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Purpose of Review: Cardiac magnetic resonance (CMR) is emerging as a valuable imaging modality for the assessment of aortic regurgitation (AR). In this review, we discuss the assessment of AR severity, left ventricular (LV) remodeling, and tissue characterization by CMR while highlighting the latest studies and addressing future research needs. Recent Findings: Recent studies have further established CMR-based thresholds of AR severity and LV remodeling that are associated with adverse clinical outcomes, and lower than current guideline criteria. In addition, tissue profiling with late gadolinium enhancement (LGE) and extracellular volume (ECV) quantification can reliably assess adverse myocardial tissue remodeling which is also associated with adverse outcomes. Summary: The strengths and reproducibility of CMR in evaluating ventricular volumes, tissue characteristics, and regurgitation severity position it as an excellent modality in evaluating and following AR patients. Advanced CMR techniques for the detection of tissue remodeling have shown significant potential and merit further investigation. [ABSTRACT FROM AUTHOR]

Background/objectives: Myocardial infarction (MI) frequently leads to cardiac remodeling and failure with impaired life quality, playing an important role in cardiovascular deaths. Although physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases, the effects of strength training (ST) on the structural and functional aspects of cardiac remodeling need to be further documented. In this study, we aimed to investigate the role of a linear block ST protocol in the rat model of MI. Methods and results: After 6 weeks of MI induction or sham surgery, male adult rats performed ST for the following 12 weeks. The ladder-based ST program was organized in three mesocycles of 4 weeks, with one load increment for each block according to the maximal carrying load test. After 12 weeks, the infarcted-trained rats exhibited an increase in performance, associated with reduced cardiac hypertrophy and pulmonary congestion compared with the untrained group. Despite not changing MI size, the ST program partially prevented cardiac dilatation and ventricular dysfunction assessed by echocardiography and hemodynamics, and interstitial fibrosis evaluated by histology. In addition, isolated cardiac muscles from infarcted-trained rats had improved contractility parameters in a steady state, and in response to calcium or stimuli pauses. Conclusions: The ST in infarcted rats increased the capacity to carry mass, associated with attenuation of cardiac remodeling and pulmonary congestion with improving cardiac function that could be attributed, at least in part, to the improvement of myocardial contractility. [ABSTRACT FROM AUTHOR]

Objective: MicroRNA-30a-5p (miR-30a-5p) has been identified as a marker of heart failure; however, its functional mechanisms in chronic heart failure (CHF) remain unknown. We aim to investigate the role of miR-30a-5p targeting sirtuin-1 (SIRT1) in myocardial remodeling in CHF via the nuclear factor-κB/NOD-like receptor 3 (NF-κB/NLRP3) signaling pathway. Methods: CHF rat models were established using aortic coarctation. The expression of miR-30a-5p, SIRT1, and the NF-κB/NLRP3 signaling pathway-related factors in CHF rats was determined. The CHF rats were then respectively treated with altered miR-30a-5p or SIRT1 to explore their roles in cardiac function, myocardial function, inflammatory response, pathological changes, and cardiomyocyte apoptosis. The binding relation between miR-30a-5p and SIRT1 was confirmed. Results: MiR-30a-5p was upregulated whereas SIRT1 was downregulated in myocardial tissues of CHF rats. MiR-30a-5p inhibition or SIRT1 overexpression improved cardiac and myocardial function, and suppressed the inflammatory response, alleviated pathological changes and inhibited cardiomyocyte apoptosis in CHF rats. MiR-30a-5p targeted SIRT1 to regulate the NF-κB/NLRP3 signaling pathway. In CHF rats, downregulated miR-30a-5p and silenced SIRT1 could reverse the beneficial effects of downregulated miR-30a-5p. Conclusion: Inhibited miR-30a-5p inhibits CHF progression via the SIRT1-mediated NF-κB/NLRP3 signaling pathway. [ABSTRACT FROM AUTHOR]

