Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses

The aim of this study was to identify correlations between electrocardiographic and echocardiographic changes in patients with silicosis prior to the occurrence of chronic pulmonary heart disease. We conducted a prospective, descriptive, analytical study, in which we included a group of 67 patients consecutively admitted to the Health Promotion and Occupational Medicine Clinic between December 2016 and January 2018, aged 47 to 78 years.There was a biochemical and electrocardiographic evaluation for each patient as well as a right ventricle echocardiographic evaluation (diameters, volumes, function). A control group, including 25 patients with benign minor diseases that required a cardiologist consultation, was also used. From the electrocardiographic point of view, slight changes were observed regarding the waves of electrical activity of the right ventricle. Taking into account the degree of ventilatory dysfunction (depending on FEV1), changes in right heart echocardiographic parameters were identified. Thus, in what the most important right ventricular parameters, including the tricuspid annular plane systolic excursion (TAPSE) or the RV index of myocardial performance (RVMPI) were concerned, values at the upper limit of normality were recorded in most patients with moderate and severe ventilatory dysfunction. Values of echocardiographic parameters of the right heart at the upper limit of normality, correlated with the degree of ventilatory dysfunction, are early markers for cardiovascular damage in patients with pulmonary silicosis prior to the occurrence of chronic pulmonary heart disease also known ascor pulmonale.

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Novel staging classification of primary mitral regurgitation based on the presence of cardiac damage

European Heart Journal ◽

10.1093/ehjci/ehaa946.1998 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A.L Van Wijngaarden ◽

Y.L Hiemstra ◽

P Van Der Bijl ◽

V Delgado ◽

N Ajmone Marsan ◽

...

Keyword(s):

Mitral Regurgitation ◽

Kidney Function ◽

Left Ventricular ◽

Prognostic Impact ◽

Cardiac Damage ◽

Stage 4 ◽

All Cause Mortality ◽

Primary Mitral Regurgitation ◽

Stage 1 ◽

Staging Classification

Abstract Background The indication for surgery in patients with severe primary mitral regurgitation (MR) is currently based on the presence of symptoms, left ventricular (LV) dilatation and dysfunction, atrial fibrillation and pulmonary hypertension. The aim of this study was to evaluate the prognostic impact of a new staging classification based on cardiac damage including the known risk factors but also including global longitudinal strain (GLS), severe left atrial (LA) dilatation and right ventricular (RV) dysfunction. Methods In total 614 patients who underwent surgery for severe primary MR with available baseline transthoracic echocardiograms were included. Patients were classified according to the extent of cardiac damage (Figure): Stage 0-no cardiac damage, Stage 1-LV damage, Stage 2-LA damage, Stage 3-pulmonary vasculature or tricuspid valve damage and Stage 4-RV damage. Patients were followed for all-cause mortality. Results Based on the proposed classification, 172 (28%) patients were classified as Stage 0, 102 (17%) as Stage 1, 134 (21%) as Stage 2, 135 (22%) as Stage 3 and 71 (11%) as Stage 4. The more advanced the stage, the older the patients were with worse kidney function, more symptoms and higher EuroScore. Kaplan-Meier curve analysis revealed that patients with more advanced stages of cardiac damage had a significantly worse survival (log-rank chi-square 35.2; p<0.001) (Figure). On multivariable analysis, age, male, chronic obstructive pulmonary disease, kidney function, and stage of cardiac damage were independently associated with all-cause mortality. For each stage increase, a 22% higher risk for all-cause mortality was observed (95% CI: 1.064–1.395; p=0.004). Conclusion In patients with severe primary MR, a novel staging classification based on the extent of cardiac damage, may help refining risk stratification, particularly including also GLS, LA dilatation and RV dysfunction in the assessment. Funding Acknowledgement Type of funding source: None

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Autophagy Deficiency by Atg4B Loss Leads to Metabolomic Alterations in Mice

Metabolites ◽

10.3390/metabo11080481 ◽

2021 ◽

Vol 11 (8) ◽

pp. 481

Author(s):

Gemma G. Martínez-García ◽

Raúl F. Pérez ◽

Álvaro F. Fernández ◽

Sylvere Durand ◽

Guido Kroemer ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Mammalian Cells ◽

