bluuebunny/crossref_metadata_2025 huggingface dataset:
The gray zone of myocardial fibrosis is a better predictor of ventricular arrhythmias than total myocardial fibrosis in patients with previous myocardial infarction
Authors: Lopes P , Freitas P , Ferreira A , Sousa J A , Rocha B , Cunha G , Cavaco D , Abecasis J , Carmo P , Saraiva C , Morgado F , Chotalal D , Feliciano S , Mendes M , Adragao P
Published: October 2021

Background

Current sudden cardiac death (SCD) risk stratification relies heavily on the assessment of left ventricular ejection fraction (LVEF), but markers that could refine risk assessment are needed. Total fibrosis mass (TFM) and “gray zone” of myocardial fibrosis (GZF) on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) have been proposed as potential arrhythmogenic substrates. The aim of our study was to determine whether TFM and GZF can predict the occurrence of ventricular arrhythmias in patients with previous myocardial infarction.

Methods

We performed a single centre retrospective study enrolling all consecutive patients with previous myocardial infarction undergoing LGE-CMR before implantable cardioverter-defibrillator (ICD) implantation for primary or secondary prevention. TFM and GZF were defined as myocardial tissue with signal-intensities >6 SD and 2–6 SD above the mean of reference myocardium, respectively. The primary endpoint was a composite of sudden arrhythmic death, appropriate ICD shock, ventricular fibrillation (VF), or sustained ventricular tachycardia (VT) as detected by the device.

Results

A total of 55 patients (mean age 62±12 years, 87% male, mean LVEF 30% ± 8%) were included. During a mean follow-up period of 34±15 months, 10 patients reached the primary endpoint (8 appropriate ICD shock, 2 sustained VT or VF). Patients who attained the primary endpoint had similar TFM (28.6g ± 14.5 vs. 23.1g ± 14.5; P=0.283) but larger GZF (25.3g ± 11.0 vs 15.6g ± 7.3; P=0.001). After adjustment for LVEF, GZF remained independently associated with the composite arrhythmic endpoint (adjusted hazard ratio [aHR]: 1.10; 95% CI: 1.03–1.17; P=0.005), whereas TFM did not (aHR: 1.02; 95% CI: 0.98–1.06; P=0.394). Decision tree analysis identified 16.4g of GZF as the best cut-off to predict life-threatening arrhythmic events. The primary endpoint occurred in 9 out of the 22 patients (41%) with GZF >16.4g, but in only 1 of the 33 patients (3%) with GZF ≤16.4g – Figure.

Conclusions

The extent of GZF seems to be a better predictor of ventricular arrhythmias than TFM. This LGE-CMR parameter may be useful to identify a subgroup of patients with previous myocardial infarction at an increased risk of life-threatening arrhythmic events.

Funding Acknowledgement

Type of funding sources: None.
Correlation between automatic and manual methods of right ventricle and left atrium strain quantification
Authors: Remior P , Monivas V , Garcia-Rodriguez D , Mirelis J G , Navarro S , Borrego A , Cavero-Gibanel M A , Martinez-Mingo A , Sanchez-Gomez A , Garcia-Gomez S , Mingo S
Published: October 2021

Introduction

Myocardial strain quantification by speckle-tracking of the right ventricle (RV) and left atrium (LA) can be performed by manual or automatic methods.

Purpose

The objective of our study is to evaluate the degree of correlation between manual measurement method and automatic software used in our imaging laboratory, in a population of healthy individuals and patients with cardiac transthyretin amyloidosis (ATTR).

Methods

Fifty-seven individuals were included, 30 patients with ATTR and 27 healthy volunteers, who underwent a transthoracic echocardiogram (TTE) from January to December 2019. Classic echocardiographic parameters and myocardial deformation were obtained according to the ASE/ EACVI guidelines. Global and free wall longitudinal strain of the RV (RVGLS, RVFWLS) and LA global strain (LAGS) analysis were obtained using speckle-tracking with two different software: QLAB Philips 10.7 and AutoSTRAIN Tomtec. Measurements analysis was performed by two experienced echocardiographers. Correlation and reproducibility analysis was performed using Pearson correlation coefficient (PCC) and intraclass correlation coefficient (ICC), respectively.

Results

Seventy-two percent were male and average age was 63±20 years. Linear correlation of RVGLS, RVFWLS and LAGS measurements with both methods reached statistical significance (table). This correlation was stronger and more reliable in the case of the LAGS. The attached figure shows the correlation between the different software in both groups.

Conclusions

AutoSTRAIN Tomtec automatic measurement method had higher reliability and correlation comparing to manual measurements performed by QLAB 10.7, especially in LA measurements. The obtained results, the application speed and the less operator's dependence of this automatic software support its routine use for RV and LA strain quantification.

Funding Acknowledgement

Type of funding sources: None. Correlation and reproducibility resultsLinear regression lines
Cardiac involvement in patients recovered from coronavirus disease-2019 (COVID-19): a systematic review
Authors: Shafiabadi N , Rastad H , Mozafarybazargany M , Talakoob H , Karim H
Published: October 2021

Background

About 47.3 million people have recovered from coronavirus disease 2019 (COVID-19). Manifestations of cardiac involvement have been noted in a significant number of patients in the acute phase. There are increasing concerns that some of these cardiac sequels may persist beyond the acute phase. If untreated, the sustained cardiac injury, especially myocarditis and fibrosis, could have severe consequences. Recent studies have assessed the presence of cardiac involvement using cardiac magnetic resonance (CMR) imaging during the post-acute phase.

