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Background: The aim of this study was to develop an animal model to investigate whether prolonged intensive endurance exercise induces RV remodeling, taking into account the involvement of Wnt/β-catenin signaling., Methods: Four-week-old male Wistar rats (100 to 125 g) were assigned to four groups (n = 8/group): 1) sixteen weeks of intensive (36 m/min) exercise (INT), 2) twelve weeks of the intensive exercise followed by four weeks of moderate intensity (18 m/min) exercise (INT + MOD), 3) twelve weeks of the intensive exercise followed by four weeks of detraining (INT + DT), and 4) sedentary rats (SED). The exercise protocols were performed five days a week for one h/day. Echocardiography, real-time PCR, western blotting, and histological staining were performed at the end of week sixteen., Results: INT rats developed concentric hypertrophy without diastolic dysfunction compared to SED (p = 0.006) and INT + DT (p = 0.035). Wnt1, β-catenin and CyclinD1 proteins in the training groups were significantly higher than SED rats (p < 0.001). Interestingly, INT rats had higher protein levels than INT + DT and INT + MOD (p < 0.001), with higher gene expression compared to SED rats (p < 0.05). There was also a significant increase in collagen deposition in INT rats compared to SED (p = 0.046) and INT + DT (p = 0.034). Furthermore, INT + MOD and INT + DT rats did not show any adverse structural, functional, or histological changes., Conclusions: Long-term intensive endurance training seems to be associated with increased collagen deposition and wall thickness in the RV through Wnt/β-catenin signaling (which is concentration dependent), without changes in diastolic function., Clinical Perspective: Over the past decades, there has been an ongoing debate about whether the structural and functional adaptations of the cardiovascular system in trained endurance athletes are benign physiological responses to training or potentially pathological changes related to disease. While the adaptations of the left heart are well-documented, the remodeling of the right heart remains a subject of discussion. To gain insights into the ability of sustained high-intensity exercise to cause adverse right ventricular (RV) remodeling, we conducted an experimental study in which male rats were trained to run vigorously for 1 h daily over a 16-week period and compared them to a parallel group of sedentary control rats. Our findings revealed that intense long-term exercise induced morphological changes along with fibrosis affecting the RV. These fibrotic changes were a result of the 16-week vigorous exercise training regimen. If these results are confirmed in humans, they suggest that prolonged high-intensity endurance exercise training may lead to adverse cardiac remodeling. Our findings have important potential implications for the assessment of cardiac remodeling in individuals engaged in high-level exercise training., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Left ventricular lead positioning represents a key step in CRT optimization. However, evidence for its guidance based on specific topographical factors and related imaging techniques is sparse., Objective: To analyze reverse remodeling (RR) and clinical events in CRT recipients based on LV cathode (LVC) position relative to latest mechanical activation (LMA) and scar as determined by cardiac magnetic resonance (CMR)., Methods: This is a retrospective single-center study of 68 consecutive Q-LV-guided CRT-D and CRT-P recipients. Through CMR-based 3D reconstructions overlayed on fluoroscopy images, LVCs were stratified as concordant, adjacent, or discordant to LMA (3 segments with latest and greatest radial strain) and scar (segments with >50% scar transmurality). The primary endpoint of RR (expressed as percentage ESV change) and secondary composite endpoint of HF hospitalizations, LVAD/heart transplant, or cardiovascular death were compared across categories., Results: LVC proximity to LMA was associated with a progressive increase in RR (percentage ESV change: concordant -47.0 ± 5.9%, adjacent -31.4 ± 3.1%, discordant +0.4 ± 3.7%), while proximity to scar was associated with sharply decreasing RR (concordant +10.7 ± 12.9%, adjacent +0.3 ± 5.3%, discordant -31.3 ± 4.4%, no scar -35.4 ± 4.8%). 4 integrated classes of LVC position demonstrated a significant positive RR gradient the more optimal the category (class I -47.0 ± 5.9%, class II -34.9 ± 2.8%, class III -5.5 ± 4.3%, class IV + 3.4 ± 5.2%). Freedom from composite secondary endpoint of HF hospitalization, LVAD/heart transplant, or cardiovascular death confirmed these trends demonstrating significant differences across both integrated as well as individual LMA and scar categories., Conclusion: Integrated CMR-determined LVC position relative to LMA and scar stratifies response to CRT., Competing Interests: Declaration of competing interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Over the last 20 years, the scientific progresses in molecular biology and genetics in combination with the increasing use in the clinical setting of contrast-enhanced cardiac magnetic resonance (CMR) for morpho-functional imaging and structural myocardial tissue characterization have provided important new insights into our understanding of the distinctive aspects of cardiomyopathy, regarding both the genetic and biologic background and the clinical phenotypic features. This has led to the need of an appropriate revision and upgrading of current nosographic framework and pathobiological categorization of heart muscle disorders. This article proposes a new definition and classification of cardiomyopathies that rely on the combination of the distinctive pathobiological basis (genetics, molecular biology and pathology) and the clinical phenotypic pattern (morpho-functional and structural features), leading to the proposal of three different disease categories, each of either genetic or non-genetic etiology and characterized by a combined designation based on both "anatomic" and "functional" features, i.e., hypertrophic/restrictive (H/RC), dilated/hypokinetic (D/HC) and scarring/arrhythmogenic cardiomyopathy (S/AC). The clinical application of the newly proposed classification approach in the real-world practice appears crucial to design a targeted clinical management and evaluation of outcomes of affected patients. Although current treatment of cardiomyopathies is largely palliative and based on drugs, catheter ablation, device or surgical interventions aimed to prevent and manage heart failure and malignant arrhythmias, better knowledge of basic mechanisms involved in the onset and progression of pathobiologically different heart muscle diseases may allow to the development of disease-specific curative therapy., Competing Interests: Declaration of competing interest No disclosures., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vericiguat has demonstrated efficacy in improving the prognosis of patients with heart failure with reduced ejection fraction (HFrEF) following recent clinical deterioration. However, its real-world impact on reducing N-terminal B-type natriuretic peptide (NT-proBNP) levels and improving ventricular remodeling remains uncertain in stable HFrEF patients receiving guideline-directed medical therapy (GDMT) over the short term., Methods: This multicenter, observational cohort study included 200 HFrEF patients. Patients were grouped based on their preference for vericiguat use. We evaluated the impact of vericiguat on HFrEF patients by analyzing the difference in the proportion of patients with NT-proBNP levels ≤1000 pg/ml between two groups after a 6-month follow-up, using logistic regression and covariance analysis. Changes in echocardiographic parameters, left ventricular reverse remodeling (LVRR) ratio, and safety outcomes were also evaluated., Results: During the 6-month follow-up, 105 patients (82.68 %) in the vericiguat group and 46 patients (63.01 %) in the control group reached the primary endpoint. Multivariate logistic regression confirmed vericiguat as a significant factor in reducing NT-proBNP levels (Model 2: odds ratio (OR) = 2.67, 95 % confidence interval (CI): 1.24-5.77, P = 0.013), but it showed no significant association with LVRR (Model 2: OR = 0.52, 95 % CI: 0.24-1.13, P = 0.097). The safety analysis indicated a higher incidence of mild to moderate gastrointestinal symptoms in the vericiguat group compared to the control group (23.62 % vs. 2.74 %, P < 0.001)., Conclusions: Vericiguat significantly reduced NT-proBNP levels in patients with chronic HErEF under GDMT but was ineffective for LVRR during the 6-month follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Functional abnormalities of the ascending aorta (AA) have been mainly reported in young patients who underwent arterial switch operation (ASO) for transposition of the great arteries (TGA)., Objectives: To compare systolic, diastolic brachial and central blood pressures (bSBP, bDBP, cSBP, cDBP), aortic biomechanical parameters, and left ventricular (LV) afterload criteria in adult ASO patients with healthy controls and to assess their relationships with LV remodeling and aortic size., Materials and Methods: Forty-one prospectively enrolled patients (16.8 to 35.8 years) and 41 age- and sex-matched healthy volunteers underwent cardiac MRI to assess LV remodeling with simultaneous brachial BP estimation. After MRI, carotid-femoral tonometry was performed to measure pulse wave velocity (cfPWV), cSBP and cDBP for further calculation of pulse pressure (cPP), AA distensibility (AA D ), and AA and LV elastance (AA E , LV E )., Results: bSBP, bDBP, cSBP,cDBP and cPP were all significantly higher in ASO group than in controls: cSBP (116.5 ± 13.8 vs 106.1 ± 12.0, p < 0.001), cDBP (72.5 ± 6.9 vs 67.1 ± 9.4, p = 0.002), cPP (44.0 ± 12.1 vs 39.1 ± 8.9, p = 0.003) and not related to aortic size. AA D were decreased in ASO patients vs controls (4.70 ± 2.72 vs 6.69 ± 2.16, p < 0.001). LV mass was correlated with bSBP, cSBP, cPP (ρ = 0.48; p < 0.001), while concentric LV remodeling was correlated with AA E (ρ = 0.60, p < 0.001) and LV E (ρ = 0.32, p = 0.04), but not with distensibility., Conclusion: Even without reaching arterial hypertension, aortic sBP and PP are increased in the adult TGA population after ASO, altering the pulsatile components of afterload and contributing to LV concentric remodeling., (Copyright © 2023. Published by Elsevier B.V.)