Tissue Homeostasis ◽

In Vivo Studies ◽

Protective Mechanism ◽

Cardiac Damage ◽

Wide Range ◽

First Time

Autophagy is an essential protective mechanism that allows mammalian cells to cope with a variety of stressors and contributes to maintaining cellular and tissue homeostasis. Due to these crucial roles and also to the fact that autophagy malfunction has been described in a wide range of pathologies, an increasing number of in vivo studies involving animal models targeting autophagy genes have been developed. In mammals, total autophagy inactivation is lethal, and constitutive knockout models lacking effectors of this route are not viable, which has hindered so far the analysis of the consequences of a systemic autophagy decline. Here, we take advantage of atg4b−/− mice, an autophagy-deficient model with only partial disruption of the process, to assess the effects of systemic reduction of autophagy on the metabolome. We describe for the first time the metabolic footprint of systemic autophagy decline, showing that impaired autophagy results in highly tissue-dependent alterations that are more accentuated in the skeletal muscle and plasma. These changes, which include changes in the levels of amino-acids, lipids, or nucleosides, sometimes resemble those that are frequently described in conditions like aging, obesity, or cardiac damage. We also discuss different hypotheses on how impaired autophagy may affect the metabolism of several tissues in mammals.

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Myofibrillar degeneration with diphtheria toxin

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0109 ◽

2020 ◽

Vol 45 (4) ◽

pp. 351-357

Author(s):

Bilge Özerman Edis ◽

Muhammet Bektaş ◽

Rüstem Nurten

Keyword(s):

Protein Synthesis ◽

Actin Filaments ◽

Diphtheria Toxin ◽

Cardiac Tissue ◽

Culture Conditions ◽

Bacterial Toxin ◽

Filamentous Actin ◽

Cardiac Damage ◽

Tissue Samples

AbstractObjectivesCardiac damage in patient with diphtheritic myocarditis is reported as the leading cause of mortality. Diphtheria toxin (DTx) is a well-known bacterial toxin inducing various cytotoxic effects. Mainly, catalytic fragment inhibits protein synthesis, induces cytotoxicity, and depolymerizes actin filaments. In this study, we aimed to demonstrate the extent of myofibrillar damage under DTx treatment to porcine cardiac tissue samples.MethodsTissue samples were incubated with DTx for 1–3 h in culture conditions. To analyze whole toxin (both fragments) distribution, conjugation of DTx with FITC was performed. Measurements were carried out with fluorescence spectrophotometer before and after dialysis. Immunofluorescence microscopy was used to show localization of DTx-FITC (15 nM) on cardiac tissue incubated for 2 h. Ultrastructural characterization of cardiac tissue samples treated with DTx (15 or 150 nM) was performed with transmission electron microscopy.ResultsDTx exerts myofibrillar disorganization. Myofilament degeneration, mitochondrial damage, vacuolization, and abundant lipid droplets were determined with 150 nM of DTx treatment.ConclusionsThis finding is an addition to depolymerization of actin filaments as a result of the DTx-actin interactions in in vitro conditions, indicating that myofilament damage can occur with DTx directly besides protein synthesis inhibition. Ultrastructural results support the importance of filamentous actin degeneration at diphtheritic myocarditis.

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Peripheral artery disease impairs myocardial perfusion through increasing pulse wave reflection: the Northern Shanghai study

European Heart Journal ◽

10.1093/ehjci/ehaa946.2352 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Yu ◽

J Teliewubai ◽

X Fan ◽

C Chi ◽

H Ji ◽

...

Keyword(s):

