraumatic stress disorder.

Conclusions
Citizen responders who participated in resuscitation reported low levels of psychological distress. Individual differences were significantly associated with levels of psychological distress and should be considered when engaging citizen responders in resuscitation.
Secondary Stroke Prevention Following Embolic Stroke of Unknown Source in the Absence of Documented Atrial Fibrillation: A Clinical Review
Authors: Kotadia Irum D. , Sim Iain , Mukherjee Rahul , O’Hare Daniel , Chiribiri Amedeo , Birns Jonathan , Bhalla Ajay , O’Neill Mark , Williams Steven E. 
Published: July 2021

Abstract

Approximately one‐third of ischemic strokes are classified as cryptogenic strokes. The risk of stroke recurrence in these patients is significantly elevated with up to one‐third of patients with cryptogenic stroke experiencing a further stroke within 10 years. While anticoagulation is the mainstay of treatment for secondary stroke prevention in the context of documented atrial fibrillation (AF), it is estimated that up to 25% of patients with cryptogenic stroke have undiagnosed AF. Furthermore, the historical acceptance of a causal relationship between AF and stroke has recently come under scrutiny, with evidence to suggest that embolic stroke risk may be elevated even in the absence of documented atrial fibrillation attributable to the presence of electrical and structural changes constituting an atrial cardiomyopathy. More recently, the term
embolic stroke of unknown source
has garnered increasing interest as a subset of patients with cryptogenic stroke in whom a minimum set of diagnostic investigations has been performed, and a nonlacunar infarct highly suspicious of embolic etiology is suspected but in the absence of an identifiable secondary cause of stroke. The ongoing ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke) randomized trial and ATTICUS (Apixiban for Treatment of Embolic Stroke of Undetermined Source) study seek to further define this novel term. This review summarizes the relationship between AF, embolic stroke, and atrial cardiomyopathy and provides an overview of the clinical relevance of cardiac imaging, electrocardiographic, and serum biomarkers in the assessment of AF and secondary stroke risk. The implications of these findings on therapeutic considerations is considered and gaps in the literature identified as areas for future study in risk stratifying this cohort of patients.
Abstract 125: Cardiac Myosin Binding Protein-C Phosphorylation Is Critical for Normal Diastolic Function
Authors: Tong Carl W , Abdalla Mohamed I , Liu Yang , Alluri Himakarnika , Dostal David E , Powers Patricia A , Moss Richard L 
Published: July 2021

Heart failure with preserved ejection fraction (HFpEF)
accounts for approximately 50% of all cases of heart failure, but there is no effective treatment of this disease. Cardiac myosin binding protein-C (MyBPC3) is a thick filament protein that is thought to slow cross-bridge cycling by inhibiting acto-myosin interaction. When phosphorylated, MyBPC3 releases its inhibition thereby accelerating cross-bridge cycling. Thus, we hypothesize that MyBPC3 phosphorylation enhances heart’s ability to relax (lusitropy). To test this idea, we expressed wild type MyBPC3(tWT), non-phosphorylatable MyBPC3(t3SA), and constitutively
phosphorylated mimetic MyBPC3(t3SD) onto MyBPC3(-/-) mouse background. We used echocardiography, voluntary running, and measurements of brain natriuretic peptide (BNP) for comparison. MyBPC3(t3SA) and MyBPC3(t3SD) hearts had similar ejection fraction as MyBPC3(tWT) hearts. MyBPC3(t3SA) hearts show depressed diastolic function revealed by slower myocardial tissue Doppler relaxation velocity at the mitral valve annulus (Ea) and an increased mitral blood flow/myocardium relaxation ratio (E/Ea). In contrast, MyBPC3(t3SD) hearts exhibited enhanced lusitropy with increased Ea and smaller E/Ea. Moreover, the findings of shorter 7-day average voluntary running distances, increased lung/body weight ratios, and increased BNP levels indicated heart failure in MyBPC3(t3SA) mice. Conversely, MyBPC3(t3SD) mice did not show signs of heart failure. Since cardiac function in MyBPC3(t3SA) mice resembles HFpEF and MyBPC3(t3SD) mice exhibit enhanced lusitropy, we conclude that phosphorylation of MyBPC3 is crucial for normal diastolic function.
Abstract 169: Angiotensin-Converting Enzyme 2: Species-Specific Features and Pharmacologic Characterization by RAS Fingerprinting
Authors: Poglitsch Marko , Domenig Oliver , Schwager Cornelia , Loibner Hans , Schuster Manfred 
Published: July 2021

