bluuebunny/crossref_metadata_2025_split huggingface dataset:
BNIP3 regulates cardiac energy metabolism by interaction with F1FO ATP-synthase
Authors: Beerlage A , Settelmeier S , Doepper H , Heinen-Weiler J , Giorgio V , Rassaf T , Hendgen-Cotta U B 
Published: October 2022

Abstract

Background
The oxidative phosphorylation (OXPHOS) that takes place in the mitochondria produces chemical energy in form of ATP, the main energy source of the heart. Proper mitochondrial function determines the contractility of the heart. Changes in myocardial ATP levels are often associated with cardiovascular disease. However, mitochondrial dysfunction remains an unmet therapeutic challenge. The F1FO ATP-synthase protein complex catalyses the last step of OXPHOS, synthesising ATP and determining the respiratory function of cardiac mitochondria. An increased ATP pool during cardiovascular challenges, regulated by F1FO ATP-synthase, could therefore significantly improve the clinical outcome of affected patients. In neurons, Bcl2-familiy members like BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) have been suggested to be involved in the regulation of metabolic efficiency through interaction with the mitochondrial F1FO ATP synthase. A similar metabolic regulation in the cardiac context remains unclear. Furthermore, BNIP3 has a significant impact on the loss of cardiomyocytes under various pathological conditions and is thus a potential mediator of energy metabolism in cardiomyocytes.

Methods and results
With native gel-electrophoresis, cardiac BNIP3 of C57BL/6J mice was first identified in higher oligomeric complexes in similar molecular weight range as mitochondrial F1FO ATP-synthase. Using 60Å-precise proximity-ligation assays to determine possible binding partners, F1FO ATP-synthase was uncovered for the first time as an interacting protein of BNIP3. This interaction was confirmed by co-immunoprecipitation of BNIP3 and F1FO ATP-synthase and by spatial localization using electron microscopy. Peptide microarray studies elucidate the f subunit of F1FO ATP-synthase as the structural interaction site. Functional analysis using extracellular flux analyser technology revealed significantly elevated mitochondrial respiratory activity in Bnip3 knock out mice and human cardiomyocytes during BNIP3 inhibition. Increased ATP levels in C57BL/6J mice after acute inhibition of BNIP3 confirmed the observed regulatory effect of BNIP3 on F1FO ATP-synthase activity. Finally, depletion of BNIP3 in mice improves stress resistance with an augmented chronotropic capacity during dobutamine-induced cardiac stress.

Conclusion
Depletion of BNIP3 suggests a regulatory role of BNIP3 in cardiac mitochondrial energy homeostasis via interaction with F1F0 ATP-synthase in oligomeric complexes. Since acute inhibition of BNIP3 activity allows positive modulation of cardiac performance by elevating the available ATP pool, this may serve as a beneficial treatment for patients with cardiovascular disease in the future.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German research foundation (DFG)
The regenerative response of cardiac interstitial cells
Authors: Jopling C 
Published: October 2022

Abstract

Understanding how certain animals are capable of regenerating their hearts will provide much needed insights into how this process can be induced in humans in order to reverse the damage caused by myocardial infarction. Currently, it is becoming increasingly evident that cardiac interstitial cells play crucial roles during cardiac regeneration. To understand how interstitial cells behave during this process, we performed single-cell RNA sequencing (scRNA-seq) of regenerating zebrafish hearts. Using a combination of immunohistochemistry, chemical inhibition and novel transgenic animals, we were able to investigate the role of cell type specific mechanisms during cardiac regeneration. This approach allowed us to identify a number of important regenerative processes within the interstitial cell populations. Here, we provide detailed insight into how interstitial cells behave during cardiac regeneration which will serve to increase our understanding of how this process could eventually be induced in humans.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence National pour la Recherche ANR-20-CE14-003 MetabOx-HeartAgence National pour la Recherche ANR-11-LABX-0015
Perivascular nerve fibres are increased in the epicardium while perivascular adipose tissue is decreased in the myocardium in patients with acute myocardial infarction
Authors: Fiet M D , Krijnen P A J , Niessen J W M 
Published: October 2022

Abstract

Background
Vasospasm is an important etiological factor in the induction of acute myocardial infarction (AMI). PeriVascular Nerve Fibres (PVNF) and PeriVascular Adipose Tissue (PVAT) play an important role in vasoregulation, although detailed information of their role in the heart is missing in AMI patients. In the present study we have analysed PVNF and PVAT in deceased AMI patients.