Excessive salt intake is accompanied by the development of cardiovascular disorders, not always associated with an increase in blood pressure (BP). Given the cardioprotective effect of soy proteins in chronic kidney disease, the question arose of the possibility of leveling dietary interventions, in particular soy proteins, the damaging effect of a high-salt diet on the cardiovascular system. The aim of this work is to study the effect of long-term use of a diet high in NaCl and soy protein on myocardial remodeling and skin histomorphology in monkeys. The study was performed on male Javan macaques (Macaca fascicularis). The control group received a standard diet (2 g NaCl/kg feed). The second was a high-salt diet (8 g NaCl/kg feed), the third was a high-salt diet and SUPRO760 soy protein (200 g/kg feed). Echocardiography, registration of BP and heart rate were performed at baseline, after 4 and 12 months. After 12 months, a histological examination of the musculocutaneous flap was performed. In all animals, BP and heart rate did not change significantly during 12 months. In macaques on a high-salt diet, by the end of the study, deterioration in systolic and diastolic functions of the left ventricle (LV) was noted. In animals receiving additional soy protein, these changes leveled out. After 12 months, macaques fed soy protein had LV myocardial mass smaller and higher LV contractility than animals fed excess salt without soy protein. In monkeys on a high-salt diet, accumulation of collagen fibers in the hypodermis, hyalinization of the cytoplasm of capillary smooth muscle cells, perivascular and perineural edema of the reticular dermis were revealed. In animals treated with soy protein, skin capillary remodeling was less pronounced. Thus, high salt intake leads to adverse structural and functional disorders of the heart and blood vessels in cynomolgus monkeys, not associated with an increase in blood pressure. The inclusion of soy isolate in the diet reduces the negative effects of a high-salt diet on the cardiovascular system. [ABSTRACT FROM AUTHOR]

Objective: We propose a deep learning-based fully automatic right ventricle (RV) segmentation technique that targets radially reconstructed long-axis (RLA) images of the center of the RV region in routine short axis (SA) cardiovascular magnetic resonance (CMR) images. Accordingly, the purpose of this study is to compare the accuracy of deep learning-based fully automatic segmentation of RLA images with the accuracy of conventional deep learning-based segmentation in SA orientation in terms of the measurements of RV strain parameters. Materials and methods: We compared the accuracies of the above-mentioned methods in RV segmentations and in measuring RV strain parameters by Dice similarity coefficients (DSCs) and correlation coefficients. Results: DSC of RV segmentation of the RLA method exhibited a higher value than those of the conventional SA methods (0.84 vs. 0.61). Correlation coefficient with respect to manual RV strain measurements in the fully automatic RLA were superior to those in SA measurements (0.5–0.7 vs. 0.1–0.2). Discussion: Our proposed RLA realizes accurate fully automatic extraction of the entire RV region from an available CMR cine image without any additional imaging. Our findings overcome the complexity of image analysis in CMR without the limitations of the RV visualization in echocardiography. [ABSTRACT FROM AUTHOR]

Lipid droplet (LD) is a kind of subcellular organelle, which originates from the endoplasmic reticulum (ER). LDs can move flexibly between other organelles and store energy in the cells. In recent years, LDs and lipid droplet–associated proteins have attracted added attention at home and abroad, especially in cardiovascular diseases. Cardiovascular diseases, especially ischemic heart disease (IHD), have always been the focus of attention because of their high morbidity and mortality. Atherosclerosis and myocardial remodeling are two important pathologic processes of IHD, and LDs and other organelles are involved in the development of the disease. The interaction between LDs and ER is involved in the formation of foam cells in atherosclerosis. And LDs, mitochondria, and lysosomes also affect the remodeling of cardiomyocytes by affecting ROS production and regulating PI3K/AKT pathways. In this article, we will review the role of LDs in IHD. [ABSTRACT FROM AUTHOR]

Ischemic heart disease (IHD) accounts for the majority of heart disease-related deaths worldwide. Ubiquitin (UB), found in all eukaryotic cells, is a highly conserved low molecular weight (~8.5 kDa) protein. A well-known intracellular function of UB is to regulate protein turnover via the UB-proteasome system. UB is a normal constituent of plasma, and elevated levels of UB are observed in the serum of patients under a variety of pathological conditions. Recent studies provide evidence for cardioprotective potential of exogenous UB in the remodeling process of the heart in IHD, including effects on cardiac myocyte apoptosis, inflammatory response, and reorganization of the vasculature and extracellular matrix. This review summarizes functions of UB with an emphasis on the role of exogenous UB in myocardial remodeling in IHD. [ABSTRACT FROM AUTHOR]