Purpose

We present a systematic review of studies assessing evidence of cardiac involvement in patients recovered from COVID-19 during the post-acute phase using Cardiac Magnetic Resonance (CMR) Imaging.

Methods

We reported this study in accordance with PRISMA. A systematic search was performed on PubMed, Embase (Elsevier), and Google scholar databases using Boolean operators and the relevant key terms covering COVID-19, Cardiac injury, CMR, and follow-up. Retrieved articles were included based on predefined eligibility criteria.

Results

Of 1406 articles retrieved from the initial search, 11 items, 9 cohort, and 2 case series studies met our eligibility criteria. The rate of raised T1 (reported in 6 articles) in patients recovered from COVID-19 varied across studies from 5% to73%. In 4 out of 9 studies, raised T2 was detected in any patients, and in remained studies, its rate ranged from 2% to 60%. In most of the included studies, LGE (myocardial or pericardial) was observed in COVID-19 survivors, ranged from 7.0% to 100%. Myocardial LGE mainly had nonischemic patterns. None of the cohort studies observed myocardial LGE in “healthy” controls. Most studies found that patients who recovered from COVID-19 had significantly a greater mean (SD) T1 and T2 compared to participants in the control group.

Conclusion

Our systematic review study found evidence of subclinical and clinical myocardial and pericardial involvement in patients recovered from COVID-19.

Funding Acknowledgement

Type of funding sources: None.
Comprehensive strain analysis in oncological patients undergoing thoracic radiotherapy: 1-year follow-up of a prospective study comparing proton vs. photon beam therapy
Authors: Cordova-Madera S N , Garcia-Bello L , Bruno G , Di Stefano C , Quintero-Martinez J A , Laack N , Corbin K , Whitaker T , Pellikka P , Herrmann J , Mutter R , Villarraga H R
Published: October 2021

Background

Proton beam therapy (PBT) is a promising radiotherapeutic method by which the proton Bragg peak may be exploited to reduce the dose to non-target normal tissues, when compared with the conventional photon treatment (PhT).

Purpose

To evaluate the mechanical function of the left ventricle by endocardial longitudinal (GLS-basic strain), circumferential (GCS) and radial strain (GRS) and systolic (SRs) and early diastolic (SRe) strain rate following thoracic radiotherapy.

Methods

Between March 2016 and March 2017, 58 patients with breast or thoracic cancer scheduled to receive radiotherapy were enrolled prospectively and, underwent 2D-STE echocardiography with basic (GLS) and comprehensive (GCS, GRS,GLSRs, GCSRs, GRSRs, GLSRe, GCSRe, GRSRe parameters) analysis at pre-treatment, mid-treatment, end of treatment, 3 month and 1 year follow-up. LVEF was calculated by the biplane Simpson technique. Shapiro-Wilk's test was performed to evaluate the normal distribution of the data. Comparison between groups was performed with Student's t-test or Wilcoxon test for quantitative variables and with Chi-Square test or Fisher's exact test for qualitative variables. Tukey-Kramer method was used to compare means during follow up. A p-value <0.05 was assumed as the level of statistical significance.

Results

Mean age was 53.3±10.9 years and 91.3% were women. PBT was used to treat 38 patients; PhT in 20. The median of the mean heart dose was lower with PBT than PhT (79±92 vs 829±1121 cGy, respectively [P<.001]). No significant changes in LVEF or GLS for PBT or PhT were seen. Comprehensive strain analysis showed changes in endocardial longitudinal, radial, and circumferential early diastolic strain rate (SRe) in patients undergoing photon beam (PhT) up to one year of follow up (Table 1). No changes were detected in the PBT group. All other variables were non-significant (Not shown).

Conclusion

This is the first longitudinal study, with a one-year follow-up, that shows the relaxation properties of LV are compromised during PhT but not PBT. These findings should be followed in time to evaluate their influence on overall heart function.

Funding Acknowledgement

Type of funding sources: None. Table 1
Left atrial strain for predicting arrhythmia recurrence after atrial fibrillation ablation: cardiac magnetic resonance rapid strain vs. feature tracking strain
Authors: Hopman L H G , Mulder M J , Van Der Laan A , Bhagirath P , Demirkiran A , Von Bartheld M B , Kemme M J B , Van Rossum A C , Allaart C P , Gotte M J W
Published: October 2021

Background

Global left atrial (LA) strain is a predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). Recently, novel rapid LA strain assessment approaches have emerged: LA long axis strain and LA AV junction strain. Currently, it remains unknown whether these rapid strain approaches can predict AF recurrence after AF ablative therapy and hence may be a simple alternative for the cumbersome LA feature tracking strain analysis.

Purpose

The present study focusses on the predictive value of different atrial strain quantification methods in relation to AF recurrence after PVI. Rapid LA strain analysis is compared to LA feature tracking strain in AF patients.

Methods

A total of 58 AF patients (78% paroxysmal AF, 64% male, mean age 61±7 years) undergoing first radiofrequency PVI ablation were included. Prior to ablation, all patients underwent cardiac magnetic resonance imaging being in sinus rhythm. LA rapid strain (long axis strain and AV junction strain) and LA feature tracking strain were derived from 2-chamber and 4-chamber cine CMR images. All patients were routinely followed up for arrhythmia recurrence through 12-lead ECGs, mobile-based one-lead ECGs, and/or Holter monitoring.

