bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac remodeling in severe hypertension, does it respond to tight blood pressure control?
Authors: El Tahlawi M , Salem S , Fahmy M , Tharwat M 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Severe hypertension (HTN) may cause target organ damage (TOD). Kidney can tolerate severe HTN to very high levels. Cardiac remodeling as TOD could be detected by elevation of biomarker Troponin.

Aim
We aim to detect the response of organs (heart & kidney) to tight control of severe HTN.

Patients & Methods
Patients admitted due to severe hypertension (BP&gt; 180/120) associated with any symptoms were enrolled. All patients were managed according to the European guidelines to the target BP. Cardiac biomarker Hs-Troponin T (hs-TNT) and serum creatinine (s.creat) were measured for all patients on admission and 24 hours later.

Results
Ninty five patients with hypertensive crisis were treated to target BP. Forty six patients had initially high hs-TNT (Group A) and 49 patients had initially normal hs-TNT (Group B). There was a highly significant difference between both groups regarding initial and follow-up s.creat with higher values in Group B (P= 0.03 and 0.004 respectively).There was high significant difference between initial and follow up s.creat values in Group B with higher values in the follow up measurements after BP control to the target (P= 0.03), while this difference is insignificant in Group A (P=0.26). Five patients in Group B developed renal failure after tight BP control. There was a significant positive correlation between hs-TNT and the follow-up s.creat (P=0.018) with more deterioration of s.creat in those having initial high hs-TNT.

Conclusion
In severe HTN, hs-TNT may be elevated due to marked afterload. Renal affection and TOD occurs before cardiac remodeling and damage due to severe HTN. Renal autoregulation occurs in chronic elevation of BP. Acute control of severe HTN leads to disrruption of renal autoregulation and renal shut down. European guidelines regarding severe HTN control should be revised. In hypertensive patients with high hs-TNT, BP should not be well controlled on the short term not to disrupt renal autoregulation.
Crucial functions of alpha-actinin 2 in the embryonic heart
Authors: Gehmlich K , Jiang A , Wadmore K , Hooper C , Douglas G , Ehler E , Broadway-Stringer S , Kalisch-Smith J , Sparrow D , Gautel M , Davies B , Watkins H 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Wellcome Trust; British Heart Foundation

Background/Introduction
Alpha-actinin is an integral protein of the Z-discs in heart and skeletal muscle cells, with important structural and signalling functions. Missense variants in alpha-actinin can cause inherited conditions, e.g. myopathies and cardiomyopathies. The underlying disease mechanisms are still unknown.

Purpose
In order to study the disease mechanisms of an alpha-actinin missense variant, which is known to cause Hypertrophic Cardiomyopathy in human patients, a mouse model was generated.

Methods
Mice carrying the alpha-actinin missense variant were generated by CRISPR-Cas9 genome editing. The heterozygous adult mice carrying the alpha-actinin variant were characterised by echocardiography and quantitative PCR. Hearts of homozygous embryos were analysed at E15.5 by high-resolution episcopic microscopy (HREM).

Results
Mice carrying a single copy of the missense variant were viable and had normal appearance. Adult heterozygous mice showed no signs of cardiomyopathy on echocardiography. However, mature male mice displayed molecular signs of cardiomyopathy, such as induction of the fetal gene programme at transcript level.
The attempt to generate adult mice homozygous for the variant failed: 9 breeding pairs produced 18 litters with 83 weaned pups, but no homozygous offspring. Embryonic lethality was confirmed and E15.5 was the latest stage homozygous pups were reliably found to be viable. At this timepoint, genotype distribution was within the expected Mendelian ratios.
HREM of the hearts at this stage revealed increased right ventricular chamber size and decreased left atrial size, when compared to wildtype littermates. Membranous ventricular septal defects were observed in 3 out of 8 homozygous hearts. Further these embryos displayed aortic stenosis and dysplasic leaflets of the pulmonary valve.