ATP-sensitive potassium (KATP) channels are participants of mechanisms of pathological myocardial remodeling containment. The aim of our work was to find the association of changes in the expression of Kir6.1, Kir6.2, SUR1, and SUR2 subunits of KATP channels with changes in heart function and structure during aging under conditions of the constant increase of vascular pressure. The experiments were carried out on young and old spontaneously hypertensive rats (SHR) and Wistar rats. The expression levels of KATP channels subunits were determined using reverse transcription and quantitative PCR. It is shown that the mRNA expression level of Kir6.1 in young SHR rats is significantly lower (6.3-fold, p = 0.035) than that of young Wistar rats that may be one of the causes of arterial hypertension in SHR. At the same time, mRNA expression of both Kir6.1 and Kir6.2 in old SHR rats was significantly higher (6.8-fold, p = 0.003, and 5.9-fold, p = 0.006, respectively) than in young hypertensive animals. In both groups of old animals, SUR2 expression was significantly reduced compared to young animals, in Wistar rats at 3.87-fold (p = 0.028) and in SHR rats at 48.2-fold (p = 0.033). Changes in SUR1 expression were not significant. Thus, significant changes in the cardiovascular system, including impaired function and structure of the heart in old SHR rats, were associated with a significant decrease in SUR2 expression that may be one of the mechanisms of heart failure decompensation. Therefore, it can be assumed that increased expression of SUR2 may be one of the protective mechanisms against pathological myocardial remodeling. [ABSTRACT FROM AUTHOR]

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia–reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency has been associated with a poor outcome in patients with heart failure (HF). We examined the role of vitamin D in the response of HF patients to cardiac resynchronization therapy (CRT). Methods: The study comprised 50 patients (30 men and 20 women) with HF undergoing CRT implantation who were prospectively enrolled. Response to CRT was defined as a combination of ≥15% reduction in left ventricular end-systolic volume (LVESV) and ≥10% improvement in the 6‑Minute Walk Test within 6 months. Patients were grouped based on their levels of vitamin D prior to CRT implantation. Clinical and echocardiographic examinations were performed prior to and 6 months after the procedure. Results: Of the patients, 11 (22%) failed to respond to CRT; two patients died within 6 months and an additional nine patients showed no improvement in the 6‑Minute Walk Test and no reduction in their baseline LVESV. A comparison was made between 25 patients with sufficient levels of vitamin D and 25 patients with insufficient levels. Nine patients (36%) in the "insufficient" group and two patients (8%) in the "sufficient" group failed to respond to CRT implantation (p = 0.037). Conclusion: Adequate serum concentrations of vitamin D play a significant role in improving the functional status of patients with systolic HF following CRT implantation. [ABSTRACT FROM AUTHOR]

Although the prevalence of arterial hypertension (AH) in athletes is significantly lower than that in the general population, the prevalence of high blood pressure (BP) and increased left ventricular mass in a number of sports with high isometric loads (speed and strength sports) is higher than that in cyclic sports with high aerobic load. Specific risk factors of hypertension in athletes include high intake of sodium, alcohol, caffeine, and a number of illicit drugs, such as erythropoietin, growth hormone, and oral contraceptives in women. The development of athletic heart is determined by training and competitive activity and generally does not lead to the disorders of systolic and diastolic function. However, elevated BP in athletes increases the risk of myocardial hypertrophy and remodeling, which is one of the possible contraindications for sports with high static loads. [ABSTRACT FROM AUTHOR]

Background: Several fatal cases of bodybuilders, following a myocardial infarction after long exposure to androgenic-anabolic steroids (AAS), are reported. In recent years, evidence has emerged of cases of heart failure related to AAS consumption, with no signs of coronary or aorta atherosclerosis. This study aims to further investigate the pathogenesis of the ventricular AAS-related remodeling performing immunohistochemistry (IHC). Method: In order to examine innate immunity activity and myocytes and endothelial cell apoptosis, IHC analyses were performed on heart tissue of two cases of bodybuilders who died after years of supratherapeutic use of metelonone and nandrolone and where no atherosclerosis or thrombosis were found, using the following antibodies: anti-CD68, anti-iNOS, anti-CD163, anti-CD 15, anti-CD8, anti-CD4, anti-HIF1 α, and in situ TUNEL staining. Results: Results confirm the experimental findings of recent research that, in the absence of other pathological factors, if intensive training is combined with AAS abuse, myocytes and endothelial cells undergo apoptotic alterations. The absence of inflammatory reactions and the presence of an increased number of M2 macrophages in the areas of fibrotic remodeling confirm that the fibrotic changes in the heart are apoptosis-related and not necrosis-related. Conclusions: In conclusion, the study indicates that, in very young subjects with chronic hypoxia-related alterations of the heart, signs of a heart failure in the other organs and a history of AAS abuse, death can be ascribed to progressive heart failure due to the direct apoptotic cardiac and endothelial changes produced by AAS. [ABSTRACT FROM AUTHOR]