The carboxypeptidase Angiotensin Converting Enzyme 2 (ACE2) is a crucial player of the Renin-Angiotensin-System (RAS) as it balances the ratio between vasoconstrictive and fibrotic Angiotensin II and vasodilative and anti-fibrotic Angiotensin 1-7. This balance is affected by ACE2 either by direct conversion of Angiotensin II to Angiotensin 1-7, or by cleavage of Angiotensin I to Angiotensin 1-9, which is further converted to Ang 1-7 by Angiotensin Converting Enzyme (ACE) or Neutral Endopeptidase (NEP). An increased activity of ACE2 leads to a shift of the RAS towards an Angiotensin 1-7 dominated pattern, which was shown to be protective in various models of cardiovascular and fibrotic diseases.
We performed a comparative pharmacologic characterization of recombinant murine and human ACE2 using natural peptide substrates for the evaluation of the substrate specific ACE2 activity in whole blood. Furthermore, we investigated the impact of ACE2 activators and inhibitors on murine and human ACE2 in whole blood using an LC-MS/MS based approach allowing the simultaneous quantification of 10 different angiotensin peptides (RAS-Fingerprinting).
The investigation of inhibitors and activators of ACE2 using our experimental setting revealed the presence of species-specific enzymatic features, which was indicated by differences between the human and murine enzyme regarding the susceptibility to pharmacologic manipulation and the specificity for different endogenous peptide substrates.
Our studies demonstrate that sequence diversity observed between recombinant human and murine ACE2 significantly affects substrate specificity and pharmacologic enzyme properties. The utilization of Angiotensin I by ACE2 generates Angiotensin 1-7 via Angiotensin 1-9 and represents a pathway of alternative RAS activation, which might have been systematically underestimated in previous studies. The strongly reduced affinity of murine ACE2 for Angiotensin I results in a lack of production of Angiotensin 1-7 via this pathway, which might be of particular importance during anti-hypertensive treatments with ACE inhibitors, where the formation of Angiotensin II is prevented while increased levels of Angiotensin I are observed in circulation.
Abstract 314: Infarct Size Reduction by Statins Requires Parkin and Mitophagy
Authors: Andres Allen M , Lee Pamela , Hernandez Genaro , Huang Chengqun , Ratliff Eric P , Thornton Christine A , Gottlieb Roberta A 
Published: July 2021

The cardioprotective effects of statins are well known yet the mechanism is unclear. Previously we showed that autophagy is required for cardioprotection from ischemia/reperfusion injury. More recently, we reported that ischemic preconditioning involves Parkin-mediated mitophagy. We hypothesized that the molecular basis of statin-mediated cardioprotection may involve mitochondrial quality control through mitophagy. HL-1 cardiomyocytes treated with simvastatin for 24hr exhibited diminished Akt/mTOR signaling, increased activation of ULK1, and upregulation of autophagy (n=3, p<0.05). Similar findings were obtained in cardiac tissue in mice 4hr after i.p. administration of simvastatin. Mevalonate addition abolished statin’s effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of HMG-CoA reductase. Statin treatment in HL-1 cells triggered mitochondrial fragmentation, translocation of Parkin and p62/SQSTM1 to the mitochondria followed by mitophagy. To establish the requirement for statin-mediated mitophagy in cardioprotection, we investigated the ability of statins to reduce infarct size in Parkin knockout (KO) mice. While statin treatment reduced infarct size from 55% of area at risk to 30% in wild type mice, it had no protective benefit in Parkin KO mice (n=4-6, p<0.05). These findings indicate that cardioprotection by HMG-CoA reductase inhibitors involves suppression of mTOR signaling and induction of Parkin-dependent mitophagy.
Figure: Statin-induced cardioprotection against I/R injury: solid bars/diamonds = wild-type; open bars/diamonds = Parkin knockout mice.
Abstract 340: From Stem Cells to Cardiomyocytes: HDAC1 Induces Cardiovascular Differentiation by Regulating SOX17-BMP2 Expression in Early Development.
Authors: Hoxha Eneda , Lambers Erin , Ramirez Veronica , Krishnamurthy Prasanna , Verma Suresh , Thal Melissa , Kishore Raj 
Published: July 2021

