bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic value of simultaneous 99mTc-sestamibi/123I-BMIPP imaging parameters for predicting the improvement of left ventricular wall motion after acute myocardial infarction using CZT SPECT system
Authors: Hida S , Fujita Y , Hatano T , Morishima T , Yamashita J , Murata N , Ito R , Chikamori T
Published: October 2021

Background

Although the presence of 99mTc-sestamibi/123I-BMIPP-mismatch, the reverse redistribution (RR) of 99mTc-sestamibi and RR of 123I-BMIPP in patients with acute myocardial infarction (AMI) are known to significant markers for predicting the improvement of LV wall motion in the infarcted territory in chronic phase, few studies were performed to analyze them by simultaneous dual-isotope imaging using cadmium-zinc-telluride (CZT) SPECT system.

Purpose

The purpose of this study was to evaluate whether the presence of 99mTc-sestamibi/123I-BMIPP-mismatch or RR of 99mTc-sestamibi, RR of 123I-BMIPP make better prediction of the improvement of LV wall motion in the infarcted territory.

Methods

We evaluated 42 consecutive patients with AMI who had undergone both dual-isotope SPECT in acute phase and stress myocardial SPECT using 99mTc-tracers in chronic phase by Discovery NM530c. The presence of 99mTc-sestamibi/123I-BMIPP-mismatch, RR of 99mTc-sestamibi and RR of 123I-BMIPP were determined using traditional definition. The improvement of LV wall motion in the infarcted territory from acute phase to chronic phase was assessed using QGS.

Results

Of 42 patients, the improvement of LV wall motion in the infarcted territory from acute phase to chronic phase was found in 29 patients. The presence of 99mTc-sestamibi/123I-BMIPP-mismatch and RR of 99mTc-sestamibi and RR of 123I-BMIPP were significantly linked to predict the improvement of LV wall motion (p=0.0001, p=0.0001 and p=0.002, respectively). To predict the improvement of LV wall motion in the infarcted territory in chronic phase, the presence of 99mTc-sestamibi/123I-BMIPP-mismatch showed sensitivity of 93%, specificity of 85% and accuracy of 91%, while RR of 99mTc-sestamibi and RR of 123I-BMIPP had sensitivities of 72%, 48%, specificities of 85%, 100% and accuracies of 76%, 64%, respectively. The multivariate discriminant analysis revealed that the combination of 99mTc-sestamibi/123I-BMIPP-mismatch, RR of 99mTc-sestamibi and RR of 123I-BMIPP best predicted the improvement of LV wall motion in the infarcted territory in chronic phase with sensitivity of 93%, specificity of 85% and accuracy of 91% (chi-square=40.6), compared with RR of 99mTc-sestamibi and RR of 123I-BMIPP only (sensitivity 79%, specificity 85% and accuracy of 81%, chi-square=16.9).

Conclusions

The addition of 99mTc-sestamibi/123I-BMIPP-mismatch on RR of 99mTc-sestamibi and RR of 123I-BMIPP in patients with AMI, help better predict the improvement of LV wall motion in the infarcted territory in chronic phase.

Funding Acknowledgement

Type of funding sources: None.
Normal ranges of global left ventricular myocardial work indices in adults: a meta-analysis
Authors: Ngo T , Truong V , Phan T , Pham T , Nguyen T , Le T , Palmer C , Chung E , Mazur W
Published: October 2021

Background

Non-invasive global myocardial work recently emerged as new parameter to characterize left ventricle function with potential advantages over both ejection fraction and global longitudinal strain.

Purpose

We aimed to perform a meta-analysis of normal ranges of non-invasive left ventricular myocardial work (MW) indices including global constructive work (GCW), global work index (GWI), global wasted work (GWW), and global work efficiency (GWE) and to identify confounding factors that may contribute to variance in reported measures.

Methods

The authors searched four databases, Pubmed, Scopus, Embase, and Cochrane Library through January 2021 using the key terms “myocardial work”,“global constructive work”, “global wasted work”, “global work index”, “global work efficiency”. Studies were included if the articles reported LV myocardial work using 2D transthoracic echocardiography in healthy normal subjects, either in the control group or comprising the entire study cohort. The weighted mean was estimated by using the random effect model with a 95% confidence interval. Heterogeneity across studies was assessed using the I2 test. Publication bias was examined by funnel plot and Egger's regression test.

Results

The search yielded 476 articles. After abstract and full text screening we included 13 datasets with 1665 patients for meta-analysis. The reported normal mean values of GCW and GWI among the studies were 2278 (95% CI, 2167 to 23878; I2=95%), and 2.010 (95% CI, 1922 to 2098, I2=97%), respectively. The mean GWE was 96.0 (95% CI, 95.6% to 96.5; I2=92%), and the mean GWW was 79.7% (95% CI, 68.8% to 90.7%; I2=90%) (Figure). Furthermore, age and gender did not significantly contribute to variations in normal values. No evidence of significant publication bias was observed in the funnel plots and the Egger test.

Conclusion

In this meta-analysis, we provide echocardiographic reference ranges for non-invasive indices of MW. These normal values should serve as a template for clinical and research use for this promising technology.