In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac function. [ABSTRACT FROM AUTHOR]

The phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of endothelin-1 and α-adrenergic signaling in cardiac hypertrophy. However, the role of PEX1 in transcriptional regulation of myocardial remodeling remains largely unknown. In the present study, we used PEX1 gain- and loss-of-function to examine the effects of PEX1 on left ventricular remodeling. Adenoviral constructs expressing PEX1, antisense PEX1, or LacZ were delivered by local injection into the anterior wall of the left ventricle in Sprague-Dawley rats. PEX1 overexpression led to induction of hypertrophic gene program and increased fibrosis. In agreement with this, the expression of genes involved in the fibrotic process, such as collagens I and III, matrix metalloproteinases (MMPs), fibronectin-1, transforming growth factor beta-1 and connective tissue growth factor, were significantly up-regulated following PEX1 overexpression, whereas silencing of PEX1 significantly inhibited the expression of pro-fibrotic genes and increased left ventricular ejection fraction and fractional shortening. In vitro luciferase reporter assays showed that PEX1 regulates the expression of MMP-9 by activating promoter. Furthermore, PEX1 gain- and loss-of-function experiments in rat neonatal cardiac fibroblasts and myocytes revealed that MMP-9 gene expression was affected by PEX1 predominantly in fibroblasts. Our results indicate that PEX1 is involved in regulating cardiac fibrosis and extracellular matrix turnover, particularly fibroblasts being responsible for the fibrosis-associated changes in gene expression. Furthermore, PEX1 activation of the MMP-9 promoter triggers the pro-fibrotic response directed by PEX1. [ABSTRACT FROM AUTHOR]

Background: To investigate whether an apoptotic process demonstrated by Tc-annexin-V (Tc-AV) uptake correlates with left ventricular remodeling (LVR) after myocardial infarction, we assessed Tc-AV uptake in rat model of myocardial ischemia and reperfusion. Methods: The left coronary artery (LCA) of 15 rats was occluded for 20 to 30 min, followed by reperfusion. After 2 weeks, Tc-AV was injected, and then 1 h later, Tl was injected after reocclusion of the LCA. Dual-tracer autoradiography was performed to assess Tc-AV uptake and the area at risk (AAR) by Tl defect. Tc-AV uptake ratio was calculated by dividing the count density of the AAR by that of the normally perfused area. In short-axis LV slices, LV cavity dilation index (DI) was calculated by dividing the area of LV cavity by that of the whole LV area. LV wall-thinning ratio (WTR) was calculated by dividing the LV wall thickness in the AAR by that of the normally perfused area. Results: Significant Tc-AV uptake in the AAR was observed in 10 rats. DI was significantly higher in rats with positive Tc-AV uptake than in rats without uptake. WTR was smaller in rats with positive Tc-AV uptake than in rats without uptake. Conclusions: The data suggest Tc-AV uptake in injured myocardium might correlate with LVR at 2 weeks after myocardial ischemia and reperfusion. [ABSTRACT FROM AUTHOR]