Cardiomyocytes derived from embryonic and induced pluripotent stem cells (ES/iPS) provide an excellent source for cell replacement therapies following myocardial ischemia. However, some of the obstacles in the realization of the full potential of iPS/ES cells arise from incomplete and poorly understood molecular mechanisms and epigenetic modifications that govern their cardiovascular specific differentiation. We identified Histone Deacetylase 1 (HDAC1) as a crucial regulator in early differentiation of mES and iPS cells. We propose a novel pathway in which HDAC1 regulates cardiovascular differentiation by regulating SOX17 which in turn regulates BMP2 signaling in differentiating pluripotent cells.
Utilizing stable HDAC1 knock-down (HDAC1-KD) cell lines, we report an essential role for HDAC1 in deacetylating regulatory regions of pluripotency-associated genes during early cardiovascular differentiation. HDAC1-KD cells show severely repressed cardiomyocyte differentiation potential. We propose a novel HDAC1-BMP2-SOX17 dependent pathway through which deacetylation of pluripotency associated genes leads to their suppression and allows for early cardiovascular-associated genes to be expressed and differentiation to occur. Furthermore, we show that HDAC1 affects DNA methylation both during pluripotency and differentiation and plays a crucial, non-redundant role in cardiovascular specific differentiation and cardiomyocyte maturation.
Our data elucidates important differences between ES and iPS HDAC1-KD cells that affect their ability to differentiate into cardiovascular lineages. As varying levels of chromatin modifying enzymes are likely to exist in patient derived iPS cells, understanding the molecular circuitry of these enzymes in ES and iPS cells is critical for their potential therapeutic applications in regenerative medicine. Further research in the molecular mechanisms involved in this process will greatly aid our understanding of the epigenetic circuitry of pluripotency and differentiation in pluripotent cells.
Abstract 079: Estrogen Receptor beta Regulation Of miRNA Expression In The Heart - A Hint For Sex Differences In Hypertrophy
Authors: Queirós Ana , Eschen Claudia , Fliegner Daniela , Regitz-Zagrosek Vera , Sanchez Ruderisch Hugo 
Published: July 2021

Sex differences (SD) in cardiovascular diseases are described and have been attributed to the effects of sex hormones, such as estrogen (E2). Our previous studies in a mouse model of pressure overload revealed SD in fibrosis and apoptosis related genes that were abolished in estrogen receptor β deficient (ERβ-/-) mice. Other studies focus on miRNA regulation by E2, but little is known about sex-specific regulation of miRNAs in heart diseases. We hypothesize that E2 and ERβ are regulators of miRNA expression in the heart potentially contributing to the molecular mechanism of SD observed in cardiovascular diseases.
This project aims to identify SD in the expression of miRNAs in a 9-week transverse aortic constriction (TAC) model and the possible role of E2 and ERβ in their regulation in the heart.
A Targetscan analysis of 80 sex-specific dysregulated genes in hypertrophy allowed identifying 157 different miRNAs that could target them. Based on their expression in the heart we selected 60 miRNAs for quantification by qRT-PCR. In WT mice, 23 miRNAs showed SD in their expression in hypertrophy, all of them showing a higher expression in males than in females. All these significant SD were abolished in ERβ-/- mice. A direct comparison of some of these miRNAs in WT and ERβ-/- female animals identified nine miRNAs significantly higher expressed in the knock-out animals (let-7e, miR-106b, miR-130a, miR-133a, miR-20a, miR-24, miR-27b, miR-29a and miR-378). In vitro studies performed using a female cardiomyocyte cell line (AC16) showed a down-regulation of eight of these miRNAs after a 48h treatment with E2, being the exception miR-133a. The latter showed however a down-regulation after 48h treatment with an ERβ specific agonist, as well as let-7e, miR-106b, miR-130a, miR-20a, miR-24, miR-27b and miR-29a. The effect of treatment with ERα was only visible as a down-regulation of miR-24, miR-29a and miR-378. The potential of these miRNAs having targets in the same pathway and acting in a synergistic way is still under investigation.
ERβ is for the first time identified as a major regulator of miRNA expression in the heart. It may play an important role in determining SD in cardiac hypertrophy, being responsible for the inhibition of miRNA expression in the female heart.
Abstract 130: Secretion of Angiogenic and Anti-apoptotic Factors Accompanies Mesenchymal Stem Cell-mediated Enhancement of Contractile Function in Engineered Cardiac Tissues
Authors: Cashman Timothy , Mayourian Joshua , Costa Kevin D 
Published: July 2021

