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1.
Arterioscler Thromb Vasc Biol ; 44(4): 954-968, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38385292

RESUMO

BACKGROUND: Venous thromboembolism is a major health problem. After thrombus formation, its resolution is essential to re-establish blood flow, which is crucially mediated by infiltrating neutrophils and monocytes in concert with activated platelets and endothelial cells. Thus, we aimed to modulate leukocyte function during thrombus resolution post-thrombus formation by blocking P-selectin/CD62P-mediated cell interactions. METHODS: Thrombosis was induced by inferior vena cava stenosis through ligation in mice. After 1 day, a P-selectin-blocking antibody or isotype control was administered and thrombus composition and resolution were analyzed. RESULTS: Localizing neutrophils and macrophages in thrombotic lesions of wild-type mice revealed that these cells enter the thrombus and vessel wall from the caudal end. Neutrophils were predominantly present 1 day and monocytes/macrophages 3 days after vessel ligation. Blocking P-selectin reduced circulating platelet-neutrophil and platelet-Ly6Chigh monocyte aggregates near the thrombus, and diminished neutrophils and Ly6Chigh macrophages in the cranial thrombus part compared with isotype-treated controls. Depletion of neutrophils 1 day after thrombus initiation did not phenocopy P-selectin inhibition but led to larger thrombi compared with untreated controls. In vitro, P-selectin enhanced human leukocyte function as P-selectin-coated beads increased reactive oxygen species production by neutrophils and tissue factor expression of classical monocytes. Accordingly, P-selectin inhibition reduced oxidative burst in the thrombus and tissue factor expression in the adjacent vessel wall. Moreover, blocking P-selectin reduced thrombus density determined by scanning electron microscopy and increased urokinase-type plasminogen activator levels in the thrombus, which accelerated caudal fibrin degradation from day 3 to day 14. This accelerated thrombus resolution as thrombus volume declined more rapidly after blocking P-selectin. CONCLUSIONS: Inhibition of P-selectin-dependent activation of monocytes and neutrophils accelerates venous thrombosis resolution due to reduced infiltration and activation of innate immune cells at the site of thrombus formation, which prevents early thrombus stabilization and facilitates fibrinolysis.


Assuntos
Monócitos , Trombose , Camundongos , Humanos , Animais , Monócitos/patologia , Selectina-P , Células Endoteliais , Tromboplastina , Infiltração de Neutrófilos , Neutrófilos
2.
Am J Physiol Heart Circ Physiol ; 326(2): H418-H425, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38099845

RESUMO

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a severe muscle illness caused by mutations in the gene encoding for the intracellular protein dystrophin. A major source for arrhythmia vulnerability in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output, and the development of reentrant circuits. Using the dystrophin-deficient mdx mouse model for human DMD, we previously reported that the lack of dystrophin causes a significant loss of peak Na+ current (INa) in ventricular cardiomyocytes. This finding provided a mechanistic explanation for ventricular conduction defects and concomitant arrhythmias in the dystrophic heart. In the present study, we explored the hypothesis that empagliflozin (EMPA), an inhibitor of sodium/glucose cotransporter 2 in clinical use to treat type II diabetes and nondiabetic heart failure, rescues peak INa loss in dystrophin-deficient ventricular cardiomyocytes. We found that INa of cardiomyocytes derived from mdx mice, which had received clinically relevant doses of EMPA for 4 wk, was restored to wild-type level. Moreover, incubation of isolated mdx ventricular cardiomyocytes with 1 µM EMPA for 24 h significantly increased their peak INa. This effect was independent of Na+-H+ exchanger 1 inhibition by the drug. Our findings imply that EMPA treatment can rescue abnormally reduced peak INa of dystrophin-deficient ventricular cardiomyocytes. Long-term EMPA administration may diminish arrhythmia vulnerability in patients with DMD.NEW & NOTEWORTHY Dystrophin deficiency in cardiomyocytes leads to abnormally reduced Na+ currents. These can be rescued by long-term empagliflozin treatment.