Funding Acknowledgement

Type of funding sources: None.
SPECT-guided myocardial perfusion and metabolic fatty acid planar imaging to assess the severity of the pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension
Authors: Ono R , Miyauchi H , Iimori T , Sawada K , Kuwabara Y , Kobayashi Y
Published: October 2021

Background

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) represent right ventricular (RV) enlargement and hypertrophy, which consequently increase the RV myocardial perfusion. Although the main energy source of myocardium is fatty acid, it remains unknown whether myocardial fatty acid metabolism is altered in loaded RV. Herein, we report a novel approach to assess the RV perfusion and fatty acid metabolism, which is called SPECT-guided planar imaging.

Purpose

To evaluate if SPECT-guided myocardial perfusion and metabolic fatty acid planar imaging reflects the severity of the pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension.

Methods

The study groups included 30 patients with CTEPH and 20 healthy controls. In these patients with CTEPH, 15 patients underwent pulmonary thromboendarterectomy (PEA). Mean pulmonary artery pressure (mPAP) by right heart catheterization was obtained in all CTEPH patients. 201Thallium (201Tl) and iodine-123-beta-methyl iodophenyl pentadecanoic acid (123I-BMIPP) planar myocardial imaging was performed in all participants. For the patients undergoing PEA, repetitive SPECT-guided 201Tl and 123I-BMIPP planar imaging was performed one year after the procedure. To assess the RV overload, the planar images were performed in left anterior oblique position, optimized to separate the RV from the left ventricular (LV) using SPECT-guided transverse imaging. We measured the total counts of 201Tl and 123I-BMIPP in both the RV and LV. Moreover, we calculated their relative counts of the RV to LV (abbreviated as HR/HL (Tl) and HR/HL (BMIPP), respectively) to determine the indices of myocardial perfusion and fatty acid metabolism, respectively.

Results

Both HR/HL (Tl) and HR/HL (BMIPP) were elevated in the CTEPH patients compared with control (0.62±0.14 vs. 0.36±0.07, p<0.01 and 0.57±0.14 vs. 0.34±0.06, p<0.01, respectively). In the CTEPH patients, average mPAP was 44.0±9.52 mmHg, which was correlated with HR/HL (Tl) (r=0.675, p<0.001) and HR/HL (BMIPP) (r=0.685, p<0.01). Furthermore, the decrease of average mPAP 1 year after PEA was positively associated with the decrease of HR/HL (Tl) (r=0.646, p<0.01) and HR/HL (BMIPP) (r=0.504, p<0.05) 1 year after PEA.

Conclusions

In patients with CTEPH, RV myocardial perfusion and fatty acid metabolism was upregulated and moderately correlated with mPAP. SPECT-guided 201Tl and 123I-BMIPP planar imaging is a novel and noninvasive imaging modality to assess the severity of PH.

Funding Acknowledgement

Type of funding sources: None.
Low endothelial shear stress, microcalcification activity and high-risk plaque features: merging computational flow modelling, OCT and 18F-NaF PET/CT
Authors: Doyle B J , Kelsey L J , Majeed K , Bellinge J , Parker L P , Richards S , Schultz C J
Published: October 2021

Background

Endothelial shear stress (ESS) has a critical role in endothelial function. Abnormal shear stress leads to endothelial dysfunction, which contributes to arterial plaque initiation and development. Four dimensional magnetic resonance can determine shear stress in the larger arteries but cannot resolve the detail needed to calculate shear stress in the coronary arteries and thus methods such as computational fluid dynamics (CFD) are required. Additionally, a key feature of biologically active plaques is microcalcification activity, and this can be detected using 18F-sodium fluoride (18F-NaF) positron emission tomography (PET). Furthermore, using high resolution optical coherence tomography (OCT), the high-risk features plaques can be visualized and quantified. We aimed to merge these three techniques to investigate if low ESS is associated with high-risk plaque features and active microcalcifications in acute coronary syndrome.

Methods

We began by merging OCT images with CTCA images to obtain detailed 3D reconstructions of the target vessel. We then simulated blood flow and calculated the ESS, from which we extracted the area of low ESS (<0.4 Pa). We quantified plaque features using OCT and measured the maximum 18F-NaF uptake, and compared data at both the coronary segment and whole artery level (Figure 1).

Results

We investigated 20 arteries from 18 patients which we obtained 38 coronary segments according to the SCCT guidelines. We found that areas of low ESS were were significantly and positively associated with high-risk plaque features: macrophage infiltration (segment, rs=0.33, p=0.043; artery, rs=0.46, p=0.041) and presence of cholesterol crystals (segment, rs=0.45, p=0.005; artery, rs=0.58, p=0.007). Vessel segments with thin-capped fibroatheroma had greater area of low ESS (20 vs 4%). The uptake of 18F-NaF was positively associated with the area of low ESS (segment, rs=0.52, p=0.001; artery, rs=0.64, p=0.002). We found that there were typically more plaque features found in regions of low ESS (Table 1).

Conclusion

Here we provide the first data associating low ESS with both high-risk plaque features and active microcalcifications in patients with acute coronary syndrome. Although our sample size is small, these data are encouraging and could lead to better understanding of how best to deem a plaque “high risk”.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): Royal Perth Hospital Medical Research Foundation Figure 1Table 1
Added prognostic value of plaque burden to computed tomography angiography anatomic assessment and myocardial perfusion imaging in patients with diabetes Mellitus
Authors: Alnabelsi T , Ahmed A I , Han Y , Al Rifai M , Nabi F , Cainzos-Achirica M , Al-Mallah M H
Published: October 2021

Introduction

Cardiac computed tomographic angiography (CCTA)-derived measures of coronary artery disease (CAD) burden such as segment involvement score (SIS), which quantifies the number of segments with plaque, have been shown to independently predict incident cardiovascular events.