Aims The aim was to evaluate the cardio-protective effect of atorvastatin in combination with standard chronic heart failure (CHF) therapy that might improve cardiac function, remodeling, and further delay the progression of CHF in patients and rats. Methods and results CHF patients ( n = 20 per group) with left ventricular ejection fraction (LV-EF) <45% were randomized into: standard anti-failure treatment alone (controls) and standard anti-failure treatment plus atorvastatin (40 mg/day) for 6 weeks. After 6 weeks, the patients were assessed using echocardiography. Laboratory evaluation for lipid profiles, high sensitive C-reactive protein (hs-CRP), cardiac troponin-T (cTnT) and malondialdehyde (MDA) were performed in all patients. In parallel, rats ( n = 10 per group) received treatment for 4 weeks and were divided as follows: saline treated (control, 1 ml intraperitoneal, IP), doxorubicin treated (2.5 mg/kg, IP), atorvastatin–doxorubicin treated (10 mg/kg, orally), and digoxin–doxorubicin treated (0.02 mg/kg, orally). The same laboratory analysis including histopathology of heart tissues was performed on the rats. In patients, atorvastatin improved heart function (increased LV-EF%, LV-fraction shorting (LV-FS%), and E/A velocity ratio; decreased LV-end diastolic diameter (LV-EDD) and LV-end systolic diameter (LV-ESD)) and significantly reduced serum lipid profiles, cTnT, hs-CRP and MDA versus patient controls. In rats, atorvastatin improved signs of CHF, systolic blood pressure, reduced serum lipid profiles, cTnT, hs-CRP and tissue MDA; less cardiac necrosis and fibrosis with enhancement of neo-vascularization versus other doxorubicin-treated rats. Conclusions Atorvastatin with standard CHF therapy improved cardiac function and remodeling. Cardio-protective “pleiotropic” actions of atorvastatin are anti-inflammatory, anti-fibrotic and anti-oxidative. Thus, atorvastatin has a potential therapeutic value in the management of CHF patients. [ABSTRACT FROM AUTHOR]

Recent studies have proposed the potential role of 5-HT receptor (5-HTR) blockade in alleviating myocardial dysfunction; hitherto, the regulatory pathway for its protective effect has remained enigmatic. In the present study, we sought to investigate the role of SB-204741, a 5-HTR blocker in isoproterenol-induced myocardial remodeling in rats and its cross-talk with apoptosis and mitogen activated protein kinase (MAPKs)/heat shock proteins (HSPs) pathway. To assess this hypothesis, we measured the effect of SB-204741 (0.25-1.0 mg/kg/day, i.p.) in isoproterenol (85 mg/kg/day, s.c.)-induced myocardial remodeling in rats. SB-204741 dose dependently improved hemodynamic and ventricular functions following isoproterenol-induced myocardial injury. This amelioration was well substantiated with reduced expression of 5-HT, inflammatory proteins (NF-κBp65, IKK-β, TNF-α, IL-6, and Cox-2), MAPKs (p-p38/p38 and p-JNK/JNK ratio) accompanied with increased protein expression of HSPs (αB-crystallin, Hsp27 and Hsp70), autophagy (LC3 and Beclin-1) and p-ERK/ERK ratio. Additionally, SB-204741 inhibited apoptotic signaling pathway as there was decreased DAPI/TUNEL positivity and protein expression of cytochrome c, Bax, and caspase-3 along with increased Bcl-2 expression. Preservation of histopathological and ultrastructural components, normalization of nitric oxide level, endogenous antioxidants and myocyte injury marker enzymes were also observed. In conclusion, inhibition of apoptosis via modulation of MAPKs/HSPs is essential for 5-HTR blockade mediated cardioprotective effect. [ABSTRACT FROM AUTHOR]

Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction. Wild type and CB2-deficient mice underwent daily brief, repetitive ischemia and reperfusion (I/R) episodes leading to ischemic cardiomyopathy. The relevance of the endocannabinoid-CB2 receptor axis was underscored by the finding that CB2 was upregulated in ischemic wild type cardiomyocytes and that anandamide level was transiently increased during I/R. CB2-deficient mice showed an increased rate of apoptosis, irreversible loss of cardiomyocytes and persistent left ventricular dysfunction 60 days after the injury, whereas wild type mice presented neither morphological nor functional defects. These defects were due to lack of cardiomyocyte protection mechanisms, as CB2-deficient hearts were in contrast to controls unable to induce switch in myosin heavy chain isoforms, antioxidative enzymes and chemokine CCL2 during repetitive I/R. In addition, a prolonged inflammatory response and adverse myocardial remodeling were found in CB2-deficient hearts because of postponed activation of the M2a macrophage subpopulation. Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development. [ABSTRACT FROM AUTHOR]