Assuntos
Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Glucosídeos , Distrofia Muscular de Duchenne , Animais , Camundongos , Humanos , Distrofina/genética , Camundongos Endogâmicos mdx , Miócitos Cardíacos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Distrofia Muscular de Duchenne/genética , Arritmias Cardíacas/metabolismo , Sódio/metabolismo , Modelos Animais de Doenças
3.
Circ Res ; 130(12): 1888-1905, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35679365

RESUMO

Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.


Assuntos
Cardiomiopatias , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Idoso , Animais , Humanos , Modelos Animais , Volume Sistólico , Função Ventricular Esquerda
4.
Rev Cardiovasc Med ; 24(1): 6, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39076867

RESUMO

Background: Geometrical alterations in the coronary resistance artery network and the potential involvement of Tenascin C (TNC) extracellular matrix protein were investigated in diabetic and control mice. Methods: Diabetes was induced by streptozotocin (STZ) injections (n = 7-11 animals in each group) in Tenascin C KO (TNC KO) mice and their Wild type (A/J) littermates. After 16-18 weeks the heart was removed and the whole subsurface network of the left coronary artery was prepared (down to branches of 40 µ m outer diameter), in situ pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 µ m pixel resolutions. Results: Diabetes induced abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed retrogradely (p < 0.001 by the χ 2 test). Networks of TNC KO mice tended to form early divisions producing parallelly running larger branches (p < 0.001 by the χ 2 probe). Networks of coronary resistance arteries were substantially more abundant in 100-180 µ m components, appearing in 2-5 mm flow distance from orifice in diabetes. This was accompanied by thickening of the wall of larger arterioles ( > 220 µ m) and thinning of the wall of smaller (100-140 µ m) arterioles (p < 0.001). Blood flow should cover larger distances in diabetic networks, but interestingly STZ-induced diabetes did not generate further geometrical changes in TNC KO mice. Conclusions: Diabetes promotes hypertrophic and hypotrophic vascular remodeling and induces vasculogenesis at well defined, specific positions of the coronary vasculature. TNC plays a pivotal role in the formation of coronary network geometry, and TNC deletion causes parallel fragmentation preventing diabetes-induced abnormal vascular morphologies.

5.
Sensors (Basel) ; 23(4)2023 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-36850659

RESUMO

Adaptive machine learning has increasing importance due to its ability to classify a data stream and handle the changes in the data distribution. Various resources, such as wearable sensors and medical devices, can generate a data stream with an imbalanced distribution of classes. Many popular oversampling techniques have been designed for imbalanced batch data rather than a continuous stream. This work proposes a self-adjusting window to improve the adaptive classification of an imbalanced data stream based on minimizing cluster distortion. It includes two models; the first chooses only the previous data instances that preserve the coherence of the current chunk's samples. The second model relaxes the strict filter by excluding the examples of the last chunk. Both models include generating synthetic points for oversampling rather than the actual data points. The evaluation of the proposed models using the Siena EEG dataset showed their ability to improve the performance of several adaptive classifiers. The best results have been obtained using Adaptive Random Forest in which Sensitivity reached 96.83% and Precision reached 99.96%.

6.
Int J Mol Sci ; 24(3)2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36768836

RESUMO

Transient receptor potential cation channel subfamily A member 1 (TRPA1), an ion channel primarily expressed on sensory neurons, can be activated by substances occurring during myocardial infarction. Aims were to investigate whether activation, inhibition, or absence of TRPA1 affects infarcts and to explore underlying mechanisms. In the context of myocardial infarction, rats received a TRPA1 agonist, an antagonist, or vehicle at different time points, and infarct size was assessed. Wild type and TRPA1 knockout mice were also compared in this regard. In vitro, sensory neurons were co-cultured with cardiomyocytes and subjected to a model of ischemia-reperfusion. Although there was a difference between TRPA1 activation or inhibition in vivo, no experimental group was different to control animals in infarct size, which also applies to animals lacking TRPA1. In vitro, survival probability of cardiomyocytes challenged by ischemia-reperfusion increased from 32.8% in absence to 45.1% in presence of sensory neurons, which depends, at least partly, on TRPA1. This study raises doubts about whether TRPA1 is a promising target to reduce myocardial damage within a 24 h period. The results are incompatible with relevant enlargements of infarcts by TRPA1 activation or inhibition, which argues against adverse effects when TRPA1 is targeted for other indications.