Purpose

We aimed to compare the added prognostic value of plaque burden to CCTA anatomic assessment and single photon emission computed tomography (SPECT) physiologic assessment in patients with diabetes undergoing both tests.

Methods

Consecutive patients with diabetes who underwent clinically indicated CCTA and SPECT myocardial imaging for suspected coronary artery disease at a tertiary care center were retrospectively identified from medical records. Stenosis severity and segment involvement score (SIS) were determined from CCTA, and presence of ischemia was determined from SPECT. Patients were followed from date of imaging for major adverse cardiovascular events (MACE; inclusive of all-cause death, non-fatal myocardial infarction, and percutaneous coronary intervention or coronary artery bypass grafting 90-days after imaging test.)

Results

A total of 778 patients were included (mean age 60.6±14.4 years, 55% males). Obstructive stenosis (left main ≥50%, all other coronary segments ≥70%) and ischemia were found in 15% and 16% of patients respectively. After a median follow-up of 31 months, 87 (11%) patients experienced a MACE. In multivariable Cox regression models, SIS significantly predicted outcomes in models including obstructive stenosis and ischemia (HR 1.17, 95% CI 1.10 - 1.24, p<0.001; 1.16, 95% CI 1.10 - 1.23, p<0.001). The addition of SIS also significantly improved discrimination (Harrel's C 0.75, p=0.006; 0.76, p=0.006 in models with CCTA obstructive stenosis and SPECT ischemia respectively). Results were consistent using subgroups of summed scores by composition of plaque (calcified vs non-calcified) and alternate definitions of obstructive stenosis.

Conclusion

Our results suggest that in high-risk patients with diabetes and suspected coronary disease, SIS has incremental prognostic value over ischemia by SPECT or stenosis by CCTA in predicting incident cardiovascular outcomes.

Funding Acknowledgement

Type of funding sources: None.
Circadian disruption on the susceptibility to sepsis-induced cardiac dysfunction: a prospective multi-modal imaging study
Authors: Pu J , Yan F , Yang Y , Xiu J , Shan P
Published: October 2021

Background

Sepsis is a significant cause of mortality, and cardiac dysfunction is one of the vital predictors for mortality of sepsis. However, the factors associated with the susceptibility to sepsis-induced cardiac dysfunction remain unclear. Disruption of circadian rhythms can profoundly influence cardiac health; however, to the knowledge of the authors, the relationship of circadian disruption to cardiac involvement in patients with sepsis is unknown.

Purpose

We aim to investigate the impact of circadian disruption on the susceptibility to sepsis-induced cardiac dysfunction.

Methods

Study patient data were obtained from the image database of EARLY-MYO-SEPSIS (EARLY assessment of MYOcardial tissue characteristics by multi-modal imaging in SEPSIS) registry, which was a prospective, multi-center registry of sepsis patients who have undergone cardiac magnetic resonance imaging (MRI) and echocardiography from 8 sites (clinical trial number NCT04513795). Cardiac involvement was evaluated using a comprehensive assessment comprising of echocardiography (with global longitudinal strain calculation), cardiac MRI and cardiac biomarker evaluation. Logistic regression was performed to identify independent predictors of left ventricular systolic dysfunction in sepsis.

Results

A total of 216 intensive care unit patients with sepsis was enrolled in the present analysis. Septic patients with a history of circadian disruption (i.e., sleep insufficiency <6 hours) presented more cardiac involvements (as indicated by edema on the cardiac MRI along with cardiac deformation and increased cardiac biomarkers) compared with those without circadian disruption history. Moreover, septic patients with a history of circadian disruption had increased mortality and incidence of heart failure. A history of circadian disruption was identified as an independent predictor of left ventricular systolic dysfunction in sepsis.

Conclusions

Our data from EARLY-MYO-SEPSIS registry demonstrated a previously unappreciated circadian sensitivity to sepsis-induced cardiac dysfunction.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by grants from the National Science Fund for Distinguished Young Scholars (81625002) and National Natural Science Foundation of China (81930007)
The microvascular endothelial redoxome established through tandem mass tag mass spectrometry
Authors: Cottrill S B , Lermant A , Cantley J , Murdoch C E , Sneddon C ,   Systems Medicine, School of Medicine, University of Dundee, UK
Published: October 2021

Redox signalling plays an important role in endothelial cell (EC) physiology and pathophysiology. Proteins sense redox signals via cysteine thiol groups. A common oxidative post-translational modification (oxPTM) on cysteine thiols is S-glutathionylation which is reversed to a free thiol state by glutaredoxin (Glrx). OxPTMs alter protein function, location and stability. Identifying which proteins undergo modification will help determine the role of redox signalling in EC function. A proteome-wide screen of human cardiac microvascular endothelial cells identified redox-sensitive proteins involved in vascular signalling mechanisms.