Results

After one year follow-up, arrhythmia recurrence (after the 90-day blanking period) was observed in 21 patients (36%), occurring after a median of 159 (119–320) days. LA long axis strain, AV junction strain, and feature tracking strain were all significantly reduced in patients with AF recurrence compared to patients without AF recurrence (long axis strain: −19.96±11.03% vs. −28.18±9.93%, P=0.005; AV junction strain: −18.08±9.69% vs. −25.60±8.79%, P=0.004; feature tracking strain: −12.54±4.16% vs. −15.94±3.50%, P=0.002, respectively, figure A to C). ROC analysis identified LA feature tracking strain as having the highest area under the curve (AUC) for predicting AF recurrence after ablative therapy (AUC: 0.75 for LA feature tracking strain, 0.71 for LA long axis strain, 0.70 for AV junction strain, figure D). Both LA rapid strain methods had a significant correlation with LA feature tracking strain (LA long axis strain vs. LA feature tracking strain, r=0.76, P<0.001 and LA AV junction strain vs. LA feature tracking strain, r=0.77, P<0.001).

Conclusion

LA rapid strain and LA feature tracking strain both have clinically relevant predictive power for prediction of AF recurrence after index PVI in AF patients. Considering the ease of LA rapid strain analysis, this method may be a valuable parameter to assess in clinical practice.

Funding Acknowledgement

Type of funding sources: None. Figure 1
Left ventricular blood flow energetics after acute ST-segment elevation myocardial infarction associate with left ventricular remodeling
Authors: Demirkiran A , Garg P , Geest R J , Berkhof H J , Nijveldt R , Greenwood J P , Plein S
Published: October 2021

Background

Myocardial infarction (MI) leads to complex changes in left ventricular (LV) haemodynamics. It remains unknown how four-dimensional (4D) acute changes in LV blood flow kinetic energy (KE) affect LV remodeling. We hypothesized that LV blood flow energetics are independently associated with adverse LV-remodeling.

Methods

In total, 69 revascularised ST-segment elevation MI patients were enrolled. All patients underwent cardiovascular magnetic resonance (CMR) examination within 2 days of the index event and at 3-month. CMR examination included cine, late gadolinium enhancement, and whole-heart 4D flow acquisitions. CMR analysis included: LV volumes, function, infarct size (indexed to body surface area), microvascular obstruction (MVO), two-dimensional, retrospective valve tracking derived mitral inflow metrics, and 4D blood flow KE components (Fig. 1). Adverse LV-remodeling was defined and categorized according to increase in LV end-diastolic volume: 10% (mild), 15% (moderate), and 20% (severe).

Results

Twenty-four patients (35%) developed mild, 17 patients (25%) moderate, 11 patients (16%) severe LV remodeling. Demographics and clinical history were comparable between patients with/without LV remodeling. In univariable logistic regression analysis, A-wave KE was associated with mild, moderate, and severe LV remodeling (p=0.03, p=0.02, p=0.02, respectively), whereas infarct size was associated with only mild LV remodeling (p=0.02). In multivariable logistic regression analysis, whilst the infarct size and A-wave KE were identified as independent markers for mild LV remodeling (p=0.03, p=0.09, respectively), A-wave KE was the only independent marker regarding moderate and severe LV remodeling (both, p<0.01). In ROC analysis for A-wave KE to be associated with the presence of adverse LV remodeling, the area under the curve was 0.67 for mild (p=0.02), 0.70 for moderate (p=0.01), 0.71 for severe (p=0.03) LV remodeling.

Conclusion

In patients with STEMI, LV hemodynamics assessment by LV blood flow KE demonstrated an incremental value to predict adverse LV-remodeling. A-wave KE early after acute MI had an independent effect on adverse LV remodeling.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): This work was supported by the British Heart Foundation [FS/10/62/28409 to S.P.] and Dutch Technology Foundation (STW), project number 11626 (JW, ME).
Visualization of fibroblast activation after myocardial infarction using 68Ga-FAPI-PET
Authors: Kupusovic J , Kessler L , Ferdinandus J , Hirmas N , Fendler W , Totzeck M , Herrmann K , Wakili R , Rischpler C , Rassaf T , Siebermair J
Published: October 2021

Introduction

Fibroblast activation protein (FAP) alpha specifically expressed by activated fibroblasts has been shown to be significantly involved in processes of tissue healing after injury, including fibrotic remodeling after myocardial infarction (MI). Positron-emission tomography (PET) with the tracer FAP-inhibitor (FAPI) is a novel diagnostic tool primarily described in oncologic patients for tumor stroma detection. We present data from a pilot study investigating patients after MI who underwent subsequent 68Ga-FAPI-PET for assessment of potential FAP-related myocardial remodeling.

Methods

In this retrospective study we analyzed a cohort of 10 post-MI patients who underwent 68Ga-FAPI-PET imaging with respect to cardiac tracer pattern. Standardized maximum and mean uptake values and total volume of tracer enrichment (fibroblast activation volume, FAV) of the infarcted area were calculated. A visual grading scale was established to assess the level of agreement between maximum localized tracer uptake and segments belonging to the supply area of the culprit vessel. Tracer uptake was correlated to clinical variables, with readers blinded to the clinical characteristics.

Results

Focal 68Ga-FAPI uptake was detected in all 10/10 patients after MI. According to our grading system for visual agreement of polar map segments and culprit lesion, we observed a very good (in 37.5% of patients) and a moderate (62.5% of patients) match between tracer uptake and the culprit lesion, respectively. We demonstrated a negative correlation of FAV uptake and left ventricular systolic function (R2=−0.69, p<0.05) and a very strong positive correlation of FAV and peak creatinine kinase level (R2=0.90, p<0.01).