Background: Understanding the macroscopic biventricular changes induced by pulmonary artery banding (PAB) in children with dilated cardiomyopathy (DCM) represents the first step to unraveling the regenerative potential of the myocardium. We herein investigated the phases of left ventricular (LV) rehabilitation in PAB responders, using a systematic echocardiographic and cardiac magnetic imaging (CMRI) surveillance protocol., Methods: We prospectively enrolled all patients with DCM treated with PAB from September-2015 at our institution. Among 9 patients, 7 positively responded to PAB and were selected. Transthoracic 2D echocardiography was performed before PAB; and 30, 60, 90, and 120 days after PAB; and at the last available follow-up. CMRI was performed before PAB (whenever possible) and one year after PAB., Results: In PAB responders, LV ejection fraction showed a modest 10% increase 30-60 days after PAB, followed by its almost complete normalization after 120  days (median of 20[10-26]% vs 56[44.5-63.5]%, at baseline and 120 days after PAB, respectively). Parallelly, the LV end-diastolic volume decreased from a median of 146(87-204)ml/m2 to 48(40-50)ml/m2. At the last available follow-up (median of 1.5 years from PAB), both echocardiography and CMRI showed a sustained positive LV response, although myocardial fibrosis was detected in all patients., Conclusions: Echocardiography and CMRI show that PAB can promote a LV remodeling process, which starts slowly and can culminate in the normalization of LV contractility and dimensions 4 months later. These results are maintained up to 1.5 years. However, CMRI showed residual fibrosis as evidence of a past inflammatory injury whose prognostic significance is still uncertain., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Echocardiographic assessment of adolescent athletes for arrhythmogenic cardiomyopathy (ACM) can be challenging owing to right ventricular (RV) exercise-related remodelling, particularly RV outflow tract (RVOT) dilation. The aim of this study is to evaluate the role of RV 2-D speckle tracking echocardiography (STE) in comparing healthy adolescent athletes with and without RVOT dilation to patients with ACM., Methods and Results: A total of 391 adolescent athletes, mean age 14.5 ± 1.7 years, evaluated at three sports academies between 2014 and 2019 were included, and compared to previously reported ACM patients (n = 38 definite and n = 39 borderline). Peak systolic RV free wall (RVFW-S l ), global and segmental strain (S l ), and corresponding strain rates (SR l ) were calculated. The participants meeting the major modified Task Force Criteria (mTFC) for RVOT dilation were defined as mTFC+ (n = 58, 14.8%), and the rest as mTFC- (n = 333, 85.2%). Mean RVFW-S l was -27.6 ± 3.4% overall, -28.2 ± 4.1% in the mTFC+ group and - 27.5 ± 3.3% in the mTFC- group. mTFC+ athletes had normal RV-FW-S l when compared to definite (-29% vs -19%, p < 0.001) and borderline ACM (-29% vs -21%, p < 0.001) cohorts. In addition, all mean global and regional S l and SR l values were no worse in the mTFC+ group compared to the mTFC- (p values range < 0.0001 to 0.1, inferiority margin of 2% and 0.1 s -1 respectively)., Conclusions: In athletes with RVOT dilation meeting the major mTFC, STE evaluation of the RV can demostrate normal function and differentiate physiological remodelling from pathological changes found in ACM, improving screening in grey-area cases., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Right ventricular (RV) afterload in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is associated with reduced myocardial contractility and ventriculoarterial coupling. The impact of increased afterload on RV myocardial deformation was assessed by comparing the characteristics of CTEPH patients to healthy controls at baseline, and by comparing characteristics of CTEPH patients before and 12 months after pulmonary endarterectomy (PEA)., Methods: Cardiac deformation and function of CTEPH patients (n = 20) and healthy controls (n = 20) were assessed by cardiac magnetic resonance (CMR). CTEPH patients were also examined with right heart catheterization before and 12 months after PEA., Results: PEA resulted in significant improvement of invasive hemodynamics and normalization of RV hypertrophy and right atrial, RV and left ventricular dimensions and volumes. RV ejection fraction improved from 30 ± 13% at baseline to 44 ± 10% at 12 months (p < 0.0001) but remained decreased compared with control subjects (54 ± 4%, p < 0.05). RV global circumferential strain (GCS) normalized 12 months after PEA, but RV global longitudinal strain (GLS) remained significantly lower in CTEPH patients than controls (baseline -12.9 ± 3.3% vs. -16.5 ± 3.6% at 12 months p < 0.01, vs. controls -19.3 ± 3.2%, p < 0.05). RV mass changes were significantly correlated with RV-ejection fraction, RV-GLS, and RV-GCS. RV-pulmonary arterial coupling with the volume method improved at 12 months (0.49 ± 0.30 vs. 0.84 ± 0.31, p < 0.0005), but remained significantly reduced compared with healthy controls (1.19 ± 0.20, p < 0.0005)., Conclusion: RV global longitudinal and circumferential myocardial three-dimensional strain by CMR improved significantly in CTEPH patients 12 months after PEA. Improvements in myocardial deformation were associated with regression of RV hypertrophy and decrease in pulmonary artery pressure., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Right ventricular (RV) failure due to pressure load is an important determinant of clinical outcome in pulmonary hypertension, congenital heart disease and left ventricular failure. The last decades it has become clear that metabolic dysregulation is associated with the development of RV-failure. However, underlying mechanisms remain to be unraveled. Recently, disruption of intracardiac lipid content has been suggested as potential inducer of RV failure. In the present study, we used a rat model of RV-dysfunction and aimed to obtain insight in temporal changes in RV-function, -remodelling and -metabolism and relate this to RV lipid content., Methods and Results: Male Wistar WU rats were subjected to pulmonary artery banding (n = 25) or sham surgery (n = 14) and cellular, hemodynamic and metabolic assessments took place after 2, 5 and 12 weeks. In this model RV dysfunction and remodelling occurred, including early upregulation of oxidative stress markers. After 12 weeks of pressure load, lipidomics revealed significant decreases of myocardial diglycerides and cardiolipins, driven by (poly-)unsaturated forms. The decrease of cardiolipins was driven by its most abundant form, tetralinoleoylcardiolipin. Mitochondrial capacity for fatty acid oxidation preserved, while the capacity for glucose oxidation increased., Conclusion: RV dysfunction due to pressure load, is associated with decreased intracardiac unsaturated lipids, especially tetralinoleoylcardiolipin. This was accompanied with preserved mitochondrial capacity regarding fatty acids oxidation, with increased capacity for glucose oxidation, and early activation of oxidative stress. We suggest that early interventions should be directed towards preservation of lipid availability as possible mean in order to prevent RV failure., (Copyright © 2019. Published by Elsevier B.V.)

Background: Left ventricular (LV) wall thickening relative to the LV radius, known as a concentric LV structure, is a mechanism that compensates for pressure overload and is related to the risk of cardiovascular events and heart failure. The prognostic value of a concentric LV structure, however, has not been examined in acute decompensated heart failure (ADHF)., Methods: This single-center, observational, retrospective, cohort study analyzed 385 consecutive patients hospitalized due to ADHF. On hospital admission, relative wall thickness (RWT) and the ratio of LV mass to LV end-diastolic volume (LVM/LVEDV) were measured by transthoracic echocardiography as markers of a concentric LV structure. The association of either RWT or LVM/LVEDV with all-cause death as the primary outcome was analyzed., Results: During the follow-up period (median, 235 days), 95 (25%) patients died. The high-RWT group had a poorer prognosis than the low-RWT group (log-rank test, P = 0.009). High RWT was a significant risk (HR: 1.95, 95% CI: 1.28-2.97, P = 0.002) in the Cox proportional hazard model analysis adjusted by the Get With The Guideline score, which is an established risk score. In contrast, there was no significant difference in survival between the low and high-LVM/LVEDV groups (P = 0.42). In the non-severe valvular disease subgroup, patients with high RWT consistently showed worse survival than the low-RWT group (P = 0.028 by log-rank test, HR: 1.96, 95% CI: 1.24-3.11, P = 0.004). There was no significant difference in survival between the low and high-LVM/LVEDV groups (P = 0.42)., Conclusions: A concentric LV structure represented by a high RWT was associated with a poor prognosis in ADHF. The lack of association between LVM/LVEDV and mortality may result from methodological issues., (Copyright © 2018. Published by Elsevier B.V.)