Methods

Human microvascular endothelial cells (HCMVEC, Lonza) were exposed to VEGF (50ng/ml, 24h) or hypoxia (0.5% O2, 24h) with adenoviral (ad) Glrx (Vectorlabs) overexpression or adLacZ (control). A tandem mass tag mass spectrometry system (TMT) coupled with a thiol-switch technique was used to quantify changes in redox sensitive thiol modifications. Protein lysates were treated with MMTS to alkylate unmodified thiols. Iodo-TMT six-plex probes were tagged to redox-sensitive sites after reversal of oxPTMs by DTT. Samples were pooled and processed by nLC-MS/MS. The abundance of each peptide in different conditions was compared with either adGlrx or adLacZ (control) expression to provide a ratio of changes in redox modifications.

Results

Iodo-TMT analysis revealed 113 unique thiol modifications identified on 78 different proteins using a ±1.5-fold threshold in a given treatment. Additionally, 44 modifications in 33 proteins were present in at least 2 different conditions, namely Glrx under VEGF and hypoxic conditions. A STRING interaction network identified clusters of 10 proteins involved in organonitrogen synthesis and 6 proteins in angiogenesis. Jagged-1 involved in the regulation of angiogenic sprouting through the Notch pathway was established as a target of redox signalling. Identified redox sensitive cysteines were found in extracellular EFG1 and the calcium binding EGF12 domains. Seven different In Silico programs (including MutationTaster, PolyPhen-2 and PANTHER) predicting the impact of substitution mutations indicated a functional affect for these redox sensitive sites, demonstrating the importance of these residues.

Conclusion

A non-biased proteomics approach identified novel thiol modifications on proteins involved in microvascular function. Future work will demonstrate the impact of these redox-sensitive thiol modifications on microvascular function to provide a better understanding of redox signalling in protein function and disease.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): MRC-DTP,European Union's Horizon 2020 research and innovation programme.
S-glutathionylation, a redox switch disrupting angiogenic balance to promote the preeclampsia phenotype
Authors: Lermant A , Rabussier G , Sneddon C , Kerr J , Lanz H , Murdoch C E
Published: October 2021

Background

Elevation of circulating anti-angiogenic factors is pivotal in the development of the preeclampsia (PE) phenotype of incomplete vascular remodelling, hypertension and kidney dysfunction during pregnancy. Oxidative stress is explicitly linked to PE with high levels measurable in the placenta. Yet antioxidant therapy has failed, in some cases worsening pregnancy outcomes. The modulation of protein activity by reversible oxidative post-translational modifications (oxPTM) under low levels of reactive oxygen species is emerging as an important “redox-switch” mechanism in cardiovascular diseases, although oxPTM have not been investigated in the context of PE. Of significance, S-glutathionylation is a common oxPTM which reversal by glutaredoxin (Grx) is predominant in preeclamptic placenta and was associated with attenuated revascularisation and sFlt-1 elevation in mice.

Purpose

We aimed to identify the molecular basis for how S-glutathionylation reversal by Grx may contribute to pregnancy-induced vascular complications by modulating angiogenic signalling at the maternofoetal interface.

Methods

We combined physiological in vivo assessment with bioinformatics proteomic analysis and exon-level microarray to investigate the role of S-glutathionylation in the development of PE phenotype. In vitro studies using primary endothelial cells (EC) and iPS-derived trophoblasts investigated the effects of oxPTM reversal on angiogenic signalling in individual placental cell types and the functional consequences were assessed in 3D models replicating early-pregnancy events.

Results

Overexpressing Grx transgenic mice (TG) developed gestational hypertension, kidney dysfunction and elevated plasma levels of the anti-angiogenic factor sFlt-1 compared to their littermate controls (WT) during timed pregnancy. Grx-mediated oxPTM reversal in EC disrupted angiogenic sprouting and promoted anti-angiogenic signals by increasing sFlt-1:PlGF ratio and decreasing endoglin levels. The rise in sFlt-1 was associated with an isoform switch promoting sFlt-e15a over sFlt-i13. In trophoblasts, Grx overexpression inhibited migration and syncytialisation and modulated angiogenic balance in a cell type-specific manner. The sFlt1-e15a:PlGF ratio was increased in syncytiotrophoblasts and decreased in extra-villous trophoblasts, while endoglin expression was decreased in both cell types. A genome-wide exon-level profiling of TG vs WT mice placenta revealed a global alteration of alternative splicing events.

Conclusion

Grx-mediated removal of oxPTM directly disrupts placental angiogenic balance via dysregulation of sFlt-1 isoforms, which may promote the PE phenotype of impaired vascular remodelling, hypertension and kidney dysfunction during pregnancy.

Funding Acknowledgement

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 - Marie Skłodowska-Curie grant agreement (iPLACENTA)
The novel proteomic signature for the detection of cardiac allograft vasculopathy
Authors: Wei D M , Trenson T , Van Keer J M , Melgarejo J , Thijs L , He T L , Latosinska A , Vanassche T , Van Aelst L , Janssens S , Van Cleemput J , Mischak H , Staessen J A , Verhamme P , Zhang Z Y
Published: October 2021

Background

Cardiac allograft vasculopathy (CAV) is the major long-term complications after heart transplantation, leading to mortality and re-transplantation. As available noninvasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV detection.

Methods

Urinary proteome was measured by capillary electrophoresis coupled to mass spectrometry in 217 heart transplantation recipients. Participants were further randomly and evenly divided into the derivation cohort and validation cohort. The proteomic signature for CAV was identified by decision tree-based machine learning in the derivation cohort and further tested in the validation cohort. The pathway analysis was investigated with Reactome Pathway Database.