Conclusion

Increased myocardial 68Ga-FAPI uptake, serving as a surrogate for FAP expression after MI, corresponds well to the supply area of the culprit coronary vessel as well as to biomarker levels of myocardial injury. This imaging technique represents a highly promising, novel bio-signal in the assessment of myocardial injury and consecutive remodeling. Large controlled studies are warranted to further evaluate the prognostic impact of this novel imaging technique.

Funding Acknowledgement

Type of funding sources: None.
Cardiac function is normal in most patients recovered from COVID-19
Authors: Tangen J , Aukrust P , Barrat-Due A , Troseid M , Christoffer Olsen I , Nezvalova-Henriksen K , Kaasine T , Dyrhol-Riise A M , Rygh Holten A , Finbraten A K , Josefsen T A , Lee K C , Haugaa K H , Skulstad H , Edvardsen T
Published: October 2021

Background

There are conflicting results regarding impaired cardiac function in patients that have recovered from COVID-19. Cardiovascular magnetic resonance (CMR) studies have revealed a very high frequency of cardiac involvement (78%) and ongoing myocardial inflammation (60%) in patients recently recovered from COVID-19. Findings are advocating further investigation of the long-term myocardial consequences of COVID-19 disease.

Purpose

We aimed to investigate left ventricular (LV) and right ventricular (RV) function by a comprehensive echocardiographic study in patients recovered from COVID-19 infection 3 months after admission to hospital.

Methods

All patients (n=92) had been hospitalized for COVID-19 and were examined with echocardiography three months after hospitalization. They were 59±13 years, and 43% were women. LV function was assessed by ejection fraction (EF) and global longitudinal strain (GLS) and RV function was measured by fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and RV GLS free wall. Tricuspid regurgitation pressure gradient was measured to estimate pulmonary artery pressure.

Results

LV EF was 63±6% and LV GLS was −18.6±2.2%. All patients had normal EF >53%, but 10 showed signs of subtle impaired LV function by LV GLS (≥ −16%). Only two of these did not have hypertension, LV hypertrophy, diabetes or other preexisting diagnosis of heart disease explaining subtle LV dysfunction. All had normal RV FAC (48±7%) and TAPSE (2.3±0.3 cm). We found modestly impaired RV longitudinal function (RV GLS free wall >−25%) in 30% patients, but none had RV GLS worse than −20%. One-third of all patients with reduced RV GLS had signs of elevated pulmonary arterial pressures, which might impact the assessment of RV function.

Conclusions

Traditional echocardiographic parameters showed normal function in all hospitalized COVID-19 patients three months after hospital admittance. Approximately one-third had subtle ventricular dysfunction detected by sensitive echocardiographic methods, but these findings could mostly be explained by systemic or pulmonary hypertension. We cannot, however, exclude that a slight reduction in cardiac function in a minority of our patients was caused by the COVID-19 infection.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): National Clinical Therapy Research in the Specialist Health Services, Norway
MicroRNA-126 mimic administration accelerates vascular perfusion recovery and angiogenesis in a hind limb ischemia model
Authors: Theofilis P , Vogiatzi G , Oikonomou E , Gazouli M , Siasos G , Katifelis H , Perrea D , Vavouranakis M , Iliopoulos D C , Tsioufis C , Tousoulis D
Published: October 2021

Background

Peripheral arterial disease caused mainly by atherosclerosis portent significant morbidity, adverse prognosis and mortality, with localized treatment approaches aiming at symptom alleviation and improvement of circulation. Recently, scientific interest has been shifted towards epigenomics, with microRNAs appearing as a future therapeutic target in ischemic cardiovascular diseases due to their potential in regulating angiogenesis.

Purpose

We investigated the pro-angiogenic effect of miRNA-126 mimic in an in vivo model of hind limb ischemia.

Methods

Ten-week-old male C57Bl/6 mice (n=20) were subjected to left femoral artery ligation and were treated with microRNA-126 mimic at a dose of 5mg/kg (Group A, n=10) or 0.2ml normal saline (Group B, n=10) on days 1, 3 and 7. Laser Doppler imaging was performed to verify successful ligation on day 0 and to evaluate differences in the ischemic-to-normal (I/N) hind limb perfusion ratio on day 7 and 28. Muscle tissue expression of microRNA-126 and vascular endothelial growth factor (VEGF) was determined via PCR.

Results

Following microRNA-126 mimic administration in Group A subjects, we noted a qualitative and quantitative stepwise increase in I/N hind limb perfusion ratio [Day 0: 0.354 (0.276, 0.455) vs. Day 8: 0.775 (0.700, 0.844) vs. Day 28: 0.681 (0.660, 0.896), p=0.001] (Figure 1, Panels A and B). In Group B a stepwise increase of lesser magnitude was observed in I/N hind limb perfusion ratio [Day 0: 0.267 (0.164, 0.383) vs. Day 8: 0.400 (0.338, 0.418) vs. Day 28: 0.539 (0.483, 0.603), p=0.074]. Importantly, over time changes of I/N hind limb perfusion ratio were significantly higher in group A compared to group B (p for interaction=0.005) (Figure 1, Panel B). Muscle tissue expression of microRNA-126 in the ischemic hind limb of Group A was 350-fold lower compared to the ischemic hind limb of Group B (p<0.001) (Figure 1, Panel C). A higher expression (14.2-fold) of VEGF in the ischemic hind limb of microRNA-126-treated mice compared to that of control group was detected (p<0.001) (Figure 1, Panel C). A statistically significant negative correlation was noted between microRNA-126 and VEGF tissue expression levels in the ischemic limbs of both Group A and B subjects whereas no correlation between microRNA-126 and VEGF was observed in the non-ischemic hind limbs of the entire study population (Figure 1, Panel D).