Conclusions
Heterozygous adult mice only displayed sub-clinical signs of disease. In contrast, the missense variant is embryonic lethal in the homozygous setting and leads to a range of morphological abnormalities in E15.5 hearts. Future work will identify how altered functions of alpha-actinin cause these changes.
S100A9 blockade ameliorates cardiac dysfunction and reduces myocardial immune infiltration in experimental autoimmune myocarditis
Authors: Jakobsson G , Mulholland M , Grentzmann A , Ljungcrantz I , Rattik S , Engelbertsen D , Schiopu A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Swedish Heart and Lung Foundation and Swedish Research Council

Background/Introduction
Autoimmune myocarditis is characterized by non-ischemic inflammatory heart injury, leading to myocardial damage and impaired cardiac function. S100A9 is an inflammatory alarmin present in large amounts in neutrophils. The role of S100A9 as a potential treatment target in myocarditis has not been fully explored.

Aim
We sought to investigate the impact of S100A9 blockade in experimental autoimmune myocarditis and assess the effects of treatment on cardiac function and immune infiltration.

Methods
BALB/C mice were immunized with αMHC peptide emulsified in Complete Freunds Adjuvant at day 0 and day 7 to induce the disease. The water-soluble small-molecule S100A9 blocker ABR-238901 was given continuously in drinking water starting on day 7. Echocardiography was performed weekly from day 21 to day 42 (n=11/group). For flow cytometry analysis, mice were sacrificed at day 21 (n=10/group).

Results
S100A9 blockade improved left ventricular ejection fraction [52.33% vs 44.87% on day 42 (p&lt;0.001)]. Cardiac output was significantly improved on day 21 (12.69 vs 11.05 mL/min, p&lt;0.05). We found a significant reduction of inflammatory cardiac infiltrates at day 21, characterized by reduced number of macrophages (p&lt;0.05), neutrophils (p&lt;0.01) and CD4+ T cells (p&lt;0.05). The cardiac draining lymph nodes contained fewer dendritic cells (p&lt;0.01), T cells (p&lt;0.05), as well as reduced numbers of inflammatory CD4+ cells producing IL-17 (p&lt;0.05).

Conclusion
Therapeutic S100A9 blockade inhibits inflammatory cardiac infiltration and improves cardiac function in experimental autoimmune myocarditis. Our findings highlight the important role of S100A9 in the pathogenesis of myocarditis and identify S100A9 blockade as a possible novel therapeutic avenue.
Collagen bundle orientation by Fourier analysis in myocardial infarction scarring
Authors: Marcos Garces V , Rios-Navarro C , Gomez-Torres F , Gavara J , De Dios E , Perez N , Diaz A , Minana G , Chorro FJ , Bodi V , Ruiz-Sauri A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” and Conselleria de Educación – Generalitat Valenciana.

Introduction
After acute myocardial infarction (AMI), the lack of oxygen and nutrients leads to cardiomyocyte necrosis and eventually to the formation of a collagen-based scar. Infarct scar characteristics, such as collagen bundle orientation, have a relevant influence on scar mechanics, the occurrence of cardiac arrhythmias, left ventricular dilation or aneurysm formation, wall stiffness, and the development of wall rupture or heart failure. However, the most adequate method for collagen bundle orientation (CBO) measurement in myocardial scar is not established.

Purpose
We aim to compare the measurement of collagen bundle orientation in infarct scar by Fourier analysis in three different histopathological techniques.

Methods
Juvenile swine (n=21) were subjected, by means of percutaneous balloon inflation, to a transient 90-min occlusion of mid left anterior descending artery followed by one month of reperfusion (chronic AMI group). Samples were obtained from the infarcted zone and stained with Masson’s trichrome, Picrosirius red and Haematoxylin-Eosin (H-E) standard protocols. Five microphotographs of the myocardial scar were taken at 200x magnification with light, polarised and confocal microscopy, respectively. A single observer measured CBO by means of Fast Fourier Transform analysis using a semi-automated protocol. Comparability between techniques was studied by the Intraclass Correlation Coefficient (ICC), the coefficient of variation (CV) and the Bland-Altman (B&A) plots and limits of agreement.