Results

We identified a proteomic signature with 27 urinary peptides, which yielded areas under the curve (AUC) of 0.83 and 0.71 in the derivation and validation cohort, respectively. In the validation cohort, it had a sensitivity of 68.4%, specificity of 73.2%, accuracy of 71.6%, negative predictive value of 81.3%. Including the proteomic signature into the basic model further improved the diagnostic accuracy with an relative integrated discrimination improvement of 25.9% and the continuous net reclassification improvement of 83.3% (p≤0.023). The pathways analysis on revealed that collagen turnover, platelet aggregation and coagulation, cell adhesion and motility might involve in the pathogenesis of CAV.

Conclusions

The proteomic signature might be valuable for the surveillance of CAV thereby reduce the frequency of invasive procedures after HTx. Moreover, the highlighted pathways might provide insights in the potential novel treatment targets for CAV.

Funding Acknowledgement

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council Advanced Researcher Grant and Proof-of-Concept Grant ROC curves of the urinary proteomicThe 25 highlighted enrichment pathways
The urinary proteomic profile of arterial stiffness in the general population
Authors: Wei D M , Melgarejo J , Thijs L , Ciarka A , Vanassche T , Van Aelst L , Janssens S , Mischak H , Staessen J A , Verhamme P , Zhang Z Y
Published: October 2021

Background

Although arterial stiffness is an independent predictor of cardiovascular outcomes, its physiopathology remains unclear.

Purpose

This study aimed to investigate the urinary proteomic profile of aortic stiffness and provide insights into pathogenetic processes of arterial stiffness by pathway analysis.

Methods

In 669 participants (mean age, 50.5 years; 48.9% men) randomly recruited from the Flemish population, we measured carotid-femoral pulse wave velocity (PWV) by applanation tonometry. The proteomics of urine samples was quantified by using capillary electrophoresis coupled mass spectrometry. The proteomic data were analysed by the orthogonal projections to latent structures, a supervised dimensional reduction statistic method and summarised as a urinary proteomic (UP) score.

Results

The mean values were 7.56±2.02 m/s for PWV and 7.59±1.95 unit for the UP score. PWV was significantly associated with the UP score before and after adjustment for the potential covariates (β coefficient: 0.81 and 0.75, respectively; p<0.001). The significant proteins in the urinary proteomic profile consisted of 43 kinds of proteins, including collagen I, II and III, fibrinogen, matrix Gla-protein, apolipoprotein A-I and A-VI. The pathways annotated by the significant proteins mainly involved in fibrosis, signal conduction, platelet activation and aggregation.

Conclusions

In conclusion, the urinary proteomic profile could be a new biomarker of aortic stiffness and the altered proteins may link to the underlying mechanisms and holds the potential to discover novel therapeutic targets for arterial stiffness.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): The Internal Funds KU Leuven (STG-18-00379) Distribution and CorrelationThe Enrichment Pathways
Improvement of outcome prediction of hospitalized patients with COVID-19 by a dual marker strategy using high-sensitive cardiac troponin I and copeptin
Authors: Kaufmann C K , Ahmed A A , Kassem M K , Freynhofer M F , Jaeger B J , Aicher G A , Equiluz-Bruck S E , Spiel A S , Vafai-Tabrizi F V , Gschwantler M G , Fasching P F , Wojta J W , Giannitsis E G , Huber K H
Published: October 2021

Background

COVID-19 has been associated with a high prevalence of myocardial injury and increased cardiovascular morbidity. Copeptin, a marker of vasopressin release, has been previously established as a risk marker in both infectious and cardiovascular disease.

Purpose

Investigate the prognostic impact of copeptin and high-sensitive cardiac troponin I (hs-cTnI) in COVID-19.

Methods

This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from June 6th to November 26th, 2020 in a tertiary care hospital. Copeptin and hs-cTnI levels on admission were collected and tested for their association with the primary composite endpoint of ICU admission or 28-day mortality.

Results

A total of 213 eligible patients with COVID-19 were included of whom 55 (25.8%) reached the primary endpoint. Median levels of copeptin and hs-cTnI at admission were significantly higher in patients with an adverse outcome (Copeptin 29.6 pmol/L, [IQR, 16.2–77.8] vs 17.2 pmol/L [IQR, 7.4–41.0] and hs-cTnI 22.8 ng/L [IQR, 11.5–97.5] vs 10.2 ng/L [5.5–23.1], P<0.001 respectively). ROC analysis demonstrated an optimal cut-off of 19.6 pmol/L for copeptin and 16.2 ng/L for hs-cTnI and an increase of either biomarker was significantly associated with the primary endpoint. The combination of raised hs-cTnI and copeptin yielded a superior prognostic value to individual measurement of biomarkers and was a strong prognostic marker upon multivariable logistic regression analysis (OR 4.274 [95% CI, 1.995–9.154], P<0.001). Addition of copeptin and hs-cTnI to established risk models improved C-statistics and net reclassification indices.

Conclusion

The combination of raised copeptin and hs-cTnI upon admission is an independent predictor of deterioration (ICU admission) or 28-day mortality in hospitalized patients with COVID-19.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bürgermeisterfond der Stadt WienLudwig Boltzmann Cluster for Cardiovascular ResearchAssociation for the Promotion of Research on Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) Copeptin and hs-cTnI in COVID-19Biomarker based risk assessment
Pace of arterial aging and its association with cardiovascular risk factors
Authors: Akopyan A , Strazhesko I , Orlova I
Published: October 2021

Introduction

Chronological age is a well-known risk factor of cardiovascular diseases (CVD). In comparison with chronological age, biological arterial age can determine person's individual pace of aging, while difference between biological and chronological arterial age (delta age) can be rated as accelerated or decelerated artery aging.

