Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

2010 ◽  
Vol 299 (1) ◽  
pp. H1-H9 ◽  
Author(s):  
Begoña López ◽  
Arantxa González ◽  
Nerea Hermida ◽  
Félix Valencia ◽  
Eduardo de Teresa ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Lysyl Oxidase ◽  
Left Ventricular ◽  
Clinical Aspects ◽  
Cross Linking ◽  
Lv Function ◽  
Cardiac Diseases ◽  
Collagen Types ◽  
And Function

Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOX-mediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function.

Heart rate reduction improves myocardial ischemia in swine: role of interventricular blood flow redistribution

1991 ◽  
Vol 261 (3) ◽  
pp. H910-H917 ◽  
Author(s):  
C. Indolfi ◽  
B. D. Guth ◽  
S. Miyazaki ◽  
T. Miura ◽  
R. Schulz ◽  
...  
Keyword(s):  
Heart Rate ◽  
Blood Flow ◽  
Left Ventricular ◽  
Regional Myocardial Blood Flow ◽  
Lv Function ◽  
Wall Thickening ◽  
Regional Dysfunction ◽  
Electrical Pacing ◽  
And Function

Regional myocardial blood flow (MBF) distribution and function upon slowing the heart rate (HR) during ischemia were studied in anesthetized swine, a species without coronary collaterals. Perfusion of the left anterior descending artery by a pump allowed controlled production of regional ischemia. Slowing tachycardia by electrical pacing (127 to 87 beats/min) caused marked improvement of regional dysfunction [% wall thickening (WTh) from 9 to 27%] and increased subendocardial MBF [from 0.31 to 0.55 ml.min-1.g-1 (P less than 0.001)] without change of subepicardial MBF. Total left ventricular (LV) MBF increased, whereas right ventricular (RV) MBF fell by 18% (P less than 0.02). The mechanism of MBF changes during slowed HR was assessed by surgically excluding the RV and comparing findings with previous experiments with RV intact when HR was slowed from 96 to 60 beats/min. A similar improvement of regional LV function occurred (8% vs. 30% WTh) with the RV excluded, but without a change in total flow to the LV bed, whereas subendocardial MBF increased and subepicardial MBF fell, indicating transmural redistribution only. These findings show that the RV vascular bed can contribute to LV perfusion in swine during ischemia, and they document the potential for “reverse RV steal” during slowed heart rate in this setting.

PATHOGENETIC ROLE OF MYOCARDIAL FIBROSIS: FOCUS ON EXTRACELLULAR MATRIX

2020 ◽  
pp. 21-24
Author(s):  
T. M. Ambrosova ◽  
T. V. Ashcheulova
Keyword(s):  
Extracellular Matrix ◽  
Left Ventricular Hypertrophy ◽  
Myocardial Fibrosis ◽  
Cardiac Remodeling ◽  
Heart Muscle ◽  
Ventricular Hypertrophy ◽  
Collagen Type ◽  
Left Ventricular ◽  
And Function

The main cardiovascular diseases affect the processes of myocardial remodeling, which further contributes to the formation of systolic or diastolic heart dysfunction. The formation of myocardial dysfunction is primarily associated with left ventricular hypertrophy when under hemodynamic loading, firstly, wall rigidity increases, secondly, myocardial fibrosis is formed. The latter is one of the key factors of the hypertrophic process caused by the accumulation of collagen, which leads to a aggravation of the left ventricle relaxation processes. Cardiac remodeling is defined as a group of molecular, cellular, and interstitial changes that are clinically manifested by alterations in the size, shape, and function of heart as a result of the heart muscle injury. It has been determined that fibrosis is an early morphological sign of injury in patients with left ventricular overload, as well as a factor in the development of diastolic and systolic dysfunctions. Compensatory left ventricular hypertrophy transforms into heart failure due to the fibrosis development. In hypertrophy the content of elastic collagen type III decreases and rigid collagen type I increases. The essential role of the extracellular matrix in myocardial fibrosis formation is emphasized. Cardiac fibrosis is a process of pathological remodeling of the extracellular matrix, which leads to abnormalities in its composition and dysfunction of the heart muscle. The extracellular matrix plays a key role in organogenesis and post−traumatic healing in tissue injuries. The study of intercellular interactions of the extracellular matrix will provide a better understanding of the mechanisms of changes in geometry and function of the heart, and investigation of the activity of matrix components will open new opportunities for targeted therapeutic effects on molecular mechanisms of cardiac remodeling. Key words: diastolic dysfunction, extracellular matrix, myocardial fibrosis, cardiomyocytes, fibroblasts.