The local inflammatory response following acute myocardial infarction (AMI) is increasingly being recognized as a central factor determining infarct healing. Myocardial inflammation can be visualized in patients using fasting 18 F-FDG PET/MRI. Although this novel biosignal correlates with long-term functional outcome, the corresponding cellular substrate is not well understood. Here we present a retrospective analysis of 29 patients with AMI who underwent revascularization, suggesting a connection between post infarction myocardial fasting 18 F-FDG uptake, monocyte platelet aggregates (MPA), and P2Y 12 inhibition. In detail, patients with high MPA percentages of CD14 high CD16 + and CD14 low CD16 + monocytes had significantly higher local 18 F-FDG uptake (SUV mean ) in the infarcted myocardium than patients with low MPA (p < 0.05). Furthermore, there was an association of high MPA percentage in all monocyte subpopulations with deteriorating ΔLV-EF after 6 months (p < 0.01), which was confirmed in an extended analysis with additional 29 patients without PET/MRI data available. In this analysis, administration of Ticagrelor was associated with lower MPA percentage of CD14 high monocyte subpopulations than Clopidogrel (p < 0.01) or Prasugrel (p < 0.05). Taken together, the findings from this analysis suggest that platelet aggregability may affect monocyte extravasation into the infarcted myocardium and influence long-term functional outcome. P2Y 12 inhibition may intervene in this pathophysiologic process. Prospective studies are needed to further examine this important relationship., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Remote ischemic conditioning (RIC) is considered a potential clinical approach to reduce myocardial infarct size and ameliorate adverse post-infarct left ventricular (LV) remodeling, however the mechanisms are unknown. The aim was to clarify the impact of RIC on Neuregulin-1 (NRG-1)/ErbBs expression, inflammation and LV hemodynamic function., Methods and Results: Male Sprague-Dawley rats were subjected to 30 min occlusion of the left coronary artery (LCA) followed by 2 weeks of reperfusion and separated into three groups: (1) sham operated (without LCA occlusion); (2) Myocardial ischemia/reperfusion (MIR) and (3) remote ischemic perconditioning group (MIR + RIPerc). Cardiac structural and functional changes were evaluated by echocardiography and on the isolated working heart system. The level of H3K4me3 at the NRG-1 promoter, and both plasma and LV tissue levels of NRG-1 were assessed. The expression of pro-inflammatory cytokines, ECM components and ErbB receptors were assessed by RT-qPCR. MIR resulted in a significant decrease in LV function and enlargement of LV chamber. This was accompanied with a decrease in the level of H3K4me3 at the NRG-1 promoter. Consequently NRG-1 protein levels were reduced in the infarcted myocardium. Subsequently, an upregulated influx of CD68+ macrophages, high expression of MMP-2 and -9 as well as an increase of IL-1β, TLR-4, TNF-α, TNC expression were observed. In contrast, RIPerc significantly decreased inflammation and improved LV function in association with the enhancement of NRG-1 levels and ErbB3 expression., Conclusions: These findings may reveal a novel anti-remodeling and anti-inflammatory effect of RIPerc, involving activation of NRG-1/ErbB3 signaling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Myocardial infarction (MI) is a common cardiovascular disease caused by myocardial ischemia. Also, microRNA (miRNA) participates in the pathophysiology of many cardiovascular diseases, which can affect stem cell transplantation in the treatment of MI. In this study, our aim is to explore effect of miR-26b on inflammatory response and myocardial remodeling through the MAPK pathway by targeting PTGS2 in mice with MI., Methods: Microarray data analysis was conducted to screen MI-related differentially expressed gens (DEGs). Relationship between miR-26b and PTGS2 was testified. Cardiac function, inflammatory reaction, infarct size, and myocardial fibrosis were observed. The miR-26b expression and mRNA and protein levels of, PTGS2, ERK, JNK and p38 and Bcl-2/Bax were examined. The effect of miR-26b on cell apoptosis was also analyzed., Results: MiR-26b was predicted to target PTGS2 further to mediate the MAPK pathway, thus affecting MI. MiR-26b negatively targeted PTGS2. MI mice showed decreased cardiac function, as well as increased inflammatory reaction, myocardial injury, area of fibrosis and myocardial cell apoptosis. After injection of miR-26b agomir or NS-398 (PTGS2 inhibitor), inflammatory response of MI mice was attenuated and myocardial remodeling induced by MI was alleviated., Conclusion: These findings indicate that miR-26b inhibits PTGS2 to activate the MAPK pathway, so as to reduce inflammatory response and improve myocardial remodeling in mice with MI., (Copyright © 2019. Published by Elsevier B.V.)

Background: CD4 + T cells are key players in regulating the inflammatory processes and physiological repair mechanisms engaged after acute myocardial infarction (AMI). Although signaling through the CD27-CD70 co-stimulatory pathway are known to be important in CD4 + T cell activation and proliferation in certain contexts, the role of the CD27-CD70 pathway in AMI remains unclear., Methods and Results: A total of 43 control subjects, 42 unstable angina patients, and 90 AMI patients were enrolled in the present study. The serum levels of soluble CD27 (sCD27) in patients were measured, revealing a significant increase in serum sCD27 levels in AMI patients within 24 h of the cardiac event, after which they decreased. Correlation analyses revealed that serum sCD27 was positively correlated with cardiac troponin I (c-TnI) (r = 0.267, P = 0.011). When anti-CD70 antibody was used to block the CD27-CD70 pathway in MI model mice, we found that this treatment increased left ventricular end-diastolic dimension (LVEDD) (P < 0.01) and left ventricular end-systolic dimension (LVESD) (P < 0.01), and decreased ejection fraction (P < 0.01). Flow cytometric analysis revealed that the percentage of regulatory T cells was lower in blocking antibody-treated mice (P < 0.01), while neutrophils levels were higher (P < 0.01). The number of CD31-positive endothelial cells (P = 0.026) and α-smooth muscle actin-positive arterioles (P < 0.01) were significantly down-regulated in anti-CD70 treated-AMI mice. The formation of the extracellular matrix (ECM) was also impaired., Conclusion: Serum sCD27 may be a potential biomarker for AMI. Blockade of the CD27-CD70 pathway worsens cardiac dysfunction, aggravates left ventricular remodeling, and impairs scar healing after AMI, resulting in heart failure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cardiac remodeling is the response of the heart to a range of pathological stimuli. Cardiac remodeling is initially adaptive; however, if sustained, it ultimately causes adverse clinical outcomes. Cardiomyocyte loss or hypertrophy, inflammation and fibrosis are hallmarks of cardiac remodeling. Proteoglycans, which are composed of glycosaminoglycans and a core protein, are a non-structural component of the extracellular matrix. The lack of proteoglycans results in cardiovascular defects during development. Moreover, emerging evidence has indicated that proteoglycans act as significant modifiers in ischemia and pressure overload-related cardiac remodeling. Proteoglycans may also provide novel therapeutic strategies for further improvement in the prognosis of cardiovascular diseases., (Copyright © 2018. Published by Elsevier B.V.)