Assuntos
Infarto do Miocárdio , Canais de Potencial de Receptor Transitório , Camundongos , Ratos , Animais , Canal de Cátion TRPA1/genética , Canais de Potencial de Receptor Transitório/genética , Miocárdio , Células Receptoras Sensoriais , Camundongos Knockout , Infarto do Miocárdio/genética
7.
Int J Mol Sci ; 24(10)2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37239853

RESUMO

Duchenne muscular dystrophy (DMD) is characterized by wasting of muscles that leads to difficulty moving and premature death, mainly from heart failure. Glucocorticoids are applied in the management of the disease, supporting the hypothesis that inflammation may be driver as well as target. However, the inflammatory mechanisms during progression of cardiac and skeletal muscle dysfunction are still not well characterized. Our objective was to characterize the inflammasomes in myocardial and skeletal muscle in rodent models of DMD. Gastrocnemius and heart samples were collected from mdx mice and DMDmdx rats (3 and 9-10 months). Inflammasome sensors and effectors were assessed by immunoblotting. Histology was used to assess leukocyte infiltration and fibrosis. In gastrocnemius, a tendency towards elevation of gasdermin D irrespective of the age of the animal was observed. The adaptor protein was elevated in the mdx mouse skeletal muscle and heart. Increased cleavage of the cytokines was observed in the skeletal muscle of the DMDmdx rats. Sensor or cytokine expression was not changed in the tissue samples of the mdx mice. In conclusion, inflammatory responses are distinct between the skeletal muscle and heart in relevant models of DMD. Inflammation tends to decrease over time, supporting the clinical observations that the efficacy of anti-inflammatory therapies might be more prominent in the early stage.


Assuntos
Distrofia Muscular de Duchenne , Camundongos , Ratos , Animais , Distrofia Muscular de Duchenne/metabolismo , Inflamassomos/metabolismo , Camundongos Endogâmicos mdx , Roedores/metabolismo , Músculo Esquelético/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças
8.
Int J Mol Sci ; 24(3)2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36768204

RESUMO

Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human disease and to study the roles of ether lipids in various cell types and tissues. However, little is known about the function of these lipids in cardiac tissue. Previous studies included case reports of cardiac defects in ether-lipid-deficient patients, but a systematic analysis of the impact of ether lipid deficiency on the mammalian heart is still missing. Here, we utilize a mouse model of complete ether lipid deficiency (Gnpat KO) to accomplish this task. Similar to a subgroup of human patients with rhizomelic chondrodysplasia punctata (RCDP), a fraction of Gnpat KO fetuses present with defects in ventricular septation, presumably evoked by a developmental delay. We did not detect any signs of cardiomyopathy but identified increased left ventricular end-systolic and end-diastolic pressure in middle-aged ether-lipid-deficient mice. By comprehensive electrocardiographic characterization, we consistently found reduced ventricular conduction velocity, as indicated by a prolonged QRS complex, as well as increased QRS and QT dispersion in the Gnpat KO group. Furthermore, a shift of the Wenckebach point to longer cycle lengths indicated depressed atrioventricular nodal function. To complement our findings in mice, we analyzed medical records and performed electrocardiography in ether-lipid-deficient human patients, which, in contrast to the murine phenotype, indicated a trend towards shortened QT intervals. Taken together, our findings demonstrate that the cardiac phenotype upon ether lipid deficiency is highly heterogeneous, and although the manifestations in the mouse model only partially match the abnormalities in human patients, the results add to our understanding of the physiological role of ether lipids and emphasize their importance for proper cardiac development and function.