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

2001 ◽  
Vol 281 (5) ◽  
pp. H1938-H1945 ◽  
Author(s):  
Chari Y. T. Hart ◽  
John C. Burnett ◽  
Margaret M. Redfield
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Rise ◽  
Left Ventricular ◽  
Lv Function ◽  
Ketamine Anesthesia ◽  
The Difference ◽  
And Function ◽  
Derivatives Of

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (τ), and the first derivatives of LV pressure rise and fall (dP/d t max and dP/d t min, respectively). During echocardiography, HR was lower in XK than AV mice (250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/d t max: 4,402 ± 798 vs. 8,250 ± 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (τ: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

scholarly journals Association between Native Myocardial T1 Mapping and Cardiac Function and Macroscopic Fibrosis in Thalassemia Major

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Alessia Pepe ◽  
Nicola Martini ◽  
Antonio De Luca ◽  
Vincenzo Positano ◽  
Laura Pistoia ◽  
...  
Keyword(s):  
Iron Overload ◽  
Myocardial Fibrosis ◽  
T1 Mapping ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
Lv Function ◽  
Myocardial Iron ◽  
Native T1 ◽  
Molli Sequence ◽  
Lv Volume

Background.Cardiovascular magnetic resonance (CMR) is the only available technique for the non-invasive quantification of MIO. The native T1 mapping has recently been proposed as an alternative to the universally adopted T2* technique, due to the higher sensitivity for detection of changes associated with mild or early iron overload. Objective.To study the association between T1 values and left ventricular (LV) function in thalassemia major (TM) and to evaluate for the first time if T1 measurements quantifying MIO are influenced by macroscopic myocardial fibrosis. Methods.146 TM patients (87 females, 38.7±11.1 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network underwent CMR. Native T1 values were obtained by Modified Look-Locker Inversion recovery (MOLLI) sequence in all 16 myocardial segments and the global value was the mean. LV function parameters were quantified by cine images. Late gadolinium enhancement (LGE) technique was used to detect macroscopic myocardial fibrosis. Results.No correlation was detected between global heart T1 values and LV volume indexes, LV mass index, or LV ejection fraction. Foourteen (9.6%) patients had an abnormal LV motion (13 hypokinesia and 1 dyskinesia) and they showed significantly lower global heart T1 values than patients without LV motion abnormalities (883.8±139.7 ms vs 959.0±91.3 ms; P=0.049). LGE images were acquired in 88 patients (60.3%) and macroscopic myocardial fibrosis was detected in 36 patients (40.9%). The 72.2% of patients had two or more foci of fibrosis. Patients with macroscopic myocardial fibrosis had significantly lower global heart T1 values (921.3±100.3 ms vs 974.5±72.7 ms; P=0.027) (Figure 1A). Data about the LGE was present for 1408 segments (88 patients x 16 segments) and 105 (7.5%) were positive. Segments with LGE had significantly lower T1 values than segments LGE-negative (905.6±110.6 ms vs 956.9±103.8 ms; P&lt;0.0001) (Figure 1B). Conclusion.No correlation between T1 values and LV function parameters was detected, probably because the majority of the patients had normal or mild abnormal LV parameters. TM patients with macroscopic myocardial fibrosis showed significantly lower T1 values suggesting that T1 measurements for quantifying MIO are not influenced by macroscopic myocardial fibrosis and an association between myocardial iron and macroscopic fibrosis, previously detected only in pediatric TM patients. Figure Disclosures Pepe: Chiesi Farmaceutici S.p.A.:Other: no profit support and speakers' honoraria;Bayer:Other: no profit support;ApoPharma Inc.:Other: no profit support.Pistoia:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.Meloni:Chiesi Farmaceutici S.p.A.:Other: speakers' honoraria.

scholarly journals miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10502
Author(s):  
Huan Guo ◽  
Xinke Zhao ◽  
Haixiang Su ◽  
Chengxu Ma ◽  
Kai Liu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Differentially Expressed Gene ◽  
Stem Loop ◽  
Cardiac Morbidity ◽  
Increased Risk ◽  
And Function

Background Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. Methods We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. Results DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation—the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

scholarly journals Serum Aldosterone Is Related to Left Ventricular Geometry and Function in Young Adults with Never-Treated Primary Hypertension

2019 ◽  
Vol 8 (7) ◽  
pp. 1045 ◽  
Author(s):  
Seong-Mi Park ◽  
Mi-Na Kim ◽  
Sua Kim ◽  
Wan-Joo Shim
Keyword(s):  
Blood Pressure ◽  
Young Adults ◽  
Left Ventricular ◽  
Primary Hypertension ◽  
Lv Function ◽  
Amino Terminal ◽  
Serum Aldosterone ◽  
Lv Mass ◽  
And Function ◽  
Normal Controls