Background: Although exercise-induced cardiac hypertrophy has been intensively investigated, its development and regression dynamics have not been comprehensively described. In the current study, we aimed to characterize the effects of regular exercise training and detraining on left ventricular (LV) morphology and function., Methods: Rats were divided into exercised (n = 12) and control (n = 12) groups. Exercised rats swam 200 min/day for 12 weeks. After completion of the training protocol, rats remained sedentary for 8 weeks (detraining period). Echocardiographic follow-up was performed regularly to obtain LV long- and short-axis recordings for speckle-tracking echocardiography analysis. Global longitudinal and circumferential strain and systolic strain rate were measured. LV pressure-volume analysis was performed using additional groups of rats to obtain haemodynamic data., Results: Echocardiographic examinations showed the development of LV hypertrophy in the exercised group. These differences disappeared during the detraining period. Strain and strain rate values were all increased after the training period, whereas supernormal values rapidly reversed to the control level after training cessation. Load-independent haemodynamic indices, e.g., preload recruitable stroke work, confirmed the exercise-induced systolic improvement and complete regression after detraining., Conclusions and Translational Aspect: Our results provide the first comprehensive data to describe the development and regression dynamics of morphological and functional aspects of physiological hypertrophy in detail. Speckle-tracking echocardiography has been proven to be feasible to follow-up changes induced by exercise training and detraining and might provide an early possibility to differentiate between physiological and pathological conditions., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: We investigated the effects of human amniotic fluid stem cells (hAFS) and rat adipose tissue stromal vascular fraction GFP-positive cells (rSVC-GFP) in a model of cardio-renal syndrome type II (CRSII)., Methods and Results: RHF was induced by monocrotaline (MCT) in 28 Sprague-Dawley rats. Three weeks later, four million hAFS or rSVC-GFP cells were injected via tail vein. BNP, sCreatinine, kidney and heart NGAL and MMP9, sCytokines, kidney and heart apoptosis and cells (Cs) engraftment were evaluated. Cell-treated rats showed a significant reduction of serum NGAL and Creatinine compared to CRSII. In both hAFS and rSVC-GFP group, kidney protein expression of NGAL was significantly lower than in CRSII (hAFS p = 0.036 and rSVC-GFP p < 0.0001) and similar to that of controls. In both hAFS and rSVC-GFP treated rats, we observed cell engraftment in the medulla and differentiation into tubular, endothelial and SMCs cells. Apoptosis was significantly decreased in cell-treated rats (hAFS 14.07 ± 1.38 and rSVC-GFP 12.67 ± 2.96 cells/mm 2 ) and similar to controls (9.85 ± 2.1 cell/mm 2 ). TUNEL-positive cells were mainly located in the kidney medulla. Pro-inflammatory cytokines were down regulated in cell-treated groups and similar to controls. In cell-treated rats, kidney and heart tissue NGAL was not complexed with MMP9 as in CRSII group, suggesting inhibition of MMPs activity., Conclusion: Cell therapy produced improvement in kidney function in rats with CRSII. This was the result of interstitial, vessel and tubular cell engraftment leading to tubular and vessel regeneration, decreased tubular cells apoptosis and mitigated pro-inflammatory milieu. Reduction of NGLA-MMP9 complexes mainly due to decrease MMPs activity prevented further negative heart remodeling., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: A reason for concentric left ventricular (LV) remodelling predicting cardiovascular outcomes independent of conventional risk factors and LV mass (LVM) has not been provided. We hypothesized that independent of LVM, concentric LV remodelling is associated with inflammatory changes rather than a pressure load on the LV., Methods: In 764 randomly selected community participants, we assessed relations between several inflammatory markers (ELISA) and LV relative wall thickness (RWT) (echocardiography), LV mass index (LVMI), and indexes of diastolic function., Results: No independent relations were noted between circulating concentrations of inflammatory markers and LVM index (LVMI) (p > 0.13 for all). However, independent of confounders including LVMI and blood pressure (BP), circulating tumour necrosis factor-α (TNF-α) (partial r = 0.14, p < 0.0005) and to a lesser degree interleukin-6 (partial r = -0.09, p < 0.02) were associated with RWT. The impact (standardized β-coefficient) of TNF-α on RWT (0.12 ± 0.03, p < 0.0005) was at least as strong as age (0.13 ± 0.05, p < 0.005), and second only to LVMI (0.27 ± 0.04, p < 0.0001), whilst neither office, 24-hour, central aortic BP, nor aortic stiffness were associated with RWT independent of LVMI. With adjustments, as compared to participants with a normal LVMI and geometry (12.7 ± 0.8), circulating TNF-α concentrations (pg/ml) were increased as much in participants with concentric LV remodelling (16.8 ± 1.5, p < 0.05) as in those with concentric LV hypertrophy (LVH) (17.0 ± 1.3, p < 0.005), whilst eccentric LVH (13.7 ± 0.9) was not. No independent relations between inflammatory markers and LV diastolic function (trans-mitral and tissue Doppler) were noted., Conclusions: Independent of LVMI, a pro-inflammatory state rather than BP load is strongly associated with LV concentric remodelling., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner., Methods: CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up., Results: In the test cohort, CDKN1C was lower in patients with a reduced EF (<40%) compared to patients with preserved EF (≥50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort., Conclusion: CDKN1C is a novel female-specific biomarker of LV function after AMI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Left ventricular (LV) remodeling remains unknown in patients with acute Type B aortic dissection (aTBAD) after thoracic endovascular aortic repair (TEVAR) during follow-up., Methods: Between May 2004 and January 2016, 163 consecutive patients (136 males, mean preoperative age: 51.06 ± 10.79 years) with aTBAD underwent TEVAR. A linear mixed model was used to evaluate risk factor influencing on LV remodeling and investigate longitudinal changes in LV thickness, diameter, volume, function and mass at preoperation, postoperation, short- and mid-term follow-up., Results: Median follow-up time was 48.0 months (quartiles 1-3, 31-84 months, maximum 147 months). LV thickness and mass followed a continuous downward trend over time. Interventricular septal thickness at end-diastole significantly decreased at mid-term follow-up (time, p < 0.001: preoperative 11.59 ± 0.14 mm vs mid-term 10.82 ± 0.15 mm, p < 0.001; postoperative 11.40 ± 0.14 mm vs mid-term 10.82 ± 0.15 mm, p = 0.006). LV posterior wall thickness at end-diastole was markedly reduced at mid-term follow-up (time, p < 0.001: preoperative 10.89 ± 0.11 mm vs mid-term 10.02 ± 0.11 mm, p < 0.001; postoperative 10.78 ± 0.13 mm vs mid-term 10.02 ± 0.11 mm, p < 0.001; short-term 10.56 ± 0.15 mm vs mid-term 10.02 ± 0.11 mm, p = 0.021). LV mass index markedly decreased during follow-up (time, p = 0.001: preoperative 129.60 ± 3.55 g/m 2 vs short-term 119.26 ± 3.19 g/m 2 , p = 0.009; preoperative 129.60 ± 3.55 g/m 2 vs mid-term 115.79 ± 3.62 g/m 2 , p = 0.003). LV function was improved, but not significantly so, during follow-up. Strict blood pressure control had no influence on LV remodeling. True lumen followed a continuous enlargement trend in terms of proximal thoracic aorta and celiac trunk level during follow-up., Conclusions: TEVAR can reverse LV remodeling and LV hypertrophy in patients with aTBAD during follow-up., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Previous studies have suggested that cytokines and growth factors may predict ventricular recovery following aortic valve replacement (AVR). The primary objective of this study was to identify cytokines that predict ventricular recovery following transcatheter AVR (TAVR)., Methods: We prospectively enrolled 121 consecutive patients who underwent TAVR. Standard echocardiographic assessment at baseline, 1-month and 1-year after TAVR included left ventricular (LV) mass index (LVMI) and global longitudinal strain (GLS). Blood samples were obtained at the time of the procedure to measure cytokines using a 63-plex Luminex platform. Partial least squares-discriminant analysis was performed to identify cytokines associated with ventricular remodeling and function at baseline as well as 1 year after TAVR., Results: The mean age was 84 ± 9 years, with a majority of male subjects (59%), a mean LVMI of 120.4 ± 45.1 g/m 2 and LVGLS of -13.0 ± 3.2%. On average, LV mass decreased by 8.1% and GLS improved by 20.3% at 1 year following TAVR. Among cytokines assayed, elevated hepatocyte growth factor (HGF) emerged as a common factor significantly associated with worse baseline LVMI and GLS as well as reduced ventricular recovery (p < 0.005). Other factors associated with ventricular recovery included a select group of vascular growth factors, inflammatory mediators and tumor necrosis factors, including VEGF-D, ICAM-1, TNFβ, and IL1β., Conclusion: We identified a network of cytokines, including HGF, that are significantly correlated with baseline LVMI and GLS, and ventricular recovery following TAVR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The association of soluble interleukin-1 receptor-like 1 (ST2) with left ventricular (LV) remodeling is unclear in patients with a first ST-segment elevation myocardial infarction (STEMI). The objective of this work was to assess the relationship between ST2, a marker of inflammation, and cardiac magnetic resonance (CMR) imaging-derived LV remodeling after a first STEMI., Methods: We prospectively evaluated 109 patients with a first STEMI treated with primary percutaneous