Methods
Sections of epicardial coronary arteries were obtained at autopsy from AMI patients (N=16) and controls without heart disease (N=7). Infarct age was between 3 and 6 hours old. Stenosis of epicardial coronary arteries was quantified in a HE stained slide. To analyse the intramyocardial vasculature samples were taken from the left ventricle of the heart (in AMI patients the infarcted area). Nerve fibres were stained using a specific S100 antibody. Putative activation of these nerves was stained using a specific antibody against neuropeptide Y (NPY). S100+ and NPY+ nerve fibres were quantified by light microscopy and were then calculated per square mm of the adventitia surface areas. PVAT was quantified using an Elastica Von Gieson (EvG) staining.

Results
Stenosis did not correlate with PVNF. AMI patients had a significant increase in PVNF in the epicardium but not in the myocardium. NPY was non-significantly increased in PVNF in the epicardium and myocardium in AMI patients compared with controls. PVAT was significantly decreased in AMI patients compared with controls.

Conclusion
The increase in PVNF in the epicardium and the decrease of PVAT in the myocardium suggest that they might play a role in AMI induction, independent of the atherosclerotic changed epicardial coronary arteries.

Funding Acknowledgement
Type of funding sources: None.
Cardiac magnetic resonance characterization and prediction of left ventricular thrombus after ST-segment elevation myocardial infarction
Authors: Bertolin-Boronat C , Marcos Garces V , Perez N , Gavara J , Lopez-Lereu M P , Monmeneu J V , Rios-Navarro C , De Dios E , Merenciano-Gonzalez H , Gabaldon-Perez A , Iraola Viana D , Bonanad C , Moratal D , Chorro F J , Bodi V 
Published: October 2022

Abstract

Background
Left ventricular thrombus (LVTh) is an uncommon yet serious complication after ST-segment elevation myocardial infarction (STEMI). Late gadolinium enhancement (LGE) sequences in cardiac magnetic resonance (CMR) imaging allows for accurate detection of LVTh. However, the implications of CMR to predict and characterize LVTh occurrence is this population is unclear.

Purpose
We aim to characterize the incidence, outcomes, and predictors of LVTh after STEMI by CMR imaging.

Methods
Our registry comprised 455 patients admitted for a first reperfused STEMI in our university hospital. Baseline characteristics were recorded. All patients underwent early (1-week) and late (6-month) CMR. Left ventricular ejection fraction (LVEF, %), infarct size (% of left ventricular mass) and microvascular obstruction (MVO, number of segments) were measured. LGE sequences were used to analyze the presence of LVTh. Patients with LVTh at 6-month CMR underwent an additional CMR 1 year after admission. Univariate and multivariate comparisons were performed to study the ocurrence of LVTh in the first 6 months after STEMI.

Results
Mean age was 58.24±11.69 years, most patients were male (82.6%) and anterior infarction occurred in more than half of the cohort (52.7%). LVTh was detected in 36 (7.9%) patients in the first 6 months after STEMI. Anticoagulation was initiated in all cases. Of these, 27 patients had LVTh at early (1-week) CMR, but 9 had LVTh at late (6-month) CMR with no prior evidence of LVTh at early CMR. A total of 6 patients had persisting LVTh at 1-year CMR (37.5% of patients with 6-month LVTh). In multivariable analysis, anterior infarction (HR 6.6 [1.91–22.83], p&lt;0.001) and 1-week CMR-LVEF (HR 0.97 [0.93–0.99], p=0.04) and MVO (HR 1.19 [1.02–1.39], p=0.03) independently predicted the occurrence of LVTh in the first 6 months after STEMI. We computed a risk score of LVTh assigning 1 point to each of these variables (anterior infarction, CMR-LVEF &lt;50% and MVO &gt;3.5 segments), which allowed us to stratify the risk of LVTh in the first 6 months after STEMI (0.6% if 0 points, 3.8% if 1 point, 14.4% if 2 points, and 31.2% if 3 points).