Assuntos
Éter , Plasmalogênios , Animais , Humanos , Camundongos , Éteres , Etil-Éteres , Coração , Mamíferos/metabolismo
9.
Basic Res Cardiol ; 117(1): 42, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-36008727

RESUMO

Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervation have a great clinical potential. Remote ischemic perconditioning (RIPerc) could markedly attenuate MI-reperfusion (MIR) injury. In this study, we aimed to assess its effects on cardiac sympathetic innervation and metabolism. Transient myocardial ischemia is induced by ligature of the left anterior descending coronary artery (LAD) in male Sprague-Dawley rats, and in vivo cardiac 2-[18F]FDG and [11C]mHED PET scans were performed at 14-15 days after ischemia. RIPerc was induced by three cycles of 5-min-long unilateral hind limb ischemia and intermittent 5 min of reperfusion during LAD occlusion period. The PET quantitative parameters were quantified in parametric polar maps. This standardized format facilitates the regional radioactive quantification in deficit regions to remote areas. The ex vivo radionuclide distribution was additionally identified using autoradiography. Myocardial neuron density (tyrosine hydroxylase positive staining) and chondroitin sulfate proteoglycans (CSPG, inhibiting neuron regeneration) expression were assessed by immunohistochemistry. There was no significant difference in the mean hypometabolism 2-[18F]FDG uptake ratio (44.6 ± 4.8% vs. 45.4 ± 4.4%) between MIR rats and MIR + RIPerc rats (P > 0.05). However, the mean [11C]mHED nervous activity of denervated myocardium was significantly elevated in MIR + RIPerc rats compared to the MIR rats (35.9 ± 7.1% vs. 28.9 ± 2.3%, P < 0.05), coupled with reduced denervated myocardium area (19.5 ± 5.3% vs. 27.8 ± 6.6%, P < 0.05), which were associated with preserved left-ventricular systolic function, a less reduction in neuron density, and a significant reduction in CSPG and CD68 expression in the myocardium. RIPerc presented a positive effect on cardiac sympathetic-nerve innervation following ischemia, but showed no significant effect on myocardial metabolism.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Animais , Fluordesoxiglucose F18 , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Rev Cardiovasc Med ; 23(2): 63, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35229554

RESUMO

BACKGROUND: Neuregulin-1 (NRG-1) is a stress-mediated transmembrane growth factor. Reduced myocardial damage and higher NRG-1 levels upon treatment with remote ischemic conditioning (RIC) has been described in rats. However, the role of NRG-1 in patients with acute myocardial infarction (MI) is unknown. Thus, we conducted a post hoc analysis of a randomized controlled trial that tested RIC in patients with MI scheduled for primary percutaneous coronary intervention (PCI). METHODS: Blood was drawn from 30 patients before RIC/PCI, within 1 hour, 4 days and 1 month later. Median left ventricular ejection fraction (LVEF) in the overall study population following MI was 48.5%. RESULTS: NRG-1 plasma levels decreased significantly following PCI/RIC and remained decreased up to 1 month following MI (p < 0.0001). We observed no association of NRG-1 with other variables, including total ischemic time, LVEF or RIC. CONCLUSIONS: Thus, we identified NRG-1 may be independently affected by MI. However, further large clinical trials are warranted to clarify this hypothesis.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Animais , Humanos , Neuregulina-1 , Intervenção Coronária Percutânea/efeitos adversos , Ratos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda
11.
Rev Cardiovasc Med ; 23(11): 368, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39076175

RESUMO

Background: Saline is still the most widely used storage and rinsing solution for vessel grafts during cardiac surgery despite knowing evidence of its negative influence on the human endothelial cell function. Aim of this study was to assess the effect of DuraGraft©, an intraoperative graft treatment solution, on human saphenous vein segments and further elaborate the vasoprotective effect on rat aortic segments in comparison to saline. Methods: Human Saphenous vein (HSV) graft segments from patients undergoing aortocoronary bypass surgery (n = 15), were randomized to DuraGraft© (n = 15) or saline (n = 15) solution before intraoperative storage. Each segment was divided into two subsegmental parts for evaluation. These segments as well as rat aortic segments stored in DuraGraft© underwent assessment of vascular function in a multichamber isometric myograph system in comparison to Krebs-Henseleit solution (KHS), a physiologic organ buffer solution. Results: Potassium-Chloride (KCL)-induced contraction depicted a tendency towards increase when treated with DuraGraft© compared to saline preservation of HSV segments (23.02 ± 14.77 vs 14.44 ± 9.13 mN, p = 0.0571). Vein segments preserved with DuraGraft© showed a significant improvement of endothelium-dependent vasorelaxation in response to cumulative concentrations of bradykinin compared to saline treated segments (p < 0.05). Rat aortic segments stored in saline showed significantly impaired vasoconstriction (3.59 ± 4.20, p < 0.0001) and vasorelaxation when compared to KHS and DuraGraft© (p < 0.0001). Conclusions: DuraGraft© demonstrated a favorable effect on graft relaxation and contraction indicating preservation of vascular endothelial function. Clinical Trial Registration Number: NCT04614077.