Purpose

The aim of this study was to assess the association of risk factors of CVD with accelerated and decelerated arterial aging in almost healthy people.

Methods

We investigated systolic blood pressure (SBP), blood chemistry (total cholesterol (TC), low- (LDL) and high-density (HDL) lipoproteins, triglycerides (TG), apolipoprotein B (ApoB), fasting glucose (FG), glycated hemoglobin (HbA1c), serum renin levels) and urinary albumine, carotid ultrasonography (presence of atherosclerotic plaques and carotid intima-media thickness), arterial stiffness (AS) and leucocyte telomere length (LTL) in 143 adults (mean age 50.31±12.98 years, 35% male, 29% have hypertension, 15% - type 2 diabetes mellitus (T2DM)). LTL was measured by real-time polymerase chain reaction. AS was measured by pulse wave velocity and augmentation index with applanation tonometry using SphygmoCor device (AtCor, Australia). Biological artery age was estimated according to the age-predicting models, based on arterial wall parameters (A. Fedintsev et al, 2017). All the subjects were divided into groups of “old” and “young” arteries according to the positive or negative delta age – difference between biological and chronological age. The data were analyzed using multivariate logistic and linear regression analysis.

Results

The main statistically significant results are shown in the table.

Arterial pace of aging is closely associated with chronological age, hypertension and glucose metabolism. There were not found any associations of arterial pace of aging with lipid, renin levels, urinary albumin and LTL.

Conclusion

Hypertension, carbohydrate metabolism are main therapeutic targets for accelerated arterial aging and CVD prevention.

Funding Acknowledgement

Type of funding sources: None. Results of regression analysis
Role of S100A4 in atherosclerosis development
Authors: Cardoso Dos Santos L M , Ambartsumian N , Grigorian M , Bochaton-Piallat M L
Published: October 2021

Background

Smooth muscle cells (SMCs) accumulate into the intima during the process of atherosclerosis, where they switch from a contractile to a synthetic phenotype. We previously identified S100A4 as being a marker of the synthetic SMCs. Recently we have shown that extracellular S100A4 induces a pro-inflammatory-like SMC phenotype and is causally related to atherosclerotic plaque progression.

Aim

To study the role of intracellular S100A4 depletion in the SMC phenotypic transition during atherosclerosis.

Methods

We used a full S100A4 knockout (KO) mouse model, where we performed left common carotid ligation and collected carotid arteries after 4 weeks. Primary SMCs were cultured from wild type (WT) and KO animals. We investigated differentiation marker expression, NFκB activation with extracellular S100A4, proliferation and migratory capacities. Results are given as mean ± SD (Fig. 1A and B).

Results

In vivo, no difference in intimal thickening (IT) size and SMC differentiation marker expression was observed between WT and S100A4 KO mice. CD68 was absent and S100A4 was only detected in WT animals in the inner layer of the IT. In vitro, no difference in differentiation marker expression, proliferation (Fig. 1A) or NFκB activation (Fig. 1C) was observed. Interestingly, migration was decreased in the absence of S100A4 (Fig. 1B)

Conclusion

The in vivo abrogation of S100A4 does not interfere with IT progression, suggesting that the lack of inflammation in this model might render S100A4 expression neglectable and disguise a possible effect of S100A4 depletion in IT progression. In vitro, S100A4 plays a role in SMC migration.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation Figure 1
No direct involvement of Phactr-1 in non-atherosclerotic arteriopathies: results from 3 different Phactr-1 transgenic knockout mice
Authors: Rubin S , Bougaran P , Martin S , Abelanet A , Delobel V , Jeanningros S , Bats M L , Dufourcq P , Couffinhal T , Duplaa C
Published: October 2021

Introduction

Genome-wide association studies have revealed robust associations of common genetic polymorphisms in the Phactr1 locus (6p24) (encoding Phosphatase and Actin Regulator 1) with cervico-cerebral artery dissection (CCeAD), spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). These common elements of genetic predisposition provide a proof of concept for important shared mechanisms at the molecular level between CCeAD, SCAD and FMD vascular diseases.

Objective

Deciphering genetic, molecular and physiological importance of PHACTR1.

Method

Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells (EC) using 2 tissue-specific Cre-driver (one of them was embryonic) and Smooth Muscle Cells (SMC) with a third tissue-specific Cre-driver to assess its role in the pathogenesis of CCeAD, SCAD or FMD.

Results

To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed firstly, a decrease in Phactr1 transcription and Phactr1 expression in EC and SMC isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology or actin organization were not different in KO mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin-II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there was no more consequences of Phactr1 deletion during embryogenesis in ECs.

Conclusion

Loss of function of PHACTR-1 in the cell types mostly involved in vascular physiology does not appear to induce a pathological vascular phenotype.