Conclusion

MicroRNA-126 mimic delivery in the ischemic hind limb of mice can accelerate vascular perfusion recovery via angiogenesis, which is mediated by VEGF expression.

Funding Acknowledgement

Type of funding sources: None. Figure 1
The uptake of trimethylamine N-oxide (TMAO) and its influence on endothelial cell identity and inflammation
Authors: Rittig S , Gaal L , Kokot K , Gaul S , Okun J , Laufs U , Boeckel J.-N
Published: October 2021

Background and purpose

Trimethylamine N-oxide (TMAO) is associated with a higher risk of atherosclerotic diseases. However, the underlying molecular mechanisms are not completely understood. Inflammation and following endothelial-to-mesenchymal transition (EndMT) – a process where endothelial cells (ECs) lose their function and phenotype and gain a mesenchymal character – contribute to the development of atherosclerosis. We therefore aimed to investigate the potential uptake of TMAO into ECs and its potential impact on inflammation and subsequent EndMT.

Methods and results

Tandem mass spectrometry revealed a time-dependent uptake of TMAO into primary human endothelial cells of 0.5 nmol/mg protein within the first 30 minutes and of 5.8 nmol/mg within 24 hours. The uptake of TMAO resulted in a significant increase of inflammation as measured by E-selectin expression (+63.8-fold). A prolonged treatment with TMAO for 3 days resulted in an increase of EndMT indicated by a significant increase of the mesenchymal marker genes Versican (+6.8-fold) and Calponin (+11.9-fold), as well as a concomitant decrease of the endothelial marker LYVE1 (−92%). For identification of a potential TMAO transporter in human endothelial cells, we screened for the expression of Solute Carrier Family member transporters in ECs. Through our research, overexpression of the carrier A5 in ECs resulted in a 36% higher intracellular TMAO concentration as early as 30 minutes. In turn, causing a knockdown of A5 prevented TMAO induced inflammation (−77.8% induction of E-Selectin) and EndMT (−98,3% induction of Versican and −461% induction of Calponin).

Conclusion

Using a large screening approach, we identified A5 as the first TMAO transporter described in ECs. TMAO uptake results in increased inflammation of ECs and induction of EndMT. The data identify a novel mechanism of TMAO uptake into human ECs that may help to better understand lifestyle-mediated effects on atherosclerosis.

Funding Acknowledgement

Type of funding sources: None.
The role of cellular senescence in aortic dissection
Authors: Nakao E , Aoki H , Majima R , Hashimoto Y , Shibata R , Hayashi M , Ohno-Urabe S , Furusho A , Nishida N , Hirakata S , Fukumoto Y
Published: October 2021

Background

Aortic dissection (AD) is a catastrophic disease that occurs suddenly. The acute mortality is high and those who survived frequently suffer from serious complications such as aneurysm formation and distal ischemia due to progressive destruction of the aortic walls. Currently, no reliable predictor is available for AD development and surgical intervention is the only therapeutic option to prevent the fatal events after AD development, because the pathogenesis of AD is largely unknown.

Clinical and experimental studies highlighted the importance of inflammation in AD pathogenesis, although the trigger of inflammation remains unclear. Recently, we found that cell proliferation precedes the inflammatory response in AD. Because cell proliferation triggers cellular senescence and senescent cells secrete of proinflammatory cytokines and matrix metalloproteinases, we hypothesized that cellular senescence may participate in AD pathogenesis.

Objective

We investigated if cellular senescence contributes to AD development and progression in a mouse model of AD.

Methods and results

A mouse AD model was created by continuous infusion of beta-aminopropionitrile and angiotensin II (BAPN+AngII), where AD starts to develop in 3 days and occurs to most of the mice in 14 days accompanied by frequent AD rupture and death. Infusion of BAPN+AngII resulted in the appearance of senescent cells that are positive for senescence-associated beta-galactosidase, and expression of senescence markers Arf and Ink4a in the aortic walls. Appearance of cellular senescence occurred in one day of BAPN+AngII infusion and continued throughout the observational period of 14 days. We examined the role of cellular senescence in AD pathogenesis by oral administration of ABT263 which is known as “senolytics” that eliminates senescent cells. ABT263 treatment reduced the expression of the senescence markers. In the vehicle-treated group, the mortality was 66.7% (12/18), whereas that of ABT263-treated group was 35% (14/20, P<0.05 by log-rank test). The severity of AD, as assessed by the lesion length in vehicle group was33.2±3.1 mm, whereas that in ABT263 group was 24.6±1.8 mm (P<0.05).

Conclusions

These findings demonstrated that cellular senescence precedes AD development, and ABT263 effectively prevented AD progression and death, indicating the involvement of cellular senescence in AD pathogenesis. Therefore, cellular senescence represents a potential predictor and a therapeutic target for AD.

