bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prohibitin‐1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis
Authors: Mattox Taylor A. , Psaltis Christine , Weihbrecht Katie , Robidoux Jacques , Kilburg‐Basnyat Brita , Murphy Michael P. , Gowdy Kymberly M. , Anderson Ethan J. 
Published: July 2021

Background
In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin‐1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown.

Methods and Results
Using a wide‐ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid‐derived 2)‐like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti‐inflammatory response and protects HL‐1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti‐inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid‐derived 2)‐like 2, but partially dependent on PI3K/AKT signaling in the heart.

Conclusions
These findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro‐survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.
The Gut Microbiome of Heart Failure With Preserved Ejection Fraction
Authors: Beale Anna L. , O’Donnell Joanne A. , Nakai Michael E. , Nanayakkara Shane , Vizi Donna , Carter Kaye , Dean Eliza , Ribeiro Rosilene V. , Yiallourou Stephanie , Carrington Melinda J. , Marques Francine Z. , Kaye David M. 
Published: July 2021

Background
Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial‐derived metabolites such as short‐chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors.

Methods and Results

We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α‐diversity (eg, number of microbes) and β‐diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF (
P
=0.001). We did not find an association between β‐diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so (
P
=0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short‐chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day;
P
=0.016).

Conclusions
We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.
Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice
Authors: Takeshita Hikari , Yamamoto Koichi , Mogi Masaki , Wang Yu , Nozato Yoichi , Fujimoto Taku , Yokoyama Serina , Hongyo Kazuhiro , Nakagami Futoshi , Akasaka Hiroshi , Takami Yoichi , Takeya Yasushi , Sugimoto Ken , Horiuchi Masatsugu , Rakugi Hiromi 
Published: July 2021

Background
The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin‐(1‐7), respectively, is the primary process that counteracts activation of the canonical renin‐angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging‐related muscle weakness.

Methods and Results
Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild‐type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS‐associated genes, inflammation‐associated genes, and senescence‐associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice.

Conclusions
Double deletion of AT2 and Mas in mice exaggerated aging‐associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging‐associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.
Age and Acute Ischemic Stroke Outcome in North American Patients With COVID‐19
Authors: Dmytriw Adam A. , Dibas Mahmoud , Schirmer Clemens M. , Settecase Fabio , Heran Manraj K. S. , Efendizade Aslan , Kühn Anna Luisa , Puri Ajit S. , Ospel Johanna , Menon Bijoy , Sivakumar Sanjeev , Mowla Ashkan , Vela‐Duarte Daniel , Linfante Italo , Dabus Guilherme , Regenhardt Robert W. , Patel Aman B. , Leslie‐Mazwi Thabele , D’Amato Salvatore , Rosenthal Joseph , Zha Alicia , Talukder Nafee , Sheth Sunil , Cooke Daniel , Leung Lester Y. , Malek Adel , Voetsch Barbara , Sehgal Siddharth , Wakhloo Ajay K. , Wu Hannah , Cohen Jake , Turkel‐Parella David , Xavier Andrew , Tiwari Ambooj ,   the North American Neurovascular COVID‐19 (NAN‐C) Consortium
Published: July 2021

Background
Acute ischemic stroke (AIS) in the context of COVID‐19 has received considerable attention for its propensity to affect patients of all ages. We aimed to evaluate the effect of age on functional outcome and mortality following an acute ischemic event.

Methods and Results

A prospectively maintained database from comprehensive stroke centers in Canada and the United States was analyzed for patients with AIS from March 14 to September 30, 2020 who tested positive for SARS‐CoV‐2. The primary outcome was Modified Rankin Scale score at discharge, and the secondary outcome was mortality. Baseline characteristics, laboratory values, imaging, and thrombectomy workflow process times were assessed. Among all 126 patients with COVID‐19 who were diagnosed with AIS, the median age was 63 years (range, 27–94). There were 35 (27.8%) patients with AIS in the aged ≤55 years group, 47 (37.3%) in the aged 56 to 70 group, and 44 (34.9%) in the aged >70 group. Intravenous tissue plasminogen activator and thrombectomy rates were comparable across these groups, (
P
=0.331 and 0.212, respectively). There was a significantly lower rate of mortality between each group favoring younger age (21.9% versus 45.0% versus 48.8%,
P
=0.047). After multivariable adjustment for possible confounders, a 1‐year increase in age was significantly associated with fewer instances of a favorable outcome of Modified Rankin Scale 0 to 2 (odds ratio [OR], 0.95; 95 CI%, 0.90–0.99;
P
=0.048) and higher mortality (OR, 1.06; 95 CI%, 1.02–1.10;
P
=0.007).