Cardiomyocytes continuously generate the contractile force to circulate blood through the body. Imbalances in contractile performance or energy supply cause adaptive responses of the heart resulting in adverse rearrangement of regular structures, which in turn might lead to heart failure. At the cellular level, cardiomyocyte remodeling includes (1) restructuring of the contractile apparatus; (2) rearrangement of the cytoskeleton; and (3) changes in energy metabolism. Dedifferentiation represents a key feature of cardiomyocyte remodeling. It is characterized by reciprocal changes in the expression pattern of 'mature' and 'immature' cardiomyocyte-specific genes. Dedifferentiation may enable cardiomyocytes to cope with hypoxic stress by disassembly of the energy demanding contractile machinery and by reduction of the cellular energy demand. Dedifferentiation during myocardial repair might provide cardiomyocytes with additional plasticity, enabling survival under hypoxic conditions and increasing the propensity to enter the cell cycle. Although dedifferentiation of cardiomyocytes has been described during tissue regeneration in zebrafish and newts, little is known about corresponding mechanisms and regulatory circuits in mammals. The recent finding that the cytokine oncostatin M (OSM) is pivotal for cardiomyocyte dedifferentiation and exerts strong protective effects during myocardial infarction highlights the role of cytokines as potent stimulators of cardiac remodeling. Here, we summarize the current knowledge about transient dedifferentiation of cardiomyocytes in the context of myocardial remodeling, and propose a model for the role of OSM in this process. [ABSTRACT FROM AUTHOR]

Every year nearly 1 million Americans with myocardial infarction suffer from acute coronary syndromes. Despite advances in reperfusion therapy, these molecular events may often lead to ventricular adverse remodeling resulting in the heart failure. This observation became a driving force to develop noninvasive imaging strategies to evaluate remodeling using concepts of molecular imaging. As such, cardiovascular imaging plays an important role in shifting the paradigm from the disease treatment to early diagnosis, prognostication, and stratification, which has a tremendous potential to alleviate socioeconomic and health care costs associated with the treatment of heart failure patients. This review is intended to be a brief overview of recent nuclear imaging techniques and applications to assess molecular events associated with the process of left ventricular (LV) remodeling following myocardial infarction (MI). The specific approaches presented here will include imaging of perfusion, viability, metabolism, cardiac neuroreceptors, angiogenesis, proteases activity, and renin-angiotensin-aldosterone system activation. We will first describe basic concepts of molecular imaging, then we will provide an overview of recent advances in molecular imaging technology, and finally we will report current nuclear imaging strategies in assessment of LV remodeling. The emphasis will be put on radiotracer-based modalities including single photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques, although other clinical imaging modalities will be also briefly discussed. We expect that in near future these targeted imaging approaches will complement standard physiological parameters and will play a crucial role in post-MI patients' stratification and development of individual therapy regimes. [ABSTRACT FROM AUTHOR]

The extracellular heterodimeric protein S100A8/A9 activates the innate immune system through activation of the receptor of advanced glycation end products (RAGE) and Toll-like receptors. As activation of RAGE has recently been associated with sustained myocardial inflammation and heart failure (HF) we studied the role of S100A8/A9 in the development of post-ischemic HF. Hypoxia led to sustained induction of S100A8/A9 accompanied by increased nuclear factor (NF-)κB binding activity and increased expression of pro-inflammatory cytokines in cardiac fibroblasts and macrophages. Knockdown of either S100A8/A9 or RAGE rescued the induction of pro-inflammatory cytokines and NF-κB activation after hypoxia. In a murine model of post-ischemic HF both cardiac RNA and protein levels of S100A8/A9 were elevated as soon as 30 min after hypoxia with sustained activation up to 28 days after ischemic injury. Treatment with recombinant S100A8/A9 resulted in reduced cardiac performance following ischemia/reperfusion. Chimera experiments after bone marrow transplantation demonstrated the importance of RAGE expression on immune cells for their recruitment to the injured myocardium aggravating post-ischemic heart failure. Signaling studies in isolated ventricles indicated that MAP kinases JNK, ERK1/2 as well as NF-κB mediate signals downstream of S100A8/A9-RAGE in post-ischemic heart failure. Interestingly, cardiac performance was not affected by administration of S100A8/A9 in RAGE-mice, which demonstrated significantly improved cardiac recovery compared to WT-mice. Our study provides evidence that sustained activation of S100A8/A9 critically contributes to the development of post-ischemic HF driving the progressive course of HF through activation of RAGE. [ABSTRACT FROM AUTHOR]