Funding Acknowledgement

Type of funding sources: None.
Pulmonary artery radiofrequency ablation in an acute porcine model of pulmonary arterial hypertension
Authors: Goncharova N , Vakhrushev A , Condori Leandro H I , Skorik Y U , Murashova L , Korobchenko L , Andreeva E , Mitrofanova L , Koshevaya E , Lebedev D , Moiseeva O , Mikhaylov E
Published: October 2021

Introduction

Pulmonary hemodynamics improvement after pulmonary artery denervation (PADN) was demonstrated in PAH. Questions arise regarding PADN perioperative effectiveness and the accuracy of the target nerves damage. The aim of the study was to evaluate whether PADN decreases pulmonary artery pressure (PAP) in acute thromboxane A2 (U46619)–induced PAH, and damages PA perivascular nerve fibers.

Materials and methods

10 male Landrace swine (34.7±5.1 kg). In 6 swine acute reversible target mean PAP of 40 mm Hg was induced with synthetic thromboxane A2 infusion (U46619). Control group: 4 swine with PADN. Hemodynamics was assessed throughout the study, PAH modeling was done before and 20 min after PADN (radiofrequency energy, 40 Watts), followed by pathology and immunohistochemical studies.

Results

The mean number of RF applications was 17.5±3.6. Pulmonary embolism (PE) was observed after PADN in 3 swine with U46619 infusion, which were excluded. There was no differences in mPAP, PVR and U46619 dosage after PADN in PAH model (12.3±3.5 vs 12.1±1 mm Hg, p=0.2; 150.4±48.7 vs 129.2±64.1 dynes s cm–5; p=0.2; 24.9±3.3 vs 22.4±4.1 mcg; p=0.18; respectively). Similar hemodynamic results were observed in the control group after PADN (mPAP; p=0.3; PVR; p=0.58). S100 expression was evident in the majority of RFA PA species and in some species loss in tyrosine hydroxylase and M1 acetylcholine receptors expression was detected with no hemodynamic correlation.

Conclusions

PADN using an electrophysiological catheter with unipolar energy does not lead to an acute PA perivascular nerve fibers destruction and detectable mPAP changes in U46619-induced PAH. Delayed nerve damage might be attributable to PADN effects observed in previous studies.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant from the Ministry of Science and Higher Education of the Russian Federation (agreement #075-15-2020-800).
Tofogliflozin improved pulmonary hypertension due to heart failure with preserved ejection fraction in mice
Authors: Joki Y J , Konishi H K , Takasu K T , Minamino T M
Published: October 2021

Introduction

Pulmonary hypertension (PH) caused by left heart diseases is categorized as the group 2 (PH-LHD). PH-LHD due to heart failure with preserved LV ejection fraction (HFpEF) is more prevalent in patients with metabolic syndrome and shows poorer prognosis than LHD without PH. Tofogliflozin (TOFO) is an SGLT2 inhibitor utilized for diabetic treatment. Recent studies revealed that the SGLT2 inhibitor has a beneficial effect on heart failure; however, it remains unclear whether the SGLT2 inhibitor is effective for the treatment of PH-LHD.

Hypothesis

We hypothesized that TOFO has a protective effect on PH with HFpEF.

Methods

We generated two murine models for PH-LHD due to HFpEF, a transverse aortic constriction (TAC) model and a high fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg) for 4weeks. In another model, AKR/J mice were fed HFD or normal chow diet and treated with TOFO (3mg/kg in water) for 20 weeks. We then measured physical data including body weight (BW), left ventricular weight (LV), right ventricular weight (RV), and right ventricular systolic pressure (RVSP) and performed echocardiography.

Results

Mice treated with TOFO demonstrated increased urine glucose level. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RV/LV ratio and RVSP in TAC mice (Figure 1). HFD fed AKR/J mice demonstrated increased BW and PH as demonstrated by increased RV/LV ratio and RVSP compared with the normal chow group. TOFO treatment ameliorated the increases of BW, RV/LV ratio, and RVSP in HFD fed AKR/J mice (Figure 2).

Conclusions

TOFO treatment improved pulmonary hypertension in two models for PH-LHD due to HFpEF, suggesting that the SGLT2 inhibitor is effective for the treatment of this condition.

Funding Acknowledgement

Type of funding sources: None. Figure 2. TOFO reduced RVSP caused by HFD
Detection of direct oral anticoagulants with the dilute Russels viper venom time – observations in a real life setting
Authors: Kloeter T , Siegemund T , Siegemund A , Laufs U , Petros S , Metze M
Published: October 2021

Background

The detection of direct oral anticoagulants (DOACs) in emergency settings still remains challenging, especially when dedicated anti-Xa or anti-IIa tests are not readily available or the specific DOAC is unknown. The dilute Russel's viper venom time (dRVVT) is widely known in lupus anticoagulant (LA) testing and may also provide helpful information regarding the residual antithrombotic activity of DOACs. Yet real world data describing the effect of DOACs on the dRVVT is scarce.

Objective

The study aimed to evaluate the sensitivity and specificity of dRVVT for different DOAC plasma levels.

Methods

A total of 80 patients were recruited – 20 patients for each approved DOAC (apixaban, edoxaban, rivaroxaban and dabigatran). Blood plasma was sampled before (baseline), 6 and 12 hours after DOAC-intake and at plasma peak time. DRVVT was measured using the LA1 screening assay for lupus anticoagulant. Plasma levels were measured by calibrated anti-Xa or anti-IIa tests. Additionally, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured.