coronary intervention who had ST2 assessed 24 h post-reperfusion. All patients underwent CMR imaging 1 week and 6 months after STEMI. The independent associations between ST2, LV diastolic and systolic volume indices, and LV ejection fraction (LVEF) were evaluated by linear mixed models., Results: The mean age of the sample was 59 ± 12 years, 85 patients (78%) were male, and 13 (11.9%) had a LVEF ≤40%. The median (IQR) of ST2 was 55.3 (38.7-94.1) pg/mL. At 1-week CMR higher ST2 was related to more infarct size and less myocardial salvage index (p < 0.01). Overall, after comprehensive multivariable adjustment, higher baseline ST2 was associated with progressive LV volume indices dilation and LVEF deterioration (p < 0.05). This effect was stronger in patients with severe 1-week structural damage, namely those with large infarct size, extensive microvascular obstruction or LVEF ≤40%., Conclusions: In patients with a first STEMI treated with primary percutaneous coronary intervention, soluble ST2 predicts dynamic changes in CMR-derived LV volumes and LVEF. Future studies must assess whether targeting interleukin-1 leads to lower ST2 levels and less LV remodeling., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Milk thistle (Silybum marianum; SM) is an herb commonly used for hepatoprotection with antioxidant and antifibrotic properties. We investigated in pigs the cardiac effects of SM intake during the acute phase of myocardial infarction (MI) and remodeling period post-MI., Methods: Study-1 tested the effect of SM use on the acute phase of MI. Hence, animals were distributed to a control group or to receive SM prior infarction (1.5 h ischemia). Animals were sacrificed after 2.5 h of reperfusion. Study-2 tested the effect of SM use in the cardiac remodeling phase. Accordingly, animals received for 10 d diet ± SM prior MI and followed the same regime for 3 weeks and then sacrificed. Study-3 tested the effect of SM in a non-infarcted heart; therefore, animals received for 10 d diet ± SM and then sacrificed., Results: Animals taking SM before MI showed a reduction in cardiac damage (decreased oxidative damage, ROS production and xanthine oxidase levels; preserved mitochondrial function; and increased myocardial salvage; p < 0.05) versus controls. Animals that remained on chronic SM intake post-MI improved left ventricular remodeling. This was associated with the attenuation of the TGFß 1 /TßRs/SMAD2/3 signaling, lower myofibroblast transdifferentiation and collagen content in the border zone (p < 0.05 vs. all other groups). Cardiac contractility improved in animals taking SM (p < 0.05 vs. post-MI-control). No changes in cardiac function or fibrosis were detected in animals on SM but without MI., Conclusion: Intake of SM protects the heart against the deleterious effects of an MI and favors cardiac healing. These benefits may be attributed to the antioxidant and antifibrotic properties of SM., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1α and IL-1β are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling., Methods: Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n = 65)., Results: IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates., Conclusion: Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Right ventricular (RV) dysfunction is recognized as a cardinal prognostic marker in systolic heart failure patients. Conflicting data exist on the interaction of RV function and left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT). This prospective monocentric trial was set up to assess the predictive value of baseline RV function and corresponding RV-pulmonary artery (PA) coupling on LV reverse remodeling after CRT., Methods: 110 patients with a CRT indication were prospectively enrolled. RV function and RV-PA interaction were analyzed at baseline using echocardiographic and invasive pressure-volume loop catheter approach. The primary endpoint was reverse LV remodeling (CRT-responder) defined as a reduction in LV end-systolic volume of ≥15% at 6 months., Results: Responders had higher RV-PA coupling ratios (single-beat end-systolic elastance/PA elastance: Ees/Ea) at baseline, which corresponded to smaller RVs with better ejection fraction and lower afterload. After multivariate adjustment, the baseline Ees/Ea remained an independent predictor for LV response (OR 14.0 [1.5-130.8], p = 0.021). Normal coupling (Ees/Ea ≥ 1) was associated with higher responder rates (RR) (86%). Progressive uncoupling was associated with lower LV-RR (Ees/Ea ≤ 1-0.5: 57%, and Ees/Ea < 0.5: 32%, p < 0.001), corresponded with higher degrees of LV impairment and severity of mitral regurgitation, and was independently associated with an adverse outcome., Conclusions: A higher baseline RV-PA coupling, reflecting a lower degree of LV-induced pulmonary hypertension and secondary RV-dysfunction, is associated with an improved LV-reverse remodeling and is independently associated with better prognosis. The value of RV-PA ratio as potential guide for CRT patient selection warrants further investigation. Clinical Trial Registration - URL: http://www.drks.de. Unique Identifier: DRKS00011133., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Women represent approximately half of heart failure hospitalizations and are disproportionately affected by heart failure with preserved ejection fraction (HFpEF). Women with signs and symptoms of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD) often have elevated left ventricular end-diastolic pressure (LVEDP). However, isolated elevated LVEDP in the absence of coronary microvascular dysfunction (CMD) is not understood., Methods: Among 244 women with signs and symptoms of ischemia, no obstructive CAD, and preserved LVEF who underwent invasive coronary reactivity testing (CRT), 43 (18%) women had no evidence of CMD. LVEDP was measured at time of CRT, and left ventricular (LV) volumes and mass were assessed by cardiac magnetic resonance (CMR) imaging., Results: Of the 43 women without CMD, 24 (56%) had elevated LVEDP [mean 18 mm Hg (SD = 3)] compared to 19 (44%) with normal LVEDP [11 mm Hg (SD = 3)]. The elevated LVEDP group had a comparatively higher systolic and diastolic blood pressure, lower LV end-diastolic volume index (EDVI), and higher mass-to-volume ratio. Other functional parameters were not significantly different., Conclusions: Among women with signs and symptoms of ischemia without obstructive CAD, absence of CMD, and preserved LVEF, isolated elevated LVEDP is associated with a significantly higher systolic and diastolic blood pressure, higher LV mass-to-volume ratio and lower LV EDVI. These results suggest these women have maladaptive remodeling to blood pressure. Given the relatively high prevalence of HFpEF in women, these hypothesis-generating results suggest that further study of ventricular remodeling is warranted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To identify the frequency and significance of notched T-waves (NTW) in elite endurance athletes., Methods: Professional cyclists were followed for 4 years with a clinical, electrocardiographic and echocardiographic assessment. Electrocardiograms were classified according to the presence or absence of NTWs; clinical and echocardiographic correlates were assessed., Results: 42 Caucasian male cyclists were included. NTW were detected in 8 (19%) cyclists who showed significantly longer QT (461 ± 15 vs 422 ± 33 ms, p < 0.01) and QTc intervals (434 ± 19 vs 383 ± 21 ms, p < 0.01), a larger left ventricular end-diastolic volume (163 ± 27 vs 137 ± 23 mL, p = 0.014), end-diastolic volume index (84 ± 13 vs 73 ± 11 mL, p = 0.037) and end-diastolic apex-to-base length (9.9 ± 0.7 vs 9.3 ± 0.5 mm. p = 0.035). There were no detected arrhythmic events, and echocardiography did not reveal any abnormalities., Conclusions: This is to our knowledge the first study reporting a high prevalence of NTW in athletes. In our small cohort of cyclists NTW were associated with QT interval prolongation and left ventricular changes. This may be indicative of underlying inhomogeneity of repolarisation. Expanding on this research could reveal a role for NTW in identifying ventricular morphological changes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patients with severe aortic stenosis (AS) are subjected to left ventricular hypertrophy (LVH) with increasing morbidity and mortality. Transcatheter aortic valve replacement (TAVR) induces reverse left ventricular remodeling which can be monitored by cardiovascular magnetic resonance (CMR). CMR is able to analyze myocardial tissue properties by magnetic relaxation times (parametric CMR). The objective of this study was to study myocardial T2 relaxation in reverse ventricular remodeling after TAVR., Methods: Forty-three patients with severe AS (19 males, 81.9 ± 4.9 years) underwent CMR with T2 mapping before and 6 months after TAVR. A cohort of age- and gender-matched volunteers served as controls. Analyzed parameters included left ventricular ejection fraction (LV-EF), mass indexed to body surface area (LVMi), interventricular septum thickness (IVS), end-diastolic volume (LVEDV), global longitudinal strain (GLS), peak diastolic strain rate (SRe) and myocardial T2 values., Results: CMR characteristics for patients with AS displayed LVH concomitant to elevated myocardial T2 values, reduced GLS and SRe. Patients with T2 values above 70.2 ms at baseline were characterized by eccentric hypertrophy with reduced LV-EF. T2 values decreased after TAVR (67.4 ± 3.4 to 63.3 ± 4.2 ms, p < 0.01) during left ventricular remodeling. Patients with T2 values above 70.2 ms at baseline exhibited pronounced reverse remodeling which proved to be a significant predictor of LV-EF improvement and LVEDV reduction in uni- and multivariate analyses., Conclusions: Multiparametric CMR can be used to characterize myocardial hypertrophy due to severe AS and to monitor myocardial adaptations after TAVR. It may provide additional information in the prediction of left ventricular remodeling after TAVR., (Copyright © 2018. Published by Elsevier B.V.)