12.
Transpl Int ; 35: 10057, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35497886

RESUMO

Objectives: Cold ischemia and subsequent reperfusion injury are non-immunologic cornerstones in the development of graft injury after heart transplantation. The nitric oxide donor S-nitroso-human-serum-albumin (S-NO-HSA) is known to attenuate myocardial ischemia-reperfusion (I/R)-injury. We assessed whether donor preservation with S-NO-HSA affects isograft injury and myocardial expression of GATA2 as well as miR-126-3p, which are considered protective against vascular and endothelial injury. Methods: Donor C57BL/6 mice received intravenous (0.1 µmol/kg/h) S-NO-HSA (n = 12), or 0.9% saline (control, n = 11) for 20 min. Donor hearts were stored in cold histidine-tryptophan-α-ketoglutarate-N solution for 12 h and underwent heterotopic, isogenic transplantation, except 5 hearts of each group, which were analysed immediately after preservation. Fibrosis was quantified and expression of GATA2 and miR-126-3p assessed by RT-qPCR after 60 days or immediately after preservation. Results: Fibrosis was significantly reduced in the S-NO-HSA group (6.47% ± 1.76 vs. 11.52% ± 2.16; p = 0.0023; 12 h-S-NO-HSA-hHTX vs. 12 h-control-hHTX). Expression of miR-126-3p was downregulated in all hearts after ischemia compared to native myocardium, but the effect was significantly attenuated when donors received S-NO-HSA (1 ± 0.27 vs. 0.33 ± 0.31; p = 0.0187; 12 h-S-NO-HSA-hHTX vs. 12 h-control-hHTX; normalized expression to U6 snRNA). Conclusion: Donor pre-treatment with S-NO-HSA lead to reduced fibrosis and preservation of myocardial miR-126-3p and GATA2 levels in murine cardiac isografts 60 days after transplantation.


Assuntos
Transplante de Coração , MicroRNAs , Animais , Fibrose , Humanos , Isoenxertos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio , Albumina Sérica Humana , Doadores de Tecidos
13.
Entropy (Basel) ; 24(11)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36421496

RESUMO

Data stream mining techniques have recently received increasing research interest, especially in medical data classification. An unbalanced representation of the classification's targets in these data is a common challenge because classification techniques are biased toward the major class. Many methods have attempted to address this problem but have been exaggeratedly biased toward the minor class. In this work, we propose a method for balancing the presence of the minor class within the current window of the data stream while preserving the data's original majority as much as possible. The proposed method utilized similarity analysis for selecting specific instances from the previous window. This group of minor-class was then added to the current window's instances. Implementing the proposed method using the Siena dataset showed promising results compared to the Skew ensemble method and some other research methods.

14.
Eur Heart J Suppl ; 23(Suppl B): B70-B72, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34220376

RESUMO

Cardiovascular diseases are not only the leading causes of mortality in Hungary but also the mortality rate is twice as high as the European Union average, so screening programmes identifying subjects with elevated blood pressure (BP) are of utmost importance. May Measurement Month (MMM) is an annual global initiative that began in 2017 aimed at raising awareness of high BP. Hungary joined the 3rd campaign of MMM in 2019 and an overview of the results are presented in this paper. An opportunistic cross-sectional survey of participants aged ≥18 years was carried out in May 2019. Hypertension was defined as systolic BP ≥140 mmHg and diastolic BP ≥90 mmHg or treatment for hypertension, statistical analysis followed the standard MMM protocol. In Hungary, 55 sites were set up in primary and secondary care facilities, in pharmacies, and in malls across all regions, in both cities and villages. Out of 2766 individuals screened, 1286 participants (46.5%) had hypertension. Out of 1869 participants not on antihypertensive medication, 389 (20.8%) had elevated BP. In the case of treated individuals (n = 897), 420 (46.8%) had uncontrolled hypertension. Almost every 2nd subject of the screened cohort had hypertension (treated and controlled, treated and uncontrolled, or untreated). In the untreated cohort, every 5th subject had elevated BP, whilst among patients on antihypertensive medication, every second had uncontrolled BP. By identifying almost one-third of the whole screened cohort with the possibility of newly diagnosed or uncontrolled hypertension, our results confirm the importance of BP screening campaigns.