Conclusions
AIS in the context of COVID‐19 affects young patients at much greater rates than pre‐pandemic controls. Nevertheless, instances of poor functional outcome and mortality are closely tied to increasing age.
Association of Nonacute Opioid Use and Cardiovascular Diseases: A Scoping Review of the Literature
Authors: Singleton Jade H. , Abner Erin L. , Akpunonu Peter D. , Kucharska‐Newton Anna M. 
Published: July 2021

BACKGROUND
In this scoping review, we identified and reviewed 23 original articles from the PubMed database that investigated the relationship between nonacute opioid use (NOU) and cardiovascular outcomes.

METHODS AND RESULTS
We defined NOU to include both long‐term opioid therapy and opioid use disorder. We summarized the association between NOU and 5 classes of cardiovascular disease, including infective endocarditis, coronary heart disease (including myocardial infarction), congestive heart failure, cardiac arrythmia (including cardiac arrest), and stroke. The most commonly studied outcomes were coronary heart disease and infective endocarditis. There was generally consistent evidence of a positive association between community prevalence of injection drug use (with opioids being the most commonly injected type of drug) and community prevalence of infective endocarditis, and between (primarily medically indicated) NOU and myocardial infarction. There was less consensus about the relationship between NOU and congestive heart failure, cardiac arrhythmia, and stroke.

CONCLUSIONS
There is a dearth of high‐quality evidence on the relationship between NOU and cardiovascular disease. Innovative approaches to the assessment of opioid exposure over extended periods of time will be required to address this need.
Abstract P150: Estrogen Protects Against and Reverses Adverse Ventricular Remodeling in Pulmonary Hypertension-Induced Right Ventricular Failure
Authors: Nadadur Rangarajan D , Umar Soban , Iorga Andrea , Matori Humann , Partow-Navid Rod , Eghbali Mansoureh 
Published: July 2021

Pulmonary hypertension (PH) leads to right-ventricular failure (RVF). RVF is characterized by adverse RV remodeling including hypertrophy and changes in the cardiac Extracellular Matrix (ECM) such as fibrosis and re-expression of cardiac fetal genes. Among the potentially re-expressed genes are the novel ECM interacting proteins Osteopontin (OPN) and Osteocalcin (OCN).
Gender differences found in experimental PH are attributed to protective effects of Estrogen (E2). We hypothesize that gender differences observed in experimental PH are partially due to the effects of E2 on the cardiac ECM, and that exogenous E2 may be able to reverse adverse RV remodeling.
Male and female rats received single monocrotaline (MCT, 60mg/kg) injection. Some rats were given E2 (42.5μg/kg/day) from day 21–30. Saline treated rats were controls. Cardiopulmonary hemodynamics were serially monitored and RV pressures (RVP) were recorded terminally. RV fibrosis was assessed by trichrome staining. Gene expression was determined by RT PCR and plasma OPN by ELISA.
All rats developed PH by day 21 and RVF by day 30. Male rats developed more severe PH-induced RVF than females (RVP=70 vs. 41.5±5 mmHg; RV/(LV+IVS)= 0.69±0.07 vs. 0.47±0.04; RVEF = 30.4±1.8 vs. 42.8±2% resp., all p<0.05). Males also revealed more severe RV fibrosis and greater re-expression of OPN (4.5 fold vs. females, p<0.05) and OCN (2-fold vs. females, p<0.05). Plasma OPN was also elevated in RVF males (1.00±0.11 in control to 1.47±0.18 pg/ml, p<0.05) but not RVF females (0.848±0.18 in control to 0.859±0.294 pg/ml, p=ns).
Since females experienced less severe RV remodeling than males, MCT injected males were treated with exogenous E2 from day 21–30. Some E2 treated male rats were sacrificed at day 30, and some were kept an additional 12 days after E2-withdrawal (E2-W group). E2 reversed PH-induced RVF (RVP=38mmHg; RV/(LV+IVS) = 0.28±0.03; RVEF=61.5±0.8%, all p<0.05 vs. male RVF) and fibrosis. OPN and OCN were fully restored following E2 withdrawal by day 42. E2 therapy also restored circulating OPN levels (p<0.05 vs. RVF) showing that OPN has potential value as a plasma marker for PH-induced RV failure.
These results suggest that E2 protects against adverse RV remodeling in females, and reverses adverse RV remodeling in males.
Abstract 144: Interstitial Formation of Adenosine and Inosine Is Proarrhythmic Through Adenosine A1 Receptor in the Developing Heart
Authors: Robin Elodie , Sabourin Jessica , Raddatz Eric 
Published: July 2021