Conclusions
CMR imaging soon after STEMI can contribute relevant prognostic value regarding LVTh occurrence after the acute event. Patients with anterior infarction, LVEF &lt;50% and MVO in &gt;3.5 segments at early (1-week) CMR have the highest risk of LVTh in the first 6 months after STEMI.

Funding Acknowledgement
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 Educaciόn – Generalitat Valenciana.
The cardioprotective effect of inhibiting SGLT1 in hyperglycemia ischemia reperfusion injury
Authors: Almalki A , Arjun S , Bell R , Yellon D 
Published: October 2022

Abstract

Background
Diabetes clinical trials have shown SGLT inhibition improves cardiovascular outcomes, yet the mechanism is not fully understood. Hyperglycemia is a common finding in diabetic and non-diabetic patients presenting with ACS and is a powerful predictor of prognosis and mortality. The role of hyperglycemia in ischemia-reperfusion injury (IRI) is not fully understood, and whether the Sodium Glucose Co-Transporter 1 (SGLT1) plays a role in infarct augmentation, before and/or after reperfusion, remains to be elucidated.

Purpose
Investigate if SGLT1 is involved in a glucotoxicity injury during IRI and whether inhibiting SGLT1 with an SGLT1 inhibitor may reduce infarct size.

Method
RT-PCR and in-situ hybridization (RNAScope) combined with Immunofluorescence integrated co detection with different cell marker techniques were used to detect SGLT1 mRNA expression in Sprague-Dawley whole myocardium and isolated primary cardiomyocytes.
An Ex-vivo Langendorff ischemia-reperfusion perfusion model was used to study the effect of high glucose (22mmol) on myocardium at reperfusion. Canagliflozin (CANA) a non-selective SGLT inhibitor (1μmoL/L to block the SGLT1 receptor and SGLT2 and 5nmol/L to block only the SGLT2 receptor) and Mizagliflozin a selective SGLT1 inhibitor (100nmol/L) was introduced following ischemia at two different glucose concentration concentrations at reperfusion and its effect on infarct size measured using triphenyltetrazolium chloride (TTC) staining.

Results
We showed that SGLT1 is homogenously expressed throughout the myocardium and is particularly evident within the vasculature. we demonstrate that hyperglycemia at reperfusion is injurious to myocardium with an increase of myocardial infarction. Our data reveal that glucose exacerbation of injury appears to be mediated via SGLT1. We have also demonstrated that high-glucose mediated injury in the isolated, perfused heart model is abrogated through the administration of a clinically available mixed SGLT2/SGLT1 inhibitor, canagliflozin, at a dose that inhibits both SGLT2 and SGLT1, but by the SGLT2-selective concentration.

Conclusion
We have shown that SGLT1 is present in the myocardium. Hyperglycemia appears to augment myocardial infarction and inhibition of SGLT1 attenuates this incre

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The government of saudi Arabia
Prognostic implications of unrecognized myocardial infarction before elective percutaneous coronary intervention
Authors: Nogami K , Hoshino M , Kanaji Y , Sugiyama T , Misawa T , Hada M , Yamaguchi M , Nagamine T , Teng Y , Ueno H , Matsuda K , Sayama K , Kakuta T 
Published: October 2022

Abstract

Background
A non-negligible proportion of myocardial infarction (MI) is not clinically recognized and unrecognized myocardial infarction (UMI) is associated with adverse outcomes.

Purpose
To determine the prevalence and prognostic significance of UMI by delayed-enhancement cardiac magnetic resonance (DE-CMR) before elective percutaneous coronary intervention (PCI).