15.
Int J Mol Sci ; 22(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34681724

RESUMO

Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague-Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, p < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, p < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca2+-sensitivities of force production (pCa50) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa50, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Carboxipeptidases/metabolismo , Pós-Condicionamento Isquêmico , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Animais , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Ventrículos do Coração/metabolismo , Masculino , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Troponina I/metabolismo , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular
16.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670747

RESUMO

BACKGROUND: Tenascin-C (TN-C) plays a maladaptive role in left ventricular (LV) hypertrophy following pressure overload. However, the role of TN-C in LV regression following mechanical unloading is unknown. METHODS: LV hypertrophy was induced by transverse aortic constriction for 10 weeks followed by debanding for 2 weeks in wild type (Wt) and TN-C knockout (TN-C KO) mice. Cardiac function was assessed by serial magnetic resonance imaging. The expression of fibrotic markers and drivers (angiotensin-converting enzyme-1, ACE-1) was determined in LV tissue as well as human cardiac fibroblasts (HCFs) after TN-C treatment. RESULTS: Chronic pressure overload resulted in a significant decline in cardiac function associated with LV dilation as well as upregulation of TN-C, collagen 1 (Col 1), and ACE-1 in Wt as compared to TN-C KO mice. Reverse remodeling in Wt mice partially improved cardiac function and fibrotic marker expression; however, TN-C protein expression remained unchanged. In HCF, TN-C strongly induced the upregulation of ACE 1 and Col 1. CONCLUSIONS: Pressure overload, when lasting long enough to induce HF, has less potential for reverse remodeling in mice. This may be due to significant upregulation of TN-C expression, which stimulates ACE 1, Col 1, and alpha-smooth muscle actin (α-SMA) upregulation in fibroblasts. Consequently, addressing TN-C in LV hypertrophy might open a new window for future therapeutics.


Assuntos
Aorta/fisiologia , Tenascina/metabolismo , Remodelação Ventricular , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Constrição Patológica , Fibroblastos/metabolismo , Ventrículos do Coração/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico , Função Ventricular
17.
Pflugers Arch ; 472(1): 61-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31822999

RESUMO

Neuronal nitric oxide synthase (nNOS) is considered a regulator of Cav1.2 L-type Ca2+ channels and downstream Ca2+ cycling in the heart. The commonest view is that nitric oxide (NO), generated by nNOS activity in cardiomyocytes, reduces the currents through Cav1.2 channels. This gives rise to a diminished Ca2+ release from the sarcoplasmic reticulum, and finally reduced contractility. Here, we report that nNOS inhibitor substances significantly increase intracellular Ca2+ transients in ventricular cardiomyocytes derived from adult mouse and rat hearts. This is consistent with an inhibitory effect of nNOS/NO activity on Ca2+ cycling and contractility. Whole cell currents through L-type Ca2+ channels in rodent myocytes, on the other hand, were not substantially affected by the application of various NOS inhibitors, or application of a NO donor substance. Moreover, the presence of NO donors had no effect on the single-channel open probability of purified human Cav1.2 channel protein reconstituted in artificial liposomes. These results indicate that nNOS/NO activity does not directly modify Cav1.2 channel function. We conclude that-against the currently prevailing view-basal Cav1.2 channel activity in ventricular cardiomyocytes is not substantially regulated by nNOS activity and NO. Hence, nNOS/NO inhibition of Ca2+ cycling and contractility occurs independently of direct regulation of Cav1.2 channels by NO.