Funding Acknowledgement

Type of funding sources: None.
Long-term post-discharge coagulation abnormalities in patients with moderate to severe COVID-19
Authors: Artemyeva G , Kalinskaya A , Dukhin O , Lebedeva A , Rozin A , Shpektor A , Vasilieva E
Published: October 2021

Introduction

Coagulopathy plays a significant role in COVID-19 pathogenesis. Benefit from anticoagulation is well established in hospitalized patients. But since there is a lack of data on coagulopathy resolution: there is no consensus in guidelines if extended anticoagulation is required.

Purpose

The purpose of our work was to analyze coagulation abnormalities at 2 to 5 months after moderate to severe COVID-19.

Methods

COVID-19 reconvalescents (CR), discharged from our hospital, were called for follow-up at 2–3 (CR1 group, 21 patients) or 5–6 (CR2 group, 26 patients) months after discharge. All CR were not on the anticoagulation therapy by that time. In addition to clinical examination and standard lab tests, we performed an FMD-test to analyze endothelial function, impedance aggregometry to analyze platelet aggregation, and a thrombodynamics test to assess thrombogenesis and fibrinolysis. The control group was recruited before the pandemic started.

Results

All CR were free from thrombotic complications after discharge from the hospital.

Endothelial function was not significantly impaired in CR compared with control, and was still in the normal range (7,07, IQR (3,36; 11,56) vs. 7,87 (5,42; 13,45)).

Platelet aggregation was significantly lower in CR1 than in the control group in ADP-induced mode (37, IQR (19; 47) vs. 46, IQR (41; 50), p=0,02) and didn't differ in other groups and other modes (Asa, TRAP-induced).

Thrombodynamics tests revealed suppression of the clot formation process in both CR1 and CR2 compared with control. There were decreased clot growth rates (μm/min) (CR1/CR2: 27,1, IQR (26,1; 29,2)/27,6, IQR (26,4; 30,0) vs. 32,2, IQR (30,0; 35,1), both p<0,001); decreased clot size (μm) (CR1/CR2: 1099, IQR (1069; 1194)/1199, IQR (1058; 1221) vs. 1304, IQR (1164; 1380), both p<0,001), and decreased optical density (arb units) (CR1/CR2: 21'607, IQR (20'363; 24'545)/22'741, IQR (21'344; 25'961) vs. 26'556, IQR (24'672; 29'387, p<0,001 and p=0,09 respectively.

Fibrinolysis was enhanced in CR groups compared with control (lysis progression was significantly higher for CR2 only, CR1/CR2: 2,9, IQR (2,5; 3,8)/3,8, IQR (2,6; 5,4) vs. 2,5, IQR (1,1; 3,4) %/min, p=0,087 and p=0,007 respectively; expected clot lysis time was shorter in both CR1 and CR2: 36,5, IQR (29,8; 44,2)/31,7, IQR (24,3; 42,7) vs. 65,9. IQR (36,3; 95,5) min, p=0,019 and p=0,016 respectively).

There was no statistical difference in clot formation and in fibrinolysis between CR1 and CR2.

Conclusion

In the deferred period (2–5 months) of COVID-19 the fibrinolysis process remains still active whereas the process of clot formation is mostly suppressed. Endothelial function assessed via the FMD test is within the normal range in the post COVID period.

Funding Acknowledgement

Type of funding sources: None.
Is endothelial dysfunction a driving force of COVID-19 induced coagulopathy?
Authors: Dukhin O , Kalinskaya A , Molodtsov I , Maltseva A , Sokorev D , Elizarova A , Glebova K , Stonogina D , Shakhidzhanov S , Spiridonov I , Ataullakhanov F , Margolis L , Shpektor A , Vasilieva E
Published: October 2021

Background/Introduction

There are numerous reports regarding the direct endothelial damage by the SARS-CoV-2 that can lead to activation of both plasma hemostasis and platelet aggregation. However, the mechanism of interaction between endothelium and haemostasis in COVID-19 remains unclear.

Purpose

The aim of our study was to assess the relationship between each link of clot formation process (endothelial function, plasma coagulation, platelet aggregation) with the severity of the disease.

Methods

58 COVID-19 patients were included in our study. Patients were divided into moderate (n=39) and severe (n=18) subgroups. All patients underwent a flow-mediated dilation (FMD) test, impedance aggregation, rotational thromboelastometry, thrombodynamics and von Willebrand factor antigen (vWF: Ag) quantification. All measurements were repeated on days 3 (point 2) and 9 (point 3) of hospitalization.

Results

COVID-19 patients demonstrated the enhanced plasma coagulation (clotting time, s 613,0 [480; 820], clot growth rate, μm/min 32,75 [29,3; 38,7]). At point 1 no significant difference in parameters of plasma coagulation between patients' subgroups was noted. At point 2 a significant decrease in the size (CS, μm 1278.0 [1216.5; 1356.5] vs 965.0 [659.8; 1098.0], p<0,01) and clot growth rate (μm/min 32,4 [29,2; 35,0] vs 17,7 [10,3; 24,4], p<0,01) under the influence of anticoagulants in the moderate subgroup compared with point 1 was observed. We didn't observe such phenomenon in severe subgroup.

There was no significant difference in platelet aggregation between subgroups at point 1. During the course of the disease the patients in the moderate and severe subgroups demonstrated a significant increase in platelet aggregation induced by arachidonic acid and ADP (severe: AUC ARA 48,0 [25,0; 59,0] vs 77,5 [55,8; 92,7], p=0,04; AUC ADP 44,0 [41,0; 56,0] vs 58,0 [45,5; 69,0], p=0,04; moderate: AUC ARA 31,5 [19,8; 50,7] vs 56,0 [39,0; 76,0], p=0,01; AUC ADP 43,0 [20,0; 59,0] vs 56,6 [50,3; 70,5], p=0,04;), in moderate subgroup the significant increase in TRAP-induced aggregation was also noted (AUC TRAP 58,0 [41,0; 69,5] vs 76,0 [58,3; 81,5], p=0,048).