Methods
In this prospective, single-center study, 236 patients with stable coronary artery disease undergoing elective and uncomplicated PCI were studied. All patients underwent DE-CMR before PCI. The prevalence of UMI was evaluated and the association of clinical and CMR-derived variables with primary MACE, defined as cardiovascular death, nonfatal MI, hospitalization for heart failure, unplanned late revascularization, and ischemic stroke was investigated.

Results
In the final analysis of 213 patients, 63 patients (29.6%) showed UMI. Target territory UMI was observed in 38 (17.8% of total, 60.3% of patients with UMI). UMI was significantly associated with sex, diabetes mellitus, left ventricular ejection fraction, SYNTAX score and fractional flow reserve in target vessels. During follow-up periods (median, 23 months), MACE was observed in 17 (27.0%) of patients with UMI, and 17 (11.3%) without (P=0.001). In a multivariable model, UMI (hazard ratio [HR] 2.18, 95% confidential interval, 1.10–4.33, P=0.001) remained as an independent predictor of MACE. Kaplan–Meier analysis indicated that the presence of UMI was significantly associated with higher incidence of MACE.

Conclusions
The prevalence of UMI in patients undergoing elective PCI was 29.6%. UMI was independently associated with an increased risk of MACE after successful PCI. Given the non-negligible prevalence and potential clinical significance of UMI, clinical studies comparing PCI and guideline directed medical therapy (GDMT) versus GDMT only strategy might have to take the presence of UMI into consideration.

Funding Acknowledgement
Type of funding sources: None.
Effect of sacubitril/valsartan and empagliflozin on systemic inflammation and scar remodeling in a swine model of myocardial infarction
Authors: Martinez-Falguera D , Monguio-Tortajada M , Ferrer Curriu G , Aranyo J , Teis A , Fadeuilhe E , Rodriguez-Leor O , Diaz-Guemez I , Courageux Y , Roura S , Bayes-Genis A , Bisbal F , Galvez-Monton C 
Published: October 2022

Abstract

Background
Angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose cotransporter 2 inhibitors (SGLT2i) lead to reduced cardiovascular death and hospitalization rates for heart failure, but mechanisms of action remain unclear.

Purpose
To evaluate the effect of ARNI and SLGT2i on cardiac function, systemic inflammation and scar remodeling in a porcine model of acute myocardial infarction (MI).

Methods
Thirty-three pigs (18 female, 15 male) with non-revascularized MI were randomized to receive treatment with beta-blocker (BB) only (BB group, n=8), empagliflozin + BB (SGLT2i group, n=8), sacubitril/valsartan + BB (ARNI group, n=9) or empagliflozin + sacubitril/valsartan + BB (SGLT2i + ARNI group, n=8) for 30 days post-MI. Cardiac function parameters were studied at 2- and 30-days post-MI by cardiac magnetic resonance imaging. The systemic immune response was analysed at baseline, 2-, 15- and 30-days post-MI to estimate 1) the absolute number of neutrophils and lymphocytes by FSC-A/SSC-A, 2) the circulating monocytes (CD172a+) and their phenotype according to CD73+, and CCR2+ expression. Animals were euthanized at 30 days, interstitial collagen and vascular density of the scar were quantified.

Results
Left ventricular ejection fraction (LVEF) and stoke volume (LVSV) improved in SGLT2i + ARNI group (P=0.02, P=0.002, respectively, 2 vs 30 days post-MI). Right ventricular ejection fraction (RVEF) and stroke volume (RVSV) improved in ARNI treatment arm (P=0.03; P=0.02, respectively, 2 vs 30 days post-MI). Significant increase in LV mass was only observed in BB group (P=0.02; 2 vs 30 days post-MI). SGLT2i and ARNI treatment prevented the acute increase in circulating leukocytes 2 days post-MI (P=0.0095; P=0.0091, respectively). Moreover, SGLT2i reduced the CCR2+ activated monocytes count at 15 days post-infarction (P=0.01). In contrast, the combined treatment increased the number of circulating monocytes (CD172a+) at 30 days (P=0.008). Reduced collagen I (P=0.04), and Col I/Col III ratio (P=0.02) was observed in ARNI group, and higher collagen III content (P=0.02) in SGLT2i group. Vascular density was significantly increased in SGLT2i + ARNI group (P=0.03).