We previously established that exogenous adenosine (ADO) induces transient arrhythmias in the developing heart via the ADO A1 receptor (A1AR) and downstream activation of NADPH oxidase/ERK and PLC/PKC pathways.
We assessed the hypothesis that both endogenous ADO and its derived compound inosine (INO) can simultaneously act in an autocrine/paracrine manner and induce rhythm and conduction disturbances.

The validated model of the spontaneously beating heart obtained from 4-day-old chick embryos was used. The basal ADO/INO ratio determined by HPLC was approximately 10. Blockade of Equilibrative Nucleoside Transporters (ENTs) by dipyridamole, which is known to increase interstitial ADO level, induced transient atrial dysrhythmias and atrio-ventricular blocks in 70% of the hearts (n=30) and, in parallel, increased ERK2 phosphorylation. When extracellular conversion of AMP to ADO by ecto-5’-nucleotidase/CD73 was inhibited by AOPCP, the dipyridamole-induced arrhythmias were prevented. The dipyridamole-induced arrhythmias and ERK2 phosphorylation were prevented by the specific antagonist of the A1AR (DPCPX) but not by antagonists of A2AAR (
SCH58261
), A2BAR (MRS1754) or A3AR (MRS1523). Interestingly, inhibition by EHNA of the conversion of ADO to INO by adenosine deaminase was not proarrhythmic whereas exogenous INO (500 µM) induced arrhythmias which were prevented by DPCPX.

In conclusion, these findings suggest that endogenous ADO and INO in the interstitial compartment of the developing heart can provoke transient pacemaking and conduction disturbances via A1AR and downstream ERK activation in an autocrine/paracrine manner. Overall, our results provide new insights into the mechanisms underlying cardiac dysfunction when a hypoxic-ischemic episode induces local overproduction of ADO and INO
Abstract 189: Activation of Voltage-Dependent Anion Channel 2 Suppresses Ca
2+
-Induced Cardiac Arrhythmia
Authors: Chen Jaunian , Schredelseker Johann , Shimizu Hirohito , Huang Jie , Lu Kui , Franklin Sarah , Vondriska Thomas , Goldhaber Joshua I , Kwon Ohyun 
Published: July 2021

Abnormal Ca2+ handling in cardiac muscle cells is associated with a wide range of human cardiac diseases, including heart failure and cardiac arrhythmias. Zebrafish tremblor (tre) mutant embryos manifest unsynchronized cardiac contractions due to a Ca2+	extrusion defect in cardiomyocytes and thus are used as an animal model for aberrant Ca2+	homeostasis-induced cardiac arrhythmia. To further dissect molecular mechanisms regulating cardiac Ca2+	homeostasis, we conducted a chemical suppressor screen on tre and found that efsevin, a synthetic compound, potently suppresses cardiac fibrillation and restores rhythmic cardiac contractions in tre embryos. In addition, the treatment with efsevin blocks the propagation of arrhythmogenic Ca2+ waves and accelerates the decay phase of Ca2+	sparks in adult murine cardiomyocytes under Ca2+ overload conditions, demonstrating that efsevin modulates Ca2+ handling in both embryonic and adult cardiac tissues. Through a biochemical pulldown assay, we identified a direct interaction between efsevin and VDAC2, a mitochondrial outer membrane voltage dependent anion channel. Overexpression of VDAC2 restores synchronized cardiac contraction in tre and knocking down VDAC2 activity abolishes the rescue effect of efsevin on tre, suggesting that efsevin modulates cardiac Ca2+	homeostasis by potentiating VDAC2 activity. We further showed that enhancing mitochondria Ca2+	uptake by overexpressing MICU or MCU suppresses cardiac fibrillation in tre just like VDAC2 does. Interestingly, this suppressive effect is absent in tre/vdac2 double deficient embryos and co-expression of VDAC2 and MICU or MCU results in synergistic rescue effect on tre, indicating a critical role for mitochondria in regulating cardiac Ca2+ handling and rhythmicity and suggesting that VDAC2 functions as a gate for transporting Ca2+ across the outer membrane. Taken together, our findings identify efsevin as a potent pharmacological tool to modulate cardiac Ca2+ handling, suggest a critical role of mitochondria in the control of cardiac rhythmicity and establish VDAC2 as a modulator of cardiac Ca2+ handling and a potential therapeutic target for the treatment of arrhythmias.
Abstract 22: Calpain-Dependent Induction of Endoplasmic Reticulum Stress in Cardiomyocyte Apoptosis and Post--Myocardial Infarction Remodeling
Authors: Zheng Dong , Ma Jian , Wei Meng , Xu Huaxi , Peng Tianqing 
Published: July 2021