Myocardial Perfusion ◽

Peripheral Artery Disease ◽

Wave Reflection ◽

Pulse Wave ◽

Ankle Brachial Index ◽

Community Dwelling ◽

Peripheral Artery ◽

Cardiac Damage ◽

Pulse Wave Reflection ◽

Artery Disease

Abstract Background Peripheral artery disease (PAD) is prevalent and substantially contributes to cardiovascular mortality particularly in the elderly, although the pathophysiological impact of PAD on heart itself still needs further investigation. In theory, PAD can increase pulse wave reflection which is an important determinant of subendocardial viability ratio (SEVR), a valuable estimate of myocardial perfusion as indicated by previous invasive studies. Thus, we hypothesize that PAD impairs myocardial perfusion through increasing pulse wave reflection. In this study, we aim to test this hypothesis in a large cohort from the Northern Shanghai Study. Methods A total of 2947 community-dwelling elderly Chinese (43.6% male, mean age: 71.3±5.9 years) were recruited. Ankle-brachial index were measured with the VP1000 device and used to diagnose PAD. Pulse wave reflection was estimated as aortic augmentation pressure (AP). Aortic BP, AP and SEVR were assessed by radial applanation tonometry. Multiple linear regression with SEVR and AP as dependent variable and PAD as independent variable, meanwhile adjusted for other covariates, were performed, respectively. Results 375 (12.7%) participants presented PAD. Compared to subjects without PAD, those with PAD showed significantly lower SEVR (126 vs. 132, P<0.001) but higher AP (19 vs. 17 mmHg, P<0.001). Multiple regression analysis revealed that both SEVR (regression coefficient [B] = −1.69, P=0.04, R2=0.61) and AP (B=1.19, P=0.04, R2=0.56) significantly associated with PAD, respectively. However, the association between SEVR and PAD was abolished when further adjusted for AP (B=−0.49, P=0.52). Similar results were obtained when inter-leg systolic BP difference was used to diagnose PAD. Conclusions PAD significantly and independently associates with myocardial perfusion; moreover, this association is mediated by increased pulse wave reflection. These findings provide a new dimension for understanding the pathophysiological mechanisms of cardiac damage of PAD. Funding Acknowledgement Type of funding source: None

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Circular RNAs in Sudden Cardiac Death Related Diseases: Novel Biomarker for Clinical and Forensic Diagnosis

Molecules ◽

10.3390/molecules26041155 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1155

Author(s):

Meihui Tian ◽

Zhipeng Cao ◽

Hao Pang

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Early Stage ◽

Diagnostic Value ◽

Circular Rnas ◽

Cardiac Damage ◽

Postmortem Diagnosis ◽

Specific Expression ◽

Forensic Practice ◽

Artery Disease

The prevention and diagnosis of sudden cardiac death (SCD) are among the most important keystones and challenges in clinical and forensic practice. However, the diagnostic value of the current biomarkers remains unresolved issues. Therefore, novel diagnostic biomarkers are urgently required to identify patients with early-stage cardiovascular diseases (CVD), and to assist in the postmortem diagnosis of SCD cases without typical cardiac damage. An increasing number of studies show that circular RNAs (circRNAs) have stable expressions in myocardial tissue, and their time- and tissue-specific expression levels might reflect the pathophysiological status of the heart, which makes them potential CVD biomarkers. In this article, we briefly introduced the biogenesis and functional characteristics of circRNAs. Moreover, we described the roles of circRNAs in multiple SCD-related diseases, including coronary artery disease (CAD), myocardial ischemia or infarction, arrhythmia, cardiomyopathy, and myocarditis, and discussed the application prospects and challenges of circRNAs as a novel biomarker in the clinical and forensic diagnosis of SCD.

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Targeting unfolded protein response: a new horizon for disease control

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2021.2 ◽

2021 ◽

Vol 23 ◽

Author(s):

Madhu Khanna ◽

Nishtha Agrawal ◽

Ramesh Chandra ◽

Gagan Dhawan

Keyword(s):

Unfolded Protein Response ◽

Disease Progression ◽

Viral Infections ◽

Cancer Type ◽

Unfolded Protein ◽

Diseased State ◽

Protein Response ◽

And Control ◽

Er Homeostasis ◽

Signalling Cascade

Abstract Unfolded protein response (UPR) is an evolutionarily conserved pathway triggered during perturbation of endoplasmic reticulum (ER) homeostasis in response to the accumulation of unfolded/misfolded proteins under various stress conditions like viral infection, diseased states etc. It is an adaptive signalling cascade with the main purpose of relieving the stress from the ER, which may otherwise lead to the initiation of cell death via apoptosis. ER stress if prolonged, contribute to the aetiology of various diseases like cancer, type II diabetes, neurodegenerative diseases, viral infections etc. Understanding the role of UPR in disease progression will help design pharmacological drugs targeting the sensors of signalling cascade acting as potential therapeutic agents against various diseases. The current review aims at highlighting the relevance of different pathways of UPR in disease progression and control, including the available pharmaceutical interventions responsible for ameliorating diseased state via modulating UPR pathways.

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