Results
Measurement of CBO in Masson’s trichrome tended to show higher (more "random-oriented") values than in Picrosirius and H-E+confocal techniques (ICC 0.79 and 0.7, p=0.001 and 0.005; B&A 0.29 to -0.02 and 0.43 to 0.01; CV 6.97% and 12.98%, respectively). However, measurement of CBO in Picrosirius and H-E+confocal techniques showed an "almost perfect" agreement (ICC 0.84, p&lt;0.001; B&A 0.28 to -0.09; CV 17.33%). Selective staining and/or visualization of collagen in these latter techniques may underlie our findings, contrary to non-selective Masson’s trichrome.

Conclusion
Picrosirius red staining (visualized with polarised microscopy) and Haematoxylin-Eosin (visualized with confocal microscopy) are comparable in terms of collagen bundle orientation measurement by Fourier analysis in an animal model of chronic infarct scar. Masson’s trichrome (visualized with light microscopy) tends to show more "random-oriented" values, potentially due to non-specific staining and visualization of non-collagenous structures such as cells, and should not be recommended for this specific purpose.
Mice deficient in endothelial cell-selective adhesion molecule develop left ventricle diastolic dysfunction
Authors: Buncha V , Fopiano KA , Tian Y , Lang L , Bagi Z 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): American Heart Association

Background
Dysfunction of vascular endothelium plays a key role in the development of left ventricular diastolic dysfunction (LVDD) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). Recently, Endothelial Cell-Selective Adhesion Molecule (ESAM) was proposed as a novel biomarker in HFpEF.
Hypothesis. ESAM plays a mechanistic role in the development of both microvascular dysfunction and LVDD.

Methods
Animals: The study was performed utilizing ESAM knockout and wild type (WT) mice. Echocardiography: Left ventricular (LV) systolic and diastolic function and LV wall thickness were assessed by small animal ultrasound imaging (Vevo3100). Blood pressure measurement: Performed with tail-cuff plethysmography method. Vascular reactivity: Pulmonary arteries (2nd and 3rd order) were isolated from ESAM KO and WT mice, vascular reactivity was assessed with wire myography method. Evaluation of myocardial vascular density: Paraformaldehyde fixed paraffin embedded heart section (40 µm thick) from WT and ESAM KO mice stained with Tomato Lectin (Lycopersicon esculentum) DyLight594 to label vasculature were used. Unbiased automated tracing of the microvasculature was performed using the VesseLucida360 software (MBF), followed by a morphometric analysis (VesseLucida Explorer).

Results
Transthoracic echocardiography analysis showed that ESAM knockout mice displayed LV diastolic dysfunction, as indicated by a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities), increased E/e’ ratio, isovolumic relaxation time (IVRT) and increased E wave deceleration time, with no change in the ejection fraction. The systolic blood pressure was not different between ESAM knockout and WT mice. Heart weight, related to body weight is increased in ESAM-deficient mice, pointing towards cardiac hypertrophy in these animals. Meanwhile, the analysis of the cardiac tissue vascularization with unbiased automated tracing of the microvasculature, reveals the decreased total vascular length per volume of the tissue in ESAM knockout mice. Using wire myography of the pulmonary artery vasodilator function we found that the endothelium-dependent, acetylcholine-induced relaxation of these arteries was significantly reduced in ESAM knockout mice, whereas endothelium-independent, nitric oxide donor, sodium nitroprusside-induced relaxation was similar in the two groups.