Background: Plasma Galectin-3 is a marker of myocardial inflammation and fibrosis, was associated with left ventricular (LV) reverse remodeling after conventional surgical mitral valve repair (MVR) and predicted clinical events in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to evaluate the association between pre-interventional Galectin-3 levels and (1) reverse LV remodeling and (2) major adverse cardiovascular events (MACE) in patients undergoing percutaneous MVR., Methods: Forty-four consecutive patients (median age 79 years, LV ejection fraction 39.5 ± 11.4%, 91% in NYHA functional class ≥III) with symptomatic moderate to severe mitral regurgitation undergoing percutaneous MVR were prospectively included. Plasma Galectin-3 levels were measured before the procedure. Echocardiographic and clinical assessment was performed at baseline and after 3 months. LV reverse remodeling was prospectively defined as a ≥10% increase in global longitudinal strain. MACE included death, myocardial infarction, heart failure related rehospitalization and stroke and was assessed after a mean follow-up time of 2 years., Results: 72.7% of the patients showed LV reverse remodeling. Pre-interventional Galectin-3 < 10 ng/ml was an independent predictor of LV reverse remodeling (OR 10.3, 95% CI 1.2-83.9, p = 0.036). 25 patients (56.8%) experienced a MACE. Patients with Galectin-3 levels ≥ 10 ng/ml had significantly more MACE than patients with Galectin-3 levels < 10 ng/ml (100% vs. 45.5%, p = 0.003). Diabetes independently predicted MACE (HR 3.1, 95% CI 1.0-9.4, p = 0.049); Galectin-3 ≥ 10 ng/ml was of borderline significance (HR 2.2, 95% CI 0.9-5.4, p = 0.088)., Conclusions: Pre-interventional plasma Galectin-3 levels are associated with LV reverse remodeling and with clinical outcome after percutaneous MVR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Doppler echocardiography is extensively used in clinical practice for the screening and detection of pulmonary hypertension (PH). It allows for accurate estimates of pulmonary artery pressures, but with moderate precision, which explains why it is more appropriate for population studies than for definitive diagnosis of PH in individual patients. Moreover, echocardiography allows one to distinguish different patterns of right ventricular remodelling in various forms of PH and enables clinically satisfactory differentiation between pre- and post-capillary PH. This article will review the methods for evaluating PH by echocardiography, while also providing an insight into specific strengths and weaknesses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Out of 163 STEMI patients, 33 presented left ventricular remodeling (LVR) as assessed by multiple cardiac magnetic resonance (CMR) scans. LVR patients were identified as EarlyLVR (LVR occurring between baseline and 3 months) or LateLVR (LVR occurring between 3 months and one year), and matched to non-remodeler patients in term of age, gender, anterior infarction, baseline LV ejection fraction and infarct size. ST2 and NT-proBNP were measured at baseline and 3 months. Systolic wall stress (SWS) was calculated by CMR. At baseline, mean levels of ST2, NT-proBNP and SWS were 67.1 ± 54.1 ng/mL, 1529 ± 1702 ng/L and 17.9 ± 7.1 10 3  N·m -2 , respectively, and did not differ among the groups. At 3 months, EarlyLVR patients presented significant higher ST2, NT-proBNP and SWS (31.6 ± 12.7 ng/mL, 1142 ± 1069 ng/L, 25.5 ± 9.7 10 3  N·m -2 ), compared to the corresponding non-remodelers (20.5 ± 8.6 ng/mL, 397 ± 273 ng/L, 18 ± 7.3 10 3  N·m -2 ; with p = 0.017, 0.040, and 0.036, respectively). LateLVR patients presented higher ST2 at 3 months than their non-remodelers (33.6 ± 15.9 versus 23.66 ± 8.7 ng/mL, p = 0.046), while NT-proBNP and SWS were not different between groups at both timepoints., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Increased inflammation was found in the left stellate ganglion (LSG) in patients with malignant ventricular arrhythmia (VA). However, the role of inflammation in LSG remodeling is unknown. This study aimed to investigate whether exogenous interleukin-1β (IL-1β) could aggravate VA through regulating LSG remodeling., Methods: Twenty-four canines who received saline (Control, n=8), IL-1β injection into the LSG (n=8) or IL-1 receptor antagonist (IL-Ra) pre-injection plus IL-1β injection (n=8) were included. Ventricular electrophysiology parameters, heart rate variability (HRV), LSG activity were measured at different time points. VA was recorded for 60min after ischemia and then LSG tissues were collected for molecular detection., Results: Compared with the control group, IL-1β injection decreased the effective refractory period, action potential duration (APD) 90 and increased the maximal slope of the restitution curve in normal hearts. Besides, the occurrence of VA was significantly increased in the IL-1β group. Additionally, IL-1β injection increased the sympathetic indices of HRV and LSG activity in normal and ischemic hearts. Mechanically, the mRNA expression of pro-inflammatory cytokines and protein expression of c-fos, nerve growth factor and neuropeptide Y in LSG were increased, whereas the expression of neuronal nitric oxide synthase was decreased in the IL-1β group. More importantly, all these effects induced by IL-1β were attenuated by IL-1Ra pre-injection., Conclusion: Increased inflammation induced by IL-1β injection aggravates ischemia induced VA through regulating the neuronal remodeling of the LSG. Inflammation induced neuroplasticity may be a novel mechanism and therapeutic target for VA., (Copyright © 2017. Published by Elsevier B.V.)

Background: MicroRNAs (miRs) have shown to exert fibrotic and anti-fibrotic effects in preclinical models of acute myocardial infarction (AMI). The aim of this study was to evaluate miR-1, miR-21, miR-29b and miR-92a as circulating biomarkers for adverse ventricular remodeling (AVR) in post-AMI patients., Methods: Plasma levels of miR-1, miR-21, miR-29b and miR-92a were measured in 44 patients of the SITAGRAMI trial population at day 4, day 9 and 6month after AMI and in 18 matched controls (CTL). MiR expression patterns were correlated with magnetic resonance imaging (MRI) parameters for AVR (absolute change (Δ) in infarct volume (IV), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) between day 4 and 6months after AMI) and a combined cardiovascular endpoint., Results: Expression of miR-1, miR-21 and miR-29b but not miR-92a was increased in AMI vs. CTL cohort showing highest miR levels at d9. However, only miR-1 and miR-29b levels significantly correlated with ΔIV and showed a trend for correlation with ΔLVEF. Only miR-29b levels at day 9 correlated with ΔLVEDV at 6-month follow-up. There was no correlation of miR levels with an adverse outcome., Conclusion: Mir-1 and miR-29b plasma levels post-AMI correlate with IV changes. In addition, miR-29b levels are associated with changes of LVEDV over time. These results provide insights into the role of miRs as diagnostic AVR surrogate markers. Further large scale clinical trials will be needed to evaluate the real prognostic relevance of these miRs with respect to a clinical implication in the future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Obesity and hypertension are two risk factors of left ventricular hypertrophy (LVH) in adults. We aimed to examine the impacts of body weight and blood pressure (BP) from childhood on adult LV geometric remodeling., Methods: The study cohort consisted of 1256 adults aged 27-42years who had 2-10 measurements of body mass index (BMI) and BP from childhood in 1987 to adulthood in 2010. We calculated the cumulative and incremental values of BMI and BP from childhood to adulthood. In adulthood, four LV geometric patterns were defined based on the values of left ventricular mass index (g/m 2.7 ) and relative wall thickness: normal geometry, concentric remodeling (CR), eccentric hypertrophy (EH) and concentric hypertrophy (CH)., Results: The prevalence of abnormal LV geometric patterns in adults was 26.4% for CR, 2.0% for EH and 2.5% for CH. For childhood values, systolic BP (Odds Ratio [OR]=1.26, 95% confidence interval [CI]=1.08-1.47) but not BMI (OR=1.06, 95%CI=0.93-1.18) was associated with adult CR, whereas BMI (OR=3.53, 95%CI=2.09-5.98) but not systolic BP (OR=1.04, 95%CI=0.65-1.66) was associated with adult EH. Both childhood BMI (OR=2.69, 95%CI=1.77-4.09) and systolic BP (OR=1.64, 95%CI=1.07-2.51) were independently associated with adult CH. For adulthood, cumulative and incremental values, BMI and systolic BP were independently associated with adult CR, EH and CH., Conclusion: Excessive body weight and elevated BP from childhood have independent influences on the development of adult LV geometric remodeling., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A subset of patients undergoing cardiac resynchronization therapy (CRT) for heart failure (HF) with severe left ventricular (LV) dysfunction experience only short-lived LV reverse remodeling. Little is known about the incidence and prognosis of this finding. We sought to identify predictors of a brief response and investigated the prognosis in a retrospective study., Methods: A total of 528 patients from a Japanese multicenter database with full echocardiography datasets were enrolled. Follow-up was 3.4±1.3years. Based on relative reduction in LV end-systolic volume (LVESV) at 6months, we categorized patients as responders (reduction in LVESV ≥15%) and non-responders (NRs; reduction in LVESV <15%). Based on reduction in LVESV at 1-2years, responders were subdivided into long-lasting responders (reduction in LVESV ≥15%) and brief responders (reduction in LVESV <15%)., Results: Of 328 responders, 50 (15%) were brief responders. Predictors of brief response were prior ventricular tachyarrhythmia, a non-left bundle-branch block (LBBB) intrinsic QRS pattern, and prior hospitalization for HF. The risk of all-cause death in brief responders was significantly lower than that in NRs (P=0.034) and tended to be higher than that in long-lasting responders (P=0.080)., Conclusions: Approximately 15% of responders were brief responders. Prior ventricular tachyarrhythmia, a non-LBBB pattern, and HF hospitalization were independent predictors of a brief response. Brief response was significantly associated with decreased risk of all-cause death compared with NRs and had a tendency toward increased risk of all-cause death compared with long-lasting responders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Patients with single ventricle (SV) circulations are at risk for ventricular dysfunction. This study investigates whether there is evidence of increased myocardial fibrosis and