Assuntos
Potenciais de Ação , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio , Miócitos Cardíacos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feminino , Ventrículos do Coração/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Ornitina/análogos & derivados , Ornitina/farmacologia , Ratos , Ratos Sprague-Dawley
18.
Am J Physiol Heart Circ Physiol ; 318(6): H1436-H1440, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32383994

RESUMO

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a degenerative muscle disease triggered by mutations in the gene encoding for the intracellular protein dystrophin. A major source for the arrhythmias in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output, and the development of reentrant mechanisms. The reason for ventricular conduction impairments and the associated arrhythmias in the dystrophic heart has remained unidentified. In the present study, we explored the hypothesis that dystrophin-deficient cardiac Purkinje fibers have reduced Na+ currents (INa), which would represent a potential mechanism underlying slowed ventricular conduction in the dystrophic heart. Therefore, by using a Langendorff perfusion system, we isolated Purkinje fibers from the hearts of adult wild-type control and dystrophin-deficient mdx mice. Enhanced green fluorescent protein (eGFP) expression under control of the connexin 40 gene allowed us to discriminate Purkinje fibers from eGFP-negative ventricular working cardiomyocytes after cell isolation. Finally, we recorded INa from wild-type and dystrophic mdx Purkinje fibers for comparison by means of the whole cell patch clamp technique. We found substantially reduced INa densities in mdx compared with wild-type Purkinje fibers, suggesting that dystrophin deficiency diminishes INa. Because Na+ channels in the Purkinje fiber membrane represent key determinants of ventricular conduction velocity, we propose that reduced INa in Purkinje fibers at least partly explains impaired ventricular conduction and the associated arrhythmias in the dystrophic heart.NEW & NOTEWORTHY Dystrophic cardiac Purkinje fibers have abnormally reduced Na+ current densities. This explains impaired ventricular conduction in the dystrophic heart.


Assuntos
Arritmias Cardíacas/metabolismo , Doença do Sistema de Condução Cardíaco/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Ramos Subendocárdicos/metabolismo , Canais de Sódio/metabolismo , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/fisiopatologia , Doença do Sistema de Condução Cardíaco/complicações , Doença do Sistema de Condução Cardíaco/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/fisiopatologia , Sódio/metabolismo
19.
Basic Res Cardiol ; 115(6): 76, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33258993

RESUMO

Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) characterized by adverse remodeling both at the myocardial and valvular levels. Persistent activation of valvular endothelial cells leads to leaflet fibrosis through endothelial-to-mesenchymal transition (EMT). Tenascin C (TNC), an extracellular matrix glycoprotein involved in cardiovascular remodeling and fibrosis, was also identified in inducing epithelial-to-mesenchymal transition. In this study, we hypothesized that TNC also plays a role in the valvular remodeling observed in ischemic MR by contributing to valvular excess EMT. Moderate ischemic MR was induced by creating a posterior papillary muscle infarct (7 pigs and 7 sheep). Additional animals (7 pigs and 4 sheep) served as controls. Pigs and sheep were sacrificed after 6 weeks and 6 months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6 weeks and 6 months, respectively, and correlated well with leaflet thickness (R = 0.68; p < 0.001 at 6 weeks, R = 0.84; p < 0.001 at 6 months). To confirm the translational potential of our findings, we obtained mitral valves from patients with ischemic cardiomyopathy presenting MR (n = 5). Indeed, TNC was also expressed in the mitral leaflets of these. Furthermore, TNC induced EMT in isolated porcine mitral valve endothelial cells (MVEC). Interestingly, Toll-like receptor 4 (TLR4) inhibition prevented TNC-mediated EMT in MVEC. We identified here for the first time a new contributor to valvular remodeling in ischemic MR, namely TNC, which induced EMT through TLR4. Our findings might set the path for novel therapeutic targets for preventing or limiting ischemic MR.


Assuntos
Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal , Insuficiência da Valva Mitral/metabolismo , Valva Mitral/metabolismo , Infarto do Miocárdio/complicações , Tenascina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/patologia , Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/patologia , Insuficiência da Valva Mitral/fisiopatologia , Carneiro Doméstico , Transdução de Sinais , Sus scrofa , Receptor 4 Toll-Like/metabolismo , Regulação para Cima
20.
Eur Heart J ; 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39016156
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