Results

All DOACs significantly prolonged the dRVVT. The effects were more pronounced at higher DOAC plasma levels. The area under the receiver operating characteristic (ROC) curve regarding a plasma level cut-off of 30 ng/ml was 0.92 (95% confidence interval (CI) 0.823 to 1.00) for apixaban, 0.97 (95% CI 0.902 to 1.00) for edoxaban, 0.87 (95% CI 0.649 to 1.00) for rivaroxaban and 0.96 (95% CI 0.871 to 1.00) for dabigatran.

Conclusion

A dose dependent effect of all approved direct oral anticoagulants (DOACs) on the dilute Russel's viper venom time (dRVVT) was documented in our real world setting, while relevant DOAC plasma levels did not affect standard coagulation tests. The negative predictive value for the dRVVT was high even at low DOAC plasma levels. The dRVVT could therefore be helpful to rule out relevant antithrombotic plasma activity caused of DOACs in emergency situations.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Universität Leipzig Figure 1. ROC curves
Interconnection of the level of uric acid at risk of development of type 2 diabetes mellitus on FINDRISC scale in women moderate and high cardiovascular risk
Authors: Komir I , Isayeva G , Emelyanova N
Published: October 2021

Aim

To establish a relationship between the level of uric acid and the risk of development of type 2 diabetes mellitus (DM2) on the FINDRISC scale in women of moderate and high cardiovascular risk.

Material and methods

103 women (average age (58,39±11,09) years) with moderate and high cardiovascular risk were examined. Women were divided into groups depending on age: 1 group of age to 50 years old, 2 groups with the age of 50–60 years old, 3 groups more than 60 years. The risk of developing the DM2 in the next 10 years was evaluated using the FINDRISC questionnaire. The level of uric acid was determined by a photometric substantial method. For statistical analysis, SPSSIBM, version 19.0.

Results

It has been established that women, in general, had an increased risk of developing DM2 (11,0 [7,0–14,0] points). The level of uric acid in them was (295,0 [230,0–380,5] μmol/l). In the distribution of women by age, there was no probable difference in uric acid levels (257,0 [249,0–257,5]; 256,0 [210,7–353,3]; 295,0 [231,0–362,5] μmol/l; p>0,05). However, the risk of developing DM2 has probably grown in women depending on age (4,00 [0,25–9,25]; 9,50 [7,00–14,00]; 14,50 [12,50–16,00] points). Uric acid correlated with the FINDRISC scale at the significance level (0,489, p=0,05). However, with the distribution of women, depending on age, we observed the interconnection of uric acid with the risk of developing DM2 at the level of significance only in women 2 groups (0,604, p=0,01).

Conclusions

The level of uric acid is interacting with the risk of developing DM2 on the FINDRISC scale in women of moderate and high cardiovascular risk at the age of 50–60 years.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Government Institution “L.T. Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”, Department of Chronic Non-communicable Disease Prevention
Suppression of telomere capping defects of Saccharomyces cerevisiae yku70 and yku80 mutants by telomerase
Authors: Holland Cory L , Sanderson Brian A , Titus James K , Weis Monica F , Riojas Angelica M , Malczewskyj Eric , Wasko Brian M , Lewis L Kevin
Published: October 2021

The Ku complex performs multiple functions inside eukaryotic cells, including protection of chromosomal DNA ends from degradation and fusion events, recruitment of telomerase, and repair of double-strand breaks (DSBs). Inactivation of Ku complex genes YKU70 or YKU80 in cells of the yeast Saccharomyces cerevisiae gives rise to mutants that exhibit shortened telomeres and temperature-sensitive growth. In this study, we have investigated the mechanism by which overexpression of telomerase suppresses the temperature sensitivity of yku mutants. Viability of yku cells was restored by overexpression of the Est2 reverse transcriptase and TLC1 RNA template subunits of telomerase, but not the Est1 or Est3 proteins. Overexpression of other telomerase- and telomere-associated proteins (Cdc13, Stn1, Ten1, Rif1, Rif2, Sir3, and Sir4) did not suppress the growth defects of yku70 cells. Mechanistic features of suppression were assessed using several TLC1 RNA deletion derivatives and Est2 enzyme mutants. Supraphysiological levels of three catalytically inactive reverse transcriptase mutants (Est2-D530A, Est2-D670A, and Est2-D671A) suppressed the loss of viability as efficiently as the wild-type Est2 protein, without inducing cell senescence. Roles of proteins regulating telomere length were also determined. The results support a model in which chromosomes in yku mutants are stabilized via a replication-independent mechanism involving structural reinforcement of protective telomere cap structures.
Decapitation strategies and the significance of Abubakar Shekau's death in Nigeria's Boko Haram crisis
Authors: Albert Isaac Olawale
Published: October 2021

Decapitation strategies have often been linked to counterterrorism. The existing literature suggests the results of these strategies are mixed. Previous studies suggest that the death of a prominent leader may not necessarily end the crisis; it all depends on the group's infrastructure, ideology, leadership traditions, and extent of its penetration in society. This article takes a critical look at the impact of a recent leadership decapitation in Nigeria. Abubakar Shekau, the leader of the Boko Haram movement in the Lake Chad Basin countries, was killed on 19 May 2021 by a faction of the movement known as the Islamic State of West African Province (ISWAP). This article argues that Shekau's case has paradoxically helped to strengthen ISWAP's position, giving it new recruits and other resources and perhaps most importantly reinforced its position with local communities. This has implications for the Nigerian state, its neighbours and, because of Boko Haram's links to ISIS, the wider war on terrorism.
Mass estimates of individual gas-bearing mesopelagic fish from in situ wideband acoustic measurements ground-truthed by biological net sampling
Authors: Agersted Mette Dalgaard , Khodabandeloo Babak , Klevjer Thor A , García-Seoane Eva , Strand Espen , Underwood Melanie J , Melle Webjørn
Published: October 2021