Background: Calpain is up-regulated and implicated in cardiomyocyte apoptosis and myocardial remodelling post myocardial infarction. Endoplasmic reticulum (ER) stress is induced and contributes to myocardial injury in a variety of cardiac diseases. This study was to investigate whether calpain plays a role in ER stress, thereby mediating apoptosis in cardiomyocytes and myocardial remodelling after infarction.
Methods and Results: In rat cardiomyoblasts H9C2 cells, over-expression of calpain-1 increased the protein levels of Bip and CHOP, indicative of ER stress, and induced apoptosis determined by a decrease in Bcl-2 and increases in caspase-3 activation and DNA fragmentation. Inhibition of calpain activity or ER stress prevented apoptosis induced by calpain-1 over-expression. In contrast, over-expression of calpain-2 failed to induce apoptosis. The induction of ER stress by calpain-1 might be mediated through SERCA2a/Calcium signaling as up-regulation of calpain-1 reduced SERCA2a protein and elevated intracellular free Calcium in H9C2 cells. In a mouse model of myocardial infarction induced by coronary artery ligation, calpain activity was increased and ER stress was induced in the infracted heart. Up-regulation of calpastatin, the endogenous calpain inhibitor, inhibited calpain activation, prevented ER stress and apoptosis, reduced myocardial remodelling and improved myocardial function after infarction in calpastatin transgenic mice compared with their wild-type littermates.
Conclusion: Calpain-1 induces ER stress through the proteolysis of SERCA2a, thereby mediating apoptosis in cardiomyocytes. Inhibition of calpain prevents ER stress and apoptosis, reduces myocardial remodelling and dysfunction after infarction. Thus, ER stress may represent a novel mechanism by which calpain mediates myocardial injury in the infracted heart.
Abstract 25: The Use of Voltage Mapping for Slow Pathway Visualization and Ablation of Atrioventricular Nodal Reentry Tachycardia in Pediatric and Young Adult Patients
Authors: Malloy Lindsey , Law Ian , Von Bergen Nicholas 
Published: July 2021

Atrioventricular nodal reentry tachycardia (AVNRT) is a common arrhythmia in both pediatric and adult patients. Ablation of the arrhythmia substrate has typically been guided by anatomical location and electrogram morphology within the triangle of Koch. Using an anatomic approach can be challenging because of unusual pathway locations and anatomic variance. The use of voltage gradient mapping has been proposed in adults to aid in identification of the “slow pathway”, guiding placement of the ablation applications. The purpose of this study was to evaluate this novel technique of voltage guided ablation of AVNRT in a pediatric patient population, with a smaller triangle of Koch.
Patients with atrioventricular nodal reentry tachycardia at the University of Iowa Children’s Hospital who underwent voltage mapping within the slow pathway area were included. Using intracardiac electrical recordings, three-dimensional voltage maps of the right atrium were created. A voltage map identified a bridge of lower voltage signals surrounded by even lower voltage tissue. This bridge was used to guide cryoablation of the slow pathway. Patient demographics, appearance of the intracardiac voltage mapping, timing of procedure, lesions to success, and total number of lesions was obtained.
In this study there were 29 patients with an average age of 14 years (range 7 to 20 years) who underwent AVNRT ablation with voltage mapping. Ten were male. In these patients there was procedural success (no inducible AVNRT, single AV node echo beat or less) in all patients. In 25 of 29 patients, there was an adequate lower voltage saddle to allow guided ablation. The successful ablation site was within the first three lesions in 15/25 patients. Total lesions ranged from 5-34. There has been recurrence in 1 patient over an average follow-up period of one year (range five months - twenty months).
The use of voltage guided ablation of a low voltage saddle in atrioventricular nodal reentry tachycardia is a technique that appears to be effective and safe in the pediatric population and has the advantage of allowing an electrically guided ablation therapy. Voltage guided ablation of atrioventricular nodal reentry tachycardia is a safe and effective technique for ablating AVNRT.