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Ventricular assist devices may function as a bridge to recovery or heart transplantation, however, little is known about its mechanisms. This study examined the role of matrix metalloproteinases (MMP)-tissue inhibitors of metalloproteinases (TIMP) axis in the process of recovery after unloading in a rat ischemic-induce heart failure (HF) model. Myocardial infarction model was created with the coronary artery ligation. The infarcted rats hearts were unloaded by heterotopic cardiac transplantation ( n = 14). 2 weeks later, the function of normal and infarcted hearts with or without loading was evaluated by Langendorff perfusion model. The hearts were then harvested and prepared for the study of expression of MMPs and TIMPs. Developed pressure in the unloading group was higher than the loading group ( P = 0.0074). Unloading increased the ratio of TIMP-1-MMP-1(1.38 ± 0.11 vs. 0.76 ± 0.09, P < 0.05), TIMP-2-MMP-2 (1.06 ± 0.10 vs. 0.33 ± 0.07, P < 0.01), TIMP-3-MMP-9(1.07 ± 0.08 vs. 0.59 ± 0.06, P < 0.05). Although MMP-1, 2, 9 were downregulated ( P < 0.01, 0.01, 0.05, respectively), TIMP-2 and TIMP-3 upregulated ( P < 0.01, 0.05, respectively), MMP-7 and TIMP-1 was not affected significantly. The infarcted cardiac function could be improved by unloading. It was attributed to downregulation of MMP-1, 2 and 9, and upregulation of TIMP-2 and -3, and furthermore, the ratio of TIMPs to MMPs was increased, which might be more sensitive than sole MMPs or TIMPs for the judgment of myocardial matrix homeostasis. [ABSTRACT FROM AUTHOR]

Intermittent hypobaric hypoxia (IHH) preconditioning protects the heart against ischemic injuries. However, little is known about the therapeutic effect of IHH on myocardial infarction (MI). The aim of this study was to test whether IHH treatment influences infarct size and cardiac performance after MI. Seven days after sham operation or left anterior descending coronary artery ligation, male Sprague-Dawley rats were randomly exposed to normoxia or one 6-h period each day of IHH (5,000 m) for 14 and 28 days. Echocardiography analysis showed that IHH significantly reduced left ventricular (LV) dilation and improved cardiac performance after 14- or 28-day treatment compared with MI-normoxic groups. The improvement of LV function was further confirmed in isolated perfused MI-IHH hearts. Such protection was associated with attenuated infarct size, myocardial fibrosis, and apoptotic cardiomyocytes. IHH treatment also enhanced coronary flow and phosphorylation of heat shock protein 27 in both sham and MI groups compared with the control groups. In addition, IHH increased the capillary density and vascular endothelial growth factor expression in peri-infarcted zones compared with sham-IHH and MI-normoxic groups. Our data demonstrated for the first time that IHH treatment exerts a therapeutic effect on MI by attenuating progressive myocardial remodeling and improving myocardial contractility. IHH treatment might provide a unique and promising therapeutic approach for ischemic heart diseases. [ABSTRACT FROM AUTHOR]

To observe the dynamic changes of the TGF-β1 expressed in the infarct and non-infarcted region of rat heart during the ventricular remodeling (day 3, 7, 28, 180), myocardial infarction rat model was made and relationship between the cytokine and indicator of myocardial remodeling was analyzed. After the detection of hemodynamic parameter was performed by the Powerlab devices, the size of myocardial infarction and the morphology change was detected by TTC and HE, respectively. The relative levels of mRNA of TGF-β1, collagen type I, III, and fetal gene beta-MHC were detected by RT-PCR. The distribution of TGF-β1 protein in the myocardium was detected by immunohistochemistry. The results showed that the size of infarction was higher than that of the sham operated groups in the infarcted group (44.5±0.5 vs 0). The difference in hemodynamic parameters between the infarcted group and sham operated group was significant ( P<0.01). HE staining showed that inflammatory cells were accumulated in the infarcted region at the beginning of the 3rd day, which lasted 4 weeks. Then, it decreased gradually. β-MHC in the non-infarcted region rose from the 3rd day, reaching its peak at the 4th week, and it decreased gradually. The ratio of the collagen type I/III showed similar changes as compared with the sham operated groups ( P<0.01). And the relative mRNA levels in the non-infarcted group were significantly higher than that in the infarcted and sham operated group ( P<0.01) at day 180. Linear regression analysis indicated that the TGF-β1 was positively correlated with the ventricular remodeling. It was concluded that the cytokine TGF-β1 participates in the process of the myocardial remodeling, which could be a strategy in the interference of myocardial remodeling. [ABSTRACT FROM AUTHOR]