A new acoustic approach to estimate the mass of individual gas-bearing fish at their resident depth at more than 400 m was tested on Cyclothone spp.. Cyclothone are small and slender, and possibly numerically underestimated globally as individuals can pass through trawl meshes. A towed instrumented platform was used at one sampling station in the Northeast Atlantic, where Cyclothone spp. dominated numerically in net catches, to measure in situ acoustic wideband target strength (TS) spectra, i.e. acoustic scattering response of a given organism (”target”) over a frequency range (here, 38 + 50–260 kHz). Fitting a viscous–elastic scattering model to TS spectra of single targets resulted in swimbladder volume estimates from where individual mass was estimated by assuming neutral buoyancy for a given flesh density, such that fish average density equals that of surrounding water. A density contrast (between fish flesh and seawater) of 1.020 resulted in similar mass–frequency distribution of fish estimated from acoustics/model and Cyclothone spp. caught in nets. The presented proof of concept has the potential to obtain relationships between TS and mass of individual gas-bearing mesopelagic fish in general.
Dynamical aspects of a restricted three-vortex problem
Authors: Sreedharan Kallyadan Sreethin , Shukla Priyanka
Published: October 2021

Point vortex systems that include vortices with constant coordinate functions are largely unexplored, even though they have reasonable physical interpretations in the geophysical context. Here, we investigate the dynamical aspects of the restricted three-vortex problem when one of the point vortices is assumed to be fixed at a location in the plane. The motion of the passive tracer is explored from a rotating frame of reference within which the free vortex with non-zero circulation remains stationary. By using basic dynamical system theory, it is shown that the vortex motion is always bounded, and any configuration of the three vortices must go through at least one collinear state. The present analysis reveals that any non-relative equilibrium solution of the vortex system either has periodic inter-vortex distances or it will asymptotically converge to a relative equilibrium configuration. The initial conditions required for different types of motion are explained in detail by exploiting the Hamiltonian structure of the problem. The underlying effects of a fixed vortex on the motion of vortices are also explored.
Evaluation of the Psychometric Properties of the Burn Specific Health Scale-Brief: A National Institute on Disability, Independent Living, and Rehabilitation Research Burn Model System Study
Authors: Amtmann Dagmar , Bamer Alyssa , McMullen Kara , Ryan Colleen M , Schneider Jeffrey C , Carrougher Gretchen J , Gibran Nicole
Published: October 2021

The Burn Specific Health Scale-Brief (BSHS-B) is a commonly used burn-specific health outcome measure that includes 40 items across nine subscales. The objective of this study was to use both classical and modern psychometric methods to evaluate psychometric properties of the BSHS-B. Data were collected postburn injury by a multisite federally funded project tracking long-term outcomes. We examined dimensionality, local dependence, item fit, and functioning of response categories, homogeneity, and floor and ceiling effects. Items were fit to Item Response Theory models for evaluation. A total of 653 adults with burn injury completed the BSHS-B. Factor analyses supported unidimensionality for all subscales, but not for a total score based on all 40 items. All nine of the subscales had significant ceiling effects. Six item pairs displayed local dependence suggesting redundance and 11 items did not fit the Item Response Theory models. At least 15 items have too many response options. Results identified numerous psychometric issues with the BSHS-B. A single summary score should never be used for any purpose. Psychometric properties of the scale need to be improved by removing redundant items, reducing response categories, and modifying or deleting problematic items. Additional conceptual work is needed to, at a minimum, revise the work subscale and optimally to revisit and clearly define the constructs measured by all the subscales. Additional items are needed to address ceiling effects.
Access to Burn Care in Low- and Middle-Income Countries: An Assessment of Timeliness, Surgical Capacity, and Affordability in a Regional Referral Hospital in Tanzania
Authors: Botman Matthijs , Hendriks Thom C C , de Haas Louise E M , Mtui Grayson S , Binnerts Joost , Nuwass Emanuel Q , Niemeijer Anuschka S , Jaspers Mariëlle E H , Winters Hay A H , Nieuwenhuis Marianne K , van Zuijlen Paul P M
Published: October 2021

This study investigates patients’ access to surgical care for burns in a low- and middle-income setting by studying timeliness, surgical capacity, and affordability. A survey was conducted in a regional referral hospital in Manyara, Tanzania. In total, 67 patients were included. To obtain information on burn victims in need of surgical care, irrespective of time lapsed from the burn injury, both patients with burn wounds and patients with contractures were included. Information provided by patients and/or caregivers was supplemented with data from patient files and interviews with hospital administration and physicians. In the burn wound group, 50% reached a facility within 24 hours after the injury. Referrals from other health facilities to the regional referral hospital were made within 3 weeks for 74% in this group. Of contracture patients, 74% had sought healthcare after the acute burn injury. Of the same group, only 4% had been treated with skin grafts beforehand, and 70% never received surgical care or a referral. Together, both groups indicated that lack of trust, surgical capacity, and referral timeliness were important factors negatively affecting patient access to surgical care. Accounting for hospital fees indicated patients routinely exceeded the catastrophic expenditure threshold. It was determined that healthcare for burn victims is without financial risk protection. We recommend strengthening burn care and reconstructive surgical programs in similar settings, using a more comprehensive health systems approach to identify and address both medical and socioeconomic factors that determine patient mortality and disability.