Conclusions
SGLT2i modulates systemic inflammatory state. ARNI reduces myocardial fibrosis and improves right ventricular function. Combined treatment improves vascular density and left cardiac function in a post-MI porcine model.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): Boehringer Ingelheim Spain, S.A, and Instituto de Salud Carlos III, CIBER Cardiovascular
Therapeutic effects of nebulization-based delivery of anti-miR-146a in experimental pulmonary arterial hypertension
Authors: Santos Peixoto Gomes J , Mendes-Ferreira P , Adao R , Maia-Rocha C , Vasconcelos I , Leite-Moreira A , Bras-Silva C 
Published: October 2022

Abstract

Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH.
This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure.
Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a−/−) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx).
Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index),decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi).
Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): This research was supported by the Portuguese Foundation for Science and Technology (FCT).
Association between plasma desmosine, a marker of elastin degradation, and total atherosclerotic burden measured by whole body magnetic resonance angiography
Authors: Ali K , Weir-Mccall J R , Khan F , Belch J , Houston J G , Mordi I R , Lang C C , Huang J T J , Choy A M 
Published: October 2022

Abstract

Background
Elastin degradation has been implicated in the pathophysiology of vulnerable atherosclerotic plaque. Desmosine is the cross-link component in the elastin molecule and is exclusively released from mature elastin breakdown, thus has the potential to be a physiologically relevant biomarker of atherosclerosis.

Objectives
The aim of the present study was: 1. To investigate whether patients with known cardiovascular disease (CVD) have higher elastin degradation as indicated by plasma desmosine (pDES); 2. to determine the relationship between pDES and total atherosclerotic burden.

Methods
We measured pDES by a validated stable isotope dilution LC-MS/MS method1 in a total of 146 subjects from the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study2. (62% male, mean age 64±8 (SD) years). This included 62 patients with prior clinical diagnosis of CVD (including coronary artery disease (CAD), cerebrovascular disease and/or lower extremity arterial disease (LEAD)), and 84 patients without a clinical diagnosis of CVD. Total atherosclerotic burden was measured by whole body magnetic resonance angiography (WB-MRA). The WB-MRA data was divided into 31 anatomical arterial segments with each segment scored according to degree of luminal narrowing: 0 = no stenosis, 1 = &lt;50% stenosis, 2 = 51–70% stenosis, 3 = 71–99% stenosis, 4 = vessel occlusion. The segment scores were summed and from this, a standardized atheroma score (SAS) was calculated by summing each individual segment's stenosis score, and divided by the number of diagnostic segments before dividing by 4 which is the maximum potential score. Relationship between SAS and pDES levels was investigated using multiple linear regression models

Results
pDES levels were significantly greater in patients with established clinical CVD compared to patients with no CVD (CVD patients, 0.56 (0.45–0.67) ng/mL; patients with no CVD, 0.47 (0.41–0.54)ng/mL; p=0.001). Median SAS for the study population was 4 (2–10). Overall pDES levels showed a strong correlation with SAS (r=0.44, p≤0.001). Univariable analysis suggested a significant association between pDES and whole-body atheroma score as measured by SAS. (β 29.31, p&lt;0.001). This association persisted in the multivariable regression model adjusting for traditional cardiovascular risk factors including age, gender, BMI, systolic blood pressure, diabetes, smoking status and LDL. (adjusted β 18.75, p=0.004)

Conclusion
pDES levels are elevated in patients with clinical CVD when compared to those with no clinical history of CVD. pDES is also strongly associated with global atheroma burden. Overall, these findings support the role of pDES as a potential biomarker for atherosclerosis.

Funding Acknowledgement
Type of funding sources: None.