Conclusion
ESAM deficiency in mice resembles a HFpEF phenotype, in that ESAM knockout mice develop endothelial dysfunction and LVDD.
Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms
Authors: Biasci V , Santini L , Hussaini S , Ferrantini C , Coppini R , Loew LM , Luther S , Campione M , Poggesi C , Pavone FS , Cerbai E , Bub G , Sacconi L 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.
Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ions channel recovery and intracellular Ca2+-cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose a novel approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination) but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing a light-gated ion channel (channelrhodopsins-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We use an optical system that uses real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role that cardiac alternans plays in spontaneous termination of ventricular tachycardias (VTs). We find that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that cardiac alternans may be beneficial in the context of self-termination of VT.
Size matters: Functional differences of progenitor cell-derived small extracellular vesicle subpopulations in cardiac repair
Authors: Van De Wakker S , Bauza Martinez J , Rios Arceo C , Willms EF , De Jong OJ , Wu W , Vader P , Sluijter JPG 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERC EVICARE, Van Herk Foundation

Introduction
The use of cardiac progenitor cell (CPC)-derived small Extracellular Vesicles (sEVs) has shown great potential to stimulate cardiac repair post myocardial infarction. sEVs are released by cells and play a role in intercellular communication through transfer of their bioactive content, like RNAs and proteins. Increasing evidence indicates that sEVs present a heterogeneous mixture of vesicle populations, depicting different functional aspects, which hampers clinical translation. Studying sEV heterogeneity could provide new insights into contributing therapeutic mechanisms underlying sEV-mediated cardiac repair.

Methods
CPC-derived sEVs were purified by flow through chromatography followed by size-exclusion chromatography (SEC) and asymmetric flow field flow fractionation (A4F) for fractionation of different sEV-subfractions. Based on the differential expression of common sEV markers, different subpopulations were determined. sEV subpopulations were further characterized using western blot, nanoparticle tracking analysis, bicinchoninic acid protein assay, transmission electron microscopy and mass spectrometry (MS). Functional differences were studied using different cellular assays to determine AKT phosphorylation, wound healing, angiogenesis and proteasome activity.

Results
SEC or A4F were used to separate distinct subpopulations of CPC-derived sEVs with a different appearance, size and function. MS analysis confirmed the differences in proteomic expression levels of classical sEV markers, as well as annexins, rab proteins, integrins, histones and proteasomal proteins. Furthermore, differences in cellular components linked to their cellular origin were found. Exposure of recipient endothelial cells to sEV subpopulations demonstrated clear functional differences. Additionally, differences in proteolytic activity of the sEV subpopulations were identified.

Conclusions
SEC and AF4 allow for isolation and in-depth study of the functional heterogeneity of sEVs. In our study, we observed the presence of different subpopulations based on size, with a different composition and biological function. Increased knowledge of sEV heterogeneity will contribute to a better understanding of the mechanisms of action of sEVs and will improve translation to the clinic and potentially an off-the-shelf approach to stimulate cardiac repair.
HDL adverse remodelling and dysfunction is a temporal feature that can be reversed
Authors: Schoch L , Sutelman P , Padro T , Badimon L , Vilahur G 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de Ciencia e Innovación (MCIN)/AEI/10.13039/501100011033 and Fondo Europeo de Desarrollo Regional (FFEDER)

Background
High-density lipoprotein (HDL) particles have been shown to undergo adverse remodelling and loss of function in the presence of comorbidities. It has been demonstrated that high low-density lipoprotein cholesterol (LDL-C) plasma levels induce compositional changes in HDL particles that render them dysfunctional. It is unknown, however, whether this HDL adverse remodelling is reversible.

Purpose
In this preclinical animal study we have investigated whether dyslipidaemia-induced HDL particle remodelling and dysfunction is a permanent adverse change or a temporal trait which can be regulated by dietary intervention.