Background: Although aldosterone has been demonstrated to induce left ventricular (LV) hypertrophy not only in primary aldosteronism but also in primary hypertension (HT), it can be affected by multiple factors, including age, and the effect of aldosterone on LV function is controversial. This study was to investigate the relationship of aldosterone to changes in LV geometry and function in young adults with never-treated HT. Methods: Seventy-five consecutive patients (age, 29.8 ± 6.3 years) with never-treated HT and 45 normal controls were enrolled. Echocardiographic values and LV global longitudinal strain (LVGLS) were obtained. Serum aldosterone concentration (SAC) and serum procollagen type III amino-terminal peptide (PIIINP) level were obtained in HT patients. Results: HT patients had higher LV mass index, higher relative wall thickness (RWT), and worse LV function than normal controls. LVGLS and e’ velocity were worse in HT patients with normal geometry than in normal controls. SAC was well correlated with LV mass index, RWT, e’ velocity, LVGLS, and PIIINP (all p < 0.05). LV geometry pattern was most related to SAC among clinical parameters (p = 0.019). LVGLS was most related to LV geometry and diastolic blood pressure. In contrast, e’ velocity was most related to PIIINP. Conclusion: Our findings may indicate that in young patients with never-treated HT, aldosterone significantly contributes to changes in LV geometry and functional impairment through its pro-hypertrophic and myocardial fibrosis effects beyond blood pressure.

scholarly journals Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway

2018 ◽  
Vol 47 (2) ◽  
pp. 579-589 ◽  
Author(s):  
Wei Li ◽  
Yaojun Lu ◽  
Ruijuan Han ◽  
Qiang Yue ◽  
Xiurong Song ◽  
...  
Keyword(s):  
Mouse Model ◽  
Progenitor Cells ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Cardiac Progenitor Cells ◽  
Cardiomyocyte Differentiation ◽  
Rt Pcr ◽  
And Function

Background/Aims: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. Methods: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. Results: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. Conclusions: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

scholarly journals Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

2014 ◽  
Vol 307 (5) ◽  
pp. H752-H761 ◽  
Author(s):  
William M. Yarbrough ◽  
Catalin Baicu ◽  
Rupak Mukherjee ◽  
An Van Laer ◽  
William T. Rivers ◽  
...  
Keyword(s):  
Pressure Overload ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Matrix Remodeling ◽  
Protective Effects ◽  
Ecm Remodeling ◽  
Hypertrophic Response ◽  
Lv Mass ◽  
And Function

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE ( n = 38), TIMP-4KO ( n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ∼25% lower in the TIMP-4KO group ( P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups ( P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

scholarly journals Case Report: Key Role of the Impella Device to Achieve Complete Revascularization in a Patient With Complex Multivessel Disease and Severely Depressed Left Ventricular Function

2021 ◽  
Vol 8 ◽  
Author(s):  
Giovanni Monizzi ◽  
Luca Grancini ◽  
Paolo Olivares ◽  
Antonio L. Bartorelli
Keyword(s):  
Coronary Artery ◽  
High Risk ◽  
Left Ventricular ◽  
Multivessel Disease ◽  
Lv Function ◽  
Complete Revascularization ◽  
Coronary Perfusion ◽  
Heart Team ◽  
Hemodynamic Support

Background: Left ventricle (LV) assist devices may be required to stabilize hemodynamic status during complex, high-risk, and indicated procedures (CHIP). We present a case in which elective hemodynamic support with the Impella CP device was essential to achieve complete revascularization with PCI in a patient with complex multivessel disease and severely depressed LV function.Case Summary: A 45-year-old male with no previous history of cardiovascular disease presented to the emergency department for new onset exertional dyspnoea. Echocardiography showed severely depressed LV function (EF 27%) that was confirmed with cardiac magnetic resonance. Two chronic total occlusions (CTOs) of the proximal right coronary artery (RCA) and left circumflex coronary artery (LCx) were found at coronary angiography. After Heart Team evaluation, PCI with Impella hemodynamic support was planned. After crossing and predilating the CTO of the LCx, ventricular fibrillation (VF) occurred. No direct current (DC) shock was performed because the patient was conscious thanks to the support provided by the Impella pump. About 1 min later, spontaneous termination of VF occurred. Afterwards, the two CTOs were successfully treated with good result and no complications. Recovery of LV function was observed at discharge. At 9 months, the patient had no symptoms and echocardiography showed an EF of 60%.Discussion: In this complex high-risk patient, hemodynamic support was essential to allow successful PCI. It is remarkable that the patient remained conscious and hemodynamically stable during VF that spontaneously terminated after 1 min, likely because the Impella pump provided preserved coronary perfusion and LV unloading. This case confirms the pivotal role of Impella in supporting CHIP, particularly in patients with multivessel disease and depressed LV function.

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