myocardial dysfunction in children after the Fontan operation., Methods: Consecutive children after the Fontan operation who underwent cardiac magnetic resonance (CMR) T1 relaxometry with a modified look-locker inversion recovery approach were included in this retrospective study. Native T1 times (T1) and extracellular volume fractions (ECV) in the free wall of the dominant ventricle (left, SLV; right, SRV) were compared with controls and correlated with hemodynamic and clinical parameters., Results: Twenty-one SV patients (9.7±4.6years; 13 SLV; 8 SRV) and 24 healthy control children (13.9±2.6years, p=0.002) were included. T1 and ECV were higher in SRV patients than in controls (1036±46ms vs 974±27ms, p<0.001; 28±4% vs 22±3%, p=0.002) and SLV patients (978±39ms, p=0.002; 23±5%, p=0.012) while there was no difference between SLV patients and controls. Age at bidirectional cavopulmonary connection was correlated with T1 (R=0.55, p=0.015), while systolic blood pressure (R=-0.68, p<0.001) and body weight (R=-0.54, p=0.012) inversely correlated with ECV. T1 negatively correlated with radial and circumferential strain by CMR feature tracking., Conclusions: Fontan patients with a SRV show increased CMR markers of diffuse myocardial fibrosis, which are associated with decreased myocardial contractility. Whether their increased fibrosis burden conveys a greater risk for long-term complications in this population remains to be investigated., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: Little is known about the adaptation of the right ventricle (RV) to endurance exercise in children. The aim of this study was to assess the effects of 5months of intensive training on RV morphology and function in preadolescent endurance athletes., Methods: Ninety-four children were evaluated in this study. Fifty-seven male competitive swimmers (aged 10.8±0.2years) were evaluated before (baseline) and after 5months of the training (peak-training), and compared to 37 age- and sex-matched non-athlete children evaluated at baseline and after 5months of natural growth. All subjects were asymptomatic, with negative family history for cardiomyopathies., Results: At baseline no differences were found between athletes and controls for indexed RV outflow tract (RVOT) (18.5±2.7 vs. 16.8±5.0mm/m 2 , p=0.18) and RV basal end-diastolic diameter (EDD) (24.9±4.1 vs. 23.6±3.0mm/m 2 , p=0.15). After 5months, indexed RVOT and RV basal EDD significantly increased in athletes (20.2±2.9mm/m 2 and 25.4±3.3mm/m 2 , p<0.0001 vs. baseline) while no differences were observed in controls (p=0.84 and p=0.25). Despite the increase in RV size, RV function remained normal in athletes, with no changes in RV fractional area change (p=0.97), s' value (p=0.22), and RV longitudinal strain (p=0.28)., Conclusions: Endurance training influences the growing heart of male preadolescent athletes with an addictive increase in RV dimensions, with a preserved RV function. Therefore, in children engaged in endurance sports the increase in RV size associated with normal RV function represents a physiological expression of the athlete's heart and should not be misinterpreted as an expression of incipient RV cardiomyopathy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atrial fibrillation (AF) is the most common heart arrhythmia, the risk of which typically increases with age. This condition is commonly associated with major cardiovascular diseases and structural heart damage, while it is rarely observed in healthy young people. However, increasing evidence indicates that paroxysmal AF can also onset in young or middle-aged and otherwise healthy endurance athletes (e.g., cyclists, runners and cross-country skiers). Here we review the topic of AF associated with strenuous endurance exercise (SEE), for example cycling, running and cross-country skiing, especially at a competitive level, and we propose the definition of a new syndrome based on the accumulating data in the literature: SEE-related AF under the acronym of 'PAFIYAMA' ('paroxysmal AF in young and middle-aged athletes'). Special emphasis is given to the proper differentiation of PAFIYAMA from 'classical AF' regarding pathophysiology, diagnosis and medical management., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Considering the high morbidity and mortality after myocardial infarction (MI), the study of compounds with potential benefits for cardiac remodeling is reasonable. Green tea (GT) (Cammellia sinensis) is the most consumed beverage in the world. The potential action mechanisms of GT include anti-inflammatory, anti-apoptotic, antioxidant, and lipid-lowering properties., Objective: This study analyzed the effects of GT on cardiac remodeling following coronary occlusion in rats., Methods: Male Wistar rats were divided into four groups: control (C), control green tea (GT), myocardial infarction (MI), and myocardial infarction and green tea (MI-GT). GT and MI-GT were fed with standard chow with 0.25% Polyphenon 60 (Sigma-Aldrich Canada, Oakville, ON, Canada). After 3months of observation, echocardiographic and isolated heart study, oxidative stress, energy metabolism, serum lipids, extracellular matrix, and apoptosis were evaluated., Results: GT reduced cardiac hypertrophy and improved systolic and diastolic dysfunction. Concerning oxidative stress, GT reduced protein carbonyl, increased Nrf-2, and restored antioxidant enzyme activity to the control pattern. Energy metabolism was affected by MI that presented with lower fatty acid oxidation and accumulation of triacylglycerol, increased serum lipids, impairment of the citric acid cycle, and oxidative phosphorylation. GT stimulated the glucose pathway and mitochondrial function after MI by increasing pyruvate dehydrogenase, Complex I, ATP synthase, and glycogen storage. In addition, MI changed the extracellular matrix including MMP-2 and TIMP-1 activity and increased apoptosis by 3-caspase, all of which were attenuated by GT., Conclusion: GT attenuated cardiac remodeling after MI, associated with improvement in systolic and diastolic dysfunction. Oxidative stress, energy metabolism, apoptosis, and extracellular matrix alterations are all potential mechanisms by which GT may take part., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: ST-segment elevation myocardial infarction (STEMI) triggers remote extracellular matrix expansion. Myocardial extracellular volume fraction (ECV), determined by cardiovascular magnetic resonance, permits quantification of interstitial space expansion. Our aim was to determine the relationship between early serum fibrosis biomarkers and 180-day post-infarct remote myocardium remodeling using ECV., Methods and Results: In 26 patients with STEMI, functional imaging, T1-mapping, and late-gadolinium-enhancement were performed on a 3-T CMR scanner at baseline (days 3 to 5) and 180days. Biomarkers were measured at days 1, 3, and 7 after STEMI. The mean initial and follow-up left ventricular ejection fraction (LVEF) were 48.3±18.1% and 52.6±12.3%, respectively. Initial infarct size was 11.6±16.8% of LV mass. ECV in the remote myocardium at 180days correlated with indexed end-systolic volume (r=0.4, p=0.045). A significant correlation was observed between galectin-3 at day 7 and ECV at 6months (r=0.428, p=0.037). A trend towards a direct correlation was found for BNP (r=0.380, p=0.059). Multivariate analysis revealed that BNP and galectin-3 were independent predictors of long-term changes in ECV and explained nearly 30% of the variance in this parameter (r 2 =0.34; p=0.01). A galectin-3 cutoff value of 10.15ng/mL was the most powerful predictor of high ECV values (≥28.5%) at follow-up. Galectin-3 at day 7 was an independent predictor of high ECV values at follow-up (OR=22.51; CI 95%: 2.1-240.72; p=0.01) with 0.76 AUC (CI: 0.574-0.964; p=0.03)., Conclusions: Galectin-3 measured acutely after STEMI is an independent predictor of increased ECV at 6-month follow-up that might be useful for long-term risk stratification., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The impact of high exercise loads on a previously healthy heart remains controversial. We examined the consequences of decades of strenuous endurance exercise at the highest competition level on heart dimensions and volumes as well as on serum biomarkers of cardiac fibrosis/remodeling., Methods and Results: We compared echocardiographic measurements and serum biomarkers of cardiac fibrosis/remodeling [troponin I, galectin-3, matrix metallopeptidase-2 and -9, N-terminal pro-brain natriuretic peptide, carboxy-terminal propeptide of type I procollagen, and soluble suppressor of tumorigenicity-2 (sST-2)/interleukin(IL)-1R4] in 53 male athletes [11 former professional ('elite') and 42 amateur-level ('sub-elite') cyclists or runners, aged 40-70years] and 18 aged-matched controls. A subset of 15 subjects (5 controls, 3 sub-elite and 7 elite athletes) also underwent cardiac magnetic resonance imaging (cMRI). Elite and sub-elite athletes had greater echocardiography-determined left ventricular myocardial mass indexed to body surface area than controls (113±22, 115.2±23.1 and 94.8±21g/m(2), respectively, p=0.008 for group effect), with similar results for left (50.5±4.4, 48.2±4.3 and 46.4±5.2mm, p=0.008) and right (38.6±3.8, 41.1±5.5 and 34.7±4.3mm, p<0.001) ventricular end-diastolic diameter, and cMRI-determined left atrial volume indexed to body surface area (62.7±8.1, 56.4±16.0 and 39.0±14.1ml/m(2), p=0.026). Two athletes showed a non-coronary pattern of small, fibrotic left ventricular patches detected by late gadolinium enhancement. No group effect was noted for biomarkers., Conclusions: Regardless of their competition level at a younger age, veteran endurance athletes showed an overall healthy, non-pathological pattern of cardiac remodeling. Nonetheless, the physiopathology of the ventricular fibrotic patches detected warrants further investigation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Aldosterone plays a pivotal role in the pathophysiology of systolic heart failure. However, whether early aldosterone antagonism improves cardiac remodeling during persistent pressure overload is unsettled. We evaluated the effects of aldosterone antagonist spironolactone on cardiac remodeling in rats with ascending aortic stenosis (AS)., Methods: Three days after inducing AS, weaning rats were randomized to receive spironolactone (AS-SPR, 20mg/kg/day) or no drug (AS) for 18weeks, and compared with sham-operated rats. Myocardial function was studied in isolated left ventricular (LV) papillary muscles., Statistical Analyses: ANOVA or Kruskal-Wallis tests., Results: Echocardiogram showed that LV diastolic (Sham 8.73±0.57; AS 8.30±1.10; AS-SPR 9.19±1.15mm) and