There were no significant differences in the FMD-test results between the patient subgroups. FMD-test results were predominantly within the reference ranges (7,1 [4,0; 8,8]).

Patients in the severe subgroup had significantly higher levels of vWF: Ag (228,0 [205,3; 240,7] vs 232,0 [226,0; 423,0], p=0,03).

Conclusion

SARS-CoV-2 infection was characterized by increased levels of vWF:Ag, that could represent the local endothelial damage, meanwhile there was no generalized endothelial dysfunction assessed via FMD-test in moderate to severe patients. At the same time the enhanced plasma coagulation in COVID-19 patients was observed.

Funding Acknowledgement

Type of funding sources: None.
Endothelial-T cell crosstalk contributes to vascular injury in fatty liver disease
Authors: Cheung C , Ng C Y , Lee K L , Wu K X , Chioh F W J , Tan K , Siau A , Muthiah M D , Chen Q F , Tan N S , Ng H H , Dan Y Y
Published: October 2021

Cardiovascular complications are often the fundamental causes of death in non-alcoholic fatty liver disease (NAFLD) patients. While there are known systemic mediators in NAFLD that may induce vascular inflammation, the mechanism of endothelial dysfunction remain understudied. In this work, we harnessed the replicative potential of blood outgrowth endothelial cells (BOECs) to develop personalized cell lines from NAFLD patients and healthy controls. Our transcriptomic analysis showed that the top interactome network enriched in NAFLD BOECs comprised of several C-C and C-X-C chemokine ligands involved in immune cell chemotaxis. We previously reported T cell infiltration in mouse model of non-alcoholic steatohepatitis, and here, we confirmed enhanced endothelial chemokine signatures in arterial histological sections. To elucidate endothelial-immune crosstalk, we performed single-cell analysis on human peripheral blood mononuclear cells and found T cell intensification in NAFLD patients compared to healthy controls. Our immunoprofiling by flow cytometry further revealed that NAFLD patients possessed higher levels CD8+ memory cells. Functionally, T cells, instead of monocytes, adhered more pronouncedly to NAFLD BOECs. In evaluating the CXCL12-CXCR4 axis in chemotaxis, CXCR4 antagonist (AMD3100) substantially modulated the migration of patient-derived CD8+ T cells towards NAFLD BOECs, which was not observed in healthy endothelial-T cell chemotaxis coculture. Finally, we validated NAFLD-associated endothelial dysfunction by enumerating two folds more circulating endothelial cells, a biomarker of vascular injury, in the blood samples of NAFLD patients than healthy controls. Our work provides insights for translation to restore blood vessel health and potentially mitigate adverse vascular events in NAFLD.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Industrial Alignment Fund Pre-Positioning grant from the Agency for Science, Technology and Research, Singapore Endothelial-T cell crosstalk in NAFLD
Proprotein convertase subtilisin/kexin type 9 links inflammation to vascular endothelial cell dysfunction
Authors: Leucker T , Amat-Codina N , Chelko S , Gerstenblith G
Published: October 2021

Vascular endothelial cell (EC) dysfunction is a pathological mediator of the development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol.

Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increased PCSK9 mRNA expression (1.98 [0.7, 3.4]-fold increase, p=0.02 vs. control) and PCSK9 protein levels (1.52±0.1-fold increase, p<0.01 vs. control) in isolated human aortic ECs. This was accompanied by reduced phosphorylated endothelial nitric oxide synthase (eNOS) protein which was 56% ± 5.6% of that in the controls (p<0.01) and NO bioavailability, which was reduced by 29% ± 22.1% compared to that in the controls (p<0.01). Finally, genetic PCSK9 reduction utilizing a PCSK9 specific siRNA in human aortic ECs resulted in the rescue of eNOS phosphorylation and NO bioavailability.

Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation of PCSK9 protein expression utilizing a small interfering RNA against PCSK9 rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Career Development Award from the American Heart Association, OAIC pilot Award
Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy: eight-year follow-up of phase 1 KAT301 study
Authors: Leikas A J , Hassinen I , Hedman A , Kivela A , Yla-Herttuala S , Hartikainen J E K
Published: October 2021

Backgound/Introduction

In phase I KAT301 trial, adenovirus-mediated intramyocardial vascular endothelial growth factor-DΔNΔC (VEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved angina at 1-year follow-up without major safety concerns.

Purpose

Our objective was to investigate the long-term safety and efficacy of AdVEGF-D GT. A total of 30 patients (24 VEGF-D and 6 randomized and blinded controls) participated in KAT301 trial.

Methods

The mean follow-up time was 8.2 years (range 6.3–10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse events (MACEs) and other predefined endpoints including cancer.

Results

MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.90; 95% confidence interval 0.09–9.32; P=0.95). Mortality and comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P=0.006) but not in control group (2.2 vs. 2.6; P=0.414).

Conclusion(s)

Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): Kuopio University Hospital Heart Center Figure 1. The incidence of MACEFigure 2. CCS class