Myocardial remodeling in SHR rats with age-related hypertrophy was characterized by elimination of cardiomyocytes, their hypertrophy, and marked increase in the volume of the connective tissue. The count of cardiomyocytes with contracture injuries and subsegmental contractures increased, and pronounced perivascular and interstitial sclerosis developed in the hypertrophic myocardium of SHR rats. Damage to the microcirculatory bed manifested in degenerative changes and destruction of some endotheliocytes. Signs of atypical intracellular regeneration in myofibrils and impairment of their longitudinal orientation were revealed in cardiomyocytes in the late stage of compensatory hypertrophy. [ABSTRACT FROM AUTHOR]

Intervention with selective endothelin (ET)A receptor antagonists within 24 h after myocardial infarction (MI) in rats has been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ETA/ETB receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention with a mixed ETA/ETB receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg·kg-1 SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48 h after MI. Treatment with SB 209670 adversely affected the postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4 ± 0.5 vs 9.1 ± 0.2 mm; LV end-systolic diameter: 8.5 ± 0.4 vs 7.2 ± 0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention with a potent, mixed ETA/ETB receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical and that potent ET receptor antagonists may be harmful during the first few days after MI. [ABSTRACT FROM AUTHOR]

The aim of the study was to find out whether the changes in nutritional status induced by different litter size during early postnatal development can influence quantitative and qualitative protein remodeling and contractile performance of the myocardium. Male Wistar rats born at the same day were pooled together at 2 days postbirth and assigned by random selection to dams in groups of 4, 8 or 16 rats/litter. The animals were investigated at the age of 4 and 16 weeks. The results revealed that the early postnatal nutritional modification altered weight parameters: whereas lower heart weight persisted in slow-growing rats until 16 weeks, higher body weight of fast-growing rats returned to the control level at the age of 16 weeks. Altered nutritional status influenced also protein remodeling of the myocardium: the concentration of all noncollagenous proteins (fractions of metabolic and contractile proteins) significantly increased in slow-growing rats, on the other hand, the concentration of collagenous proteins (pepsin-soluble and -insoluble fractions) was higher in fast-growing animals. The changes were, however, only transitional: three months after the end of the weaning period most protein changes returned to the control level. However, higher concentration of total blood lipids and triglycerides in fast-growing rats persisted until adulthood. Nutritional changes had, however, only minor effect on ventricular performance. No differences among groups were observed in basal values of the left ventricular pressure, while the maximum pressure attained after an acute ventricular loading and the contractile reserve were significantly decreased in slowgrowing 4 week old rats. The functional consequence of altered nutritional status during weaning was only transitional, in agreement with the transient character of most structural and biochemical markers of myocardial remodeling. [ABSTRACT FROM AUTHOR]

Fibrosis is an established morphological feature of the structural myocardial remodeling that occurs in several cardiac diseases. This feature confers an increased risk for adverse cardiovascular events such as ventricular dysfunction and arrhythmias. The molecular mechanisms that lead to a fibrogenic cardiac phenotype are still being elucidated. A small number of studies have demonstrated that altered expression of several microRNAs (miRNAs) in myocardial fibrosis is associated with ischemia or mechanical overload; however, much work is still required to identify which miRNAs have a direct role in the development of fibrosis, and which develop alterations in expression that are secondary to the cardiac insult. Characterization of individual miRNAs or miRNA expression profiles that are specifically associated with myocardial fibrosis might allow us to develop diagnostic tools and innovative therapies for fibrogenic cardiac diseases. [ABSTRACT FROM AUTHOR]