systolic (Sham 4.57±0.67; AS 3.61±1.49; AS-SPR 4.62±1.48mm) diameters, left atrial diameter (Sham 5.80±0.44; AS 7.15±1.22; AS-SPR 8.02±1.17mm), and LV mass were higher in AS-SPR than AS. Posterior wall shortening velocity (Sham 38.5±3.8; AS 35.6±5.6; AS-SPR 31.1±3.8mm/s) was lower in AS-SPR than Sham and AS; E/A ratio was higher in AS-SPR than Sham. Developed tension was lower in AS and AS-SPR than Sham. Time to peak tension was higher in AS-SPR than Sham and AS after post-rest contraction. Right ventricle weight was higher in AS-SPR than AS, suggesting more severe heart failure in AS-SPR than AS. Interstitial collagen fractional area and myocardial hydroxyproline concentration were higher in AS than Sham. Metalloproteinase-2 and -9 activity, evaluated by zymography, did not differ between groups., Conclusion: Early spironolactone administration causes further hypertrophy in cardiac chambers, and left ventricular dilation and dysfunction in rats with AS-induced chronic pressure overload., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Suppression of frequent premature ventricular contractions (PVCs) does not systematically lead to an expected reversal of PVC-induced cardiomyopathy and determinants of left ventricular ejection fraction (LVEF) recovery (reverse remodeling) after ablation remain largely unknown., Methods: Ninety-six consecutive patients with a suspicion of PVC induced-cardiomyopathy were retrospectively included. Parameters potentially related to reverse remodeling (>10% increase in LVEF) were analyzed in patients w/wo long-term success (decrease in PVC burden >80%)., Results: Over a mean follow-up of 24±21months, long-term ablation success was obtained in 76 patients (79%). In these, reverse remodeling was observed in 63 (83%) (LVEF 39±8 to 56±8%, p<0.0001). In multivariate analysis, only an older age (and marginally a lower PVC QRS amplitude) was independently associated with the lack of reverse remodeling. Only 10 of the 35 patients who initially should have received an ICD for primary prevention remained candidates for implantation after ablation. Lack of reverse remodeling was significantly linked to a higher mortality., Conclusion: Reverse remodeling was observed in 83% of patients with frequent PVC and unexplained cardiomyopathy undergoing long-term successful ablation of the PVC. A younger age was independently correlated with the occurrence of reverse remodeling., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Non-traditional EKG parameters such as QRS pattern and QRS duration (QRSd) are being investigated in acute coronary syndrome as prognostic markers. Following an infarction, the heart attempts to compensate for myocardial loss through remodeling which eventually lowers the ejection fraction (LVEF). Our objective is to evaluate the relationship between the QRSd at the time of NSTEMI and extent of coronary artery disease (CAD) and changes in LVEF., Methods and Results: Patients admitted with NSTEMI between 08/01/2006 and 9/30/2012 were included. Patients were classified into high or low QRSd at cutoff value of 90ms noted on initial EKG after excluding bundle-branch block. A total of 536 patients with mean age of 66±14years were included. 49% were male and majority were African American (73%). Patients within the higher QRSd group had a lower LVEF at the time of the NSTEMI compared to those with QRSd <90ms (47±15% vs. 50±13%; p<0.038). The LVEF remained lower in the high QRS group on follow up to 12months (47±15% vs. 52±11%; p<0.001). The high QRSd group had a higher incidence of severe LV dysfunction at baseline (27% vs. 18%; p<0.045). Logistic regression analysis revealed that a QRSd ≥90ms was also independently associated with a severely reduced LVEF on follow-up (OR=2.7; CI 1.55-4.69; p<0.001)., Conclusion: QRSd ≥90ms at the time of NSTEMI is predictive of three-vessel/left main coronary artery involvement and a lower LVEF. This depression in LVEF is maintained for up to 12months. Thus, the QRSd at time of NSTEMI has additional prognostic significance., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Physical exercise attenuates myocardial infarction (MI)-induced cardiac remodeling. However, it is unsettled whether late exercise modulates post-infarction cardiac remodeling differentially according to infarct size. We investigated the effects of exercise started at late stage heart failure on cardiac remodeling in rats with moderate and large sized MI., Methods: Three months after MI, rats were assigned into sedentary and exercise groups. Exercise rats underwent treadmill for three months. After assessing infarct size by histological analysis, rats were subdivided into four groups: moderate MI sedentary (Mod MI-Sed; n=7), Mod MI exercised (Mod MI-Ex; n=7), Large MI-Sed (n=11), and Large MI-Ex (n=10)., Results: Before exercise, MI-induced cardiac changes were demonstrated by comparing results to a Sham group; alterations were more intense in rats with large than moderate MI size. Systolic function, evaluated by echocardiogram using the variation in LV fractional area change between after and before exercise, was improved in exercise than sedentary groups. Calsequestrin expression increased in exercised compared to sedentary groups. L-type calcium channel was higher in Mod MI-Ex than Mod MI-Sed. SERCA2a, phospholamban, and Na(+)/Ca(2+) exchanger expression did not differ between groups., Conclusion: Late exercise improves systolic function and modulates intracellular calcium signaling proteins in rats with moderate and large MI., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Prognostic value of myocardial fibrosis in patients with non-ischemic idiopathic dilated cardiomyopathy (DCM) is not well-defined. We sought to assess the association of focal and diffuse myocardial fibrosis with left ventricular reversed remodeling (LVRR)., Methods: Patients with DCM who underwent cardiac MRI with baseline and subsequent follow-up echocardiography were included in the study. Post-contrast T1 times were corrected for renal function, body size, gadolinium dose and time after Gadolinium injection. Patients were followed over a median time of 29months to evaluate changes of left ventricular end-systolic volume (LVESV). A Linear Mixed Model was used to assess the relationship between the LVESV during follow-up, corrected post-T1 value delayed hyperenhancement (DHE), and modified Seattle Heart Failure Score (SHFS)., Results: A total of 103 patients (mean age 51±15years, 61% male) were evaluated. The mean LVEF was 33±11%, LVESVi 62±39ml/m(2), and T1 time 416±98. DHE was identified in 45 patients (44%). Patients with focal DHE (n=45) had higher LVESVi at baseline and during follow-up (p=0.024). Post T1 value >450 was an independent predictor of LVRR at the follow-up (Δ=24.6ml/m(2) SE 14.6ml/2, p=0.0480) in patients despite the presence of DHE, even after adjusting for their SHFS., Conclusion: While DCM patients with focal DHE demonstrated greater adverse LV remodeling than those without focal fibrosis, diffuse fibrosis independently predicts LVRR in DCM patients in patients despite the presence of focal fibrosis., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objectives: Beta-blockers have improved the prognosis of patients with dilated cardiomyopathy as they improve left ventricular (LV) systolic function and structure, which are crucial for myocardial recovery. However, to date, no accurate methods can predict the effectiveness of β-blocker therapy. Our goal was to evaluate whether peripheral endothelial function could be a useful predictor for β-blocker responses and related LV reverse remodeling (LVRR) in patients with idiopathic dilated cardiomyopathy (IDC)., Methods: Fifty-two IDC patients were recruited and underwent brachial artery flow-mediated dilation (FMD). Beta-blockers were titrated to doses tolerable for each patient. LV function and structure were measured by echocardiography. A positive response to β-blockers was defined as an increase of ≥10% in LV ejection fraction (LVEF). LVRR was defined as an increase of ≥10% in LVEF and a decrease of ≥15% in LV end-systolic volume (LVESV)., Results: Baseline FMD was 8.4±3.0% in IDC patients and significantly lower than healthy controls. At three-month follow-up, 54% of patients had a positive β-blocker response and 40% achieved LVRR. Patients with a positive response to β-blockers or with LVRR had significantly higher baseline FMD values than those without. FMD was the most significant predictor of changes in LVEF and LVESV. The sensitivity and specificity of baseline FMD to predict β-blocker responses was 64.3% and 83.3%, respectively, and to predict LVRR was 61.9% and 80.6%, respectively. Beta-blockers themselves did not influence FMD values., Conclusions: FMD could serve as an independent predictor for monitoring β-blocker therapy effectiveness in IDC patients., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Cardiac resynchronization therapy (CRT) is an effective treatment for left ventricular reverse remodeling (LVRR) in patients with congestive heart failure (HF) and ventricular dyssynchrony. Melatonin is a secretory product of the pineal gland with highly beneficial effects from any tissues including the heart. Herein, we investigated whether the response to CRT is associated with levels of melatonin before CRT implantation in patients with HF and ventricular dyssynchrony., Methods: Diurnal melatonin levels were performed in serum from 93 patients with HF and ventricular dyssynchrony before CRT implantation. Moreover, we calculated the MADIT-CRT score. Evaluation of patients at 1-year follow-up included an echocardiographic study since the patients were categorized as responders if they presented both a reduction in left ventricular end-systolic volume index >10% and an increase in left ventricular ejection fraction >10%., Results: At 1-year, 34 patients (36.5%) were considered responders to CRT according to the predefined criteria. The diurnal melatonin levels were significantly lower in the non-responder group (9.9±2.84 vs 14.7±2.32pg/mL). After adjustment by multivariate analysis, diurnal serum melatonin levels (P<0.001) and diabetes mellitus (P=0.03) were predictors of LVRR. On Cox regression analysis, diurnal serum melatonin levels (P<0.001) and left atrial volume<40mL/m(2) (P=0.04) remained independent predictors of the adverse clinical events. The area under of curve for the prediction LVRR of melatonin (0.91, 95%CI 0.85-0.97; P<0.001) was significantly higher compared to MADIT-CRT score (0.69, 95%CI 0.58-0.80; P=0.002)., Conclusion: Diurnal levels of melatonin before CRT implantation are associated with LVRR at 12month follow-up., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)