Methods
After 10 days of high-fat diet (HFD) and reaching LDL-C levels of 392.8±94.9 mg/dL, the HDL particles of 15 pigs were characterized. Thereafter, pigs were randomly distributed into two arms. While group 1 was maintained on the same HFD (n=9), group 2 was switched to a normocholesterolemic diet (NCD; n=8) up to day 40. Blood was drawn at days 0 (baseline), 1, 3, 5, and 10 (to characterize HDL dysfunction over the 10-day period of dyslipidaemia induction), and at days 25 and 40 (to assess the HDL particle evolution in the intervention period). We assessed: a) HDL function [cholesterol efflux capacity (CEC) and antioxidant potential]; b) HDL particle number and size by nuclear magnetic resonance; c) oxidative susceptibility of LDL particles; d) HDL protein content of APOA-I, APOM, and APOC-III; and e) biochemical parameters.

Results
Up to day 10 there was a time-dependent increase in LDL-C levels that progressively induced the impairment of HDL CEC and antioxidant activity, higher HDL particle numbers, increased formation of conjugated dienes, and lower HDL-APOM content (p&lt;0.01 vs baseline). All these parameters exhibited a plateau at day 10 and remained unchanged up to day 40 in those animals that were kept on HFD. Interestingly, in these animals a strong negative correlation was observed between HDL CEC and HDL-C levels (p&lt;0.0001), with larger HDL particles being detected at day 40 (p&lt;0.05 vs. baseline). On the contrary, all these parameters returned to physiological levels (baseline) in those animals that switched to a NCD (p=ns vs baseline). No changes were detected in APOA-I- and APOC-III- HDL content among animal groups and over time.

Conclusion
In the present study we evidence for the first time that dyslipidaemia-induced HDL particle remodelling and dysfunction is not a permanent adverse change. The implementation of a healthy dietary intervention acutely reverses HDL adverse remodelling and dysfunction in a preclinical animal model.
Expression of MMP2, MMP9 and PGP 9.5 in human aorta in patients with coronary artery disease
Authors: Patel N , Chandrashekhar R 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: None.
Atherosclerosis has been recognised as inflammatory conditions which involves activation of MMPs of which increased MMP2 & MMP9 expression has been correlated with the development of human aortic plaques.The Sympathetic Nervous System exerts complex control over inflammation in atherosclerosis both: on systemic scale and at the regional level.Protein gene product9.5 (PGP9.5) is a cytoplasmic neuron & is a reliable marker for visualisation of the cardiovascular system innervation.There have been no studies in the existing literature on the expression of PGP 9.5 and MMP2, MMP9 on human aorta.Aim:To study the expression of MMP2, MMP9 and PGP9.5 in the human aorta & gain insights into atherosclerosis & neural modulation in the aorta.Materials &

Methods
This is a single centre, prospective cohort, pilot study with a sample size of 87 patients,done over 2 years at AIMS,Kochi.During CABG, punch biopsy of the aorta taken & processed.One paraffin embedded section used for routine H&E staining & others used for IHC.IHC detection kits use 3, 3’-DABChromogen as a substrate of HRP for visualisation of antigenic structures in the tissues.Positive & negative control tissue were run for all 3 Antibodies.Interpretation done as Diffuse/Focal & Intense/Moderate/ Weak classification based on intensity signals observed on IHC by an experienced Cardiac Pathologist.Results:7 Controls with well matched baseline characteristics: Controls-Aorta samples taken from patients who were undergoing Aortic Valve Surgery for Aortic Valve disease with normal coronaries documented on a coronary angiogram.65.9% of patients with Positive MMP2 & 28.6 % of patients in the Control group was found to have significant difference when compared to positive & negative outcomes amongst the 2 groups.89.3% of patients with positive MMP2 had significant co-relation with PGP9.5 levels expressed in the same specimen analysed.MMP9 also had a p value of 0.002 suggesting a significant co-relation between MMP9 & PGP9.5.Statistically significant Co-relation seen between the Age, CRP & the levels of MMP 9 expressed in the Aorta observed.MMP2 & MMP9 expression have a definite & significant co-expression with PGP9.5 expression in human aorta,suggesting a novel marker of neuromodulation in atherosclerotic process in human aorta.
Expression of MMP2, MMP9 and PGP 9.5 in human aorta in patients with coronary artery disease