Previous studies using three-dimensional engineered cardiac tissues (ECT) demonstrated beneficial effects of mesenchymal stem cells (MSC) on contractile function, recapitulating findings in animal studies and in clinical trials. But the mechanisms by which MSC effect this functional enhancement remain unclear. This study tested the hypothesis that MSC-mediated enhancement of ECT function involves paracrine signaling, independent of direct cell-cell interaction with cardiomyocytes (CM).
To create ECT, CM were isolated from neonatal rat ventricles, mixed with 2.0 mg/ml bovine type I collagen and 0.9 mg/ml Matrigel, and pipetted into a custom elastomeric mold with integrated force sensing end-posts. Two types of ECT were created: one containing 1.5 million CM (“CM-only”) and the other containing 1.5 million CM supplemented with 150,000 MSC (“MSC-CM hybrid”). Contractile function of CM-only ECT was then assessed during 2-Hz pacing either in the presence or absence of hybrid tissues sharing the same media. Media surrounding the tissues was also collected and analyzed via protein microarray (RayBiotech) combined with Ingenuity Pathway Analysis software.

CM-only ECT cultured for 5 days showed aligned and compacted structure with a cross-sectional area of 0.39 ± 0.03 mm
2
and a twitch force of 4.7 ± 0.7 N (mean ± SD; n = 6). In CM-only tissues co-cultured for 5 days in shared media alongside hybrid tissues, cross-sectional area was unchanged (0.42 ± 0.02 mm
2
, p = 0.17, n=3), but twitch force increased two-fold to 9.8 ± 6.5 N (p = 0.08). Threshold voltage for electrical pacing of CM-only ECT also decreased from 0.54 ± 0.12 V/mm to 0.39 ± 0.07 V/mm when co-cultured with hybrid ECT (p = 0.097). Protein microarray analysis of the shared co-culture conditioned media showed enrichment (relative to CM-only conditioned media) of the angiogenic factors VEGF (1240x) and IL-1 (8.6x) as well as the cardiac anti-apoptotic/pro-survival factors TNF (194x), bFGF (55x), and bNGF (14.9x).

In conclusion, these findings support paracrine signaling, independent of direct cell-cell contact, as one mechanism of MSC-mediated enhancement of CM function in rat ECT. Identification and isolation of defined cardiotropic factors may lead to novel molecular therapies for cardiac repair.
Abstract 198: Stim/orai Channel Complex In Normal And Hypertrophied Adult Cardiac Myocytes
Authors: Hulot Jean-sebastien , Saliba Youakim , Fauconnier Jeremy , Keck Mathilde , Bénard Ludovic , Marchand Alexandre , Farès Nassim , Lompré Anne-Marie 
Published: July 2021

Cardiac myocytes use Ca2+ not only in excitation-contraction coupling but also as a signaling molecule for cardiac growth. It is however unclear how Ca2+ triggers signaling in cardiac myocytes in the presence of the rapid and large Ca2+ fluctuations that occur during excitation-contraction coupling. We have recently reported that stromal interaction molecule 1 (STIM1), a calcium sensor in the sarcoplasmic reticulum, is a critical element in promoting cardiomyocyte growth through the control of a previously unrecognized sarcolemmal voltage-independent current. Our goal was to characterize the plasma membrane partners that contribute to STIM1-dependent currents in normal and hypertrophied adult cardiac myocytes.
We firstly characterized the expression profile of TRPCs and ORAIs proteins in both normal and hypertrophied ventricular myocytes from abdominal aortic banded rats. The expression of TRPC1, 3, 4, 5 and 6 and of ORAI1 - 3 was identified with an up-regulation of TRPC1 in hypertrophied cells. We then used a non-viral method to deliver cy3-tagged siRNAs to ventricular myocytes to knock-down the candidate channels. The cardiac myocytes were isolated and whole cell patch-clamp technique as well as Fura-2 imaging were performed to measure the currents in cy3-labelled and in control cardiac myocytes. Our data demonstrated that the drug-inducible STIM1-dependent store-operated calcium entry was marginal in normal myocytes but was enhanced in hypertrophied myocytes. In addition, a basal inwardly rectifying current was observed in hypertrophied but not in control myocytes. This spontaneous current was recorded in the absence of calcium store depletion, required STIM1 expression and meets the characteristics of Arachidonate-Regulated Calcium selective (ARC) channels. ORAI silencing completely inhibited both store-dependent and store-independent currents suggesting the critical implication of ORAIs whereas TRPCs were only marginally involved.
In conclusion, ORAI channels are involved in STIM1-dependent currents observed in hypertrophied adult cardiac myocytes. In addition to store-operated calcium entry, the STIM1/ORAI complex provides an alternative, store-independent pathway for agonist-activated Ca2+ entry.