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This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although β-adrenergic receptor (β-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the β-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. NEW & NOTEWORTHY We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic β-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome.

Introduction: Atrial fibrillation (AF) is accompanied by various types of remodeling, including volumetric enlargement and histological degeneration. Electrical remodeling reportedly reflects histological degeneration., Purpose: To clarify the differences in determinants and clinical impacts among types of remodeling., Methods: This observational study included 1118 consecutive patients undergoing initial ablation for AF. Patients were divided into four groups: minimal remodeling (left atrial volume index [LAVI] < mean value and no low-voltage area [LVA], n = 477); volumetric remodeling (LAVI ≥ mean value and no LVA, n = 361); electrical remodeling (LAVI < mean value and LVA presence, n = 96); and combined remodeling (LAVI ≥ mean value and LVA presence, n = 184). AF recurrence and other clinical outcomes were followed up for 2 and 5 years, respectively., Results: Major determinants of each remodeling pattern were high age for electrical (odds ratio = 2.32, 95% confidence interval = 1.68-3.25) and combined remodeling (2.57, 1.88-3.49); female for electrical (3.85, 2.21-6.71) and combined remodeling (4.92, 2.90-8.25); persistent AF for combined remodeling (7.09, 3.75-13.4); and heart failure for volumetric (1.71, 1.51-2.53) and combined remodeling (2.21, 1.30-3.75). Recurrence rate after initial ablation increased in the order of minimal remodeling (20.1%), volumetric (27.4%) or electrical remodeling (36.5%), and combined remodeling (50.0%, p < .0001). A composite endpoint of heart failure, stroke, and death occurred in the order of minimal (3.4%), volumetric (7.5%) or electrical (8.3%), and combined remodeling (15.2%, p < .0001)., Conclusion: Volumetric, electrical, and combined remodeling were each associated with a unique patient background, and defined rhythm and other clinical outcomes., (© 2023 Wiley Periodicals LLC.)

Background: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling., Methods: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function., Findings: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment., Conclusions: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure., Funding: NIH, ASTRO, AHA, Longer Life Foundation., Competing Interests: Declaration of interests A.J. has a pending patent for fusion protein nanodiscs for the treatment of heart failure and eye disease, is a member of the scientific advisory board of Mobius Scientific, and receives research funding from AstraZeneca and Bitterroot Bio, unrelated to the studies in this manuscript., (Published by Elsevier Inc.)

Mitigation of cardiac autonomic dysregulation by neuromodulation technologies is emerging as a new therapeutic modality of heart failure (HF). This recent progress has necessitated the identification of a biomarker for the quantification of sympathovagal balance, the potential target of 'neuromodulation' strategies. The currently available autonomic nervous system assessment parameters do not truly reflect the sympathovagal balance of the ventricle. Protein kinase A (PKA) is an intracellular enzyme that plays a major role in the pathophysiology of functional and structural ventricular remodeling in HF. Interestingly, sympathetic and parasympathetic activations exert reciprocal influence on the activity of PKA. The current review attempts to evaluate the potential concept and feasibility of using in vitro assessment of PKA activity as a marker of sympathovagal balance in HF., Competing Interests: Declaration of competing interest TWD is supported by the National Institute on Aging NIH (R21AG075639) and the Heart Rhythm Institute, University of Oklahoma HSC. AY is supported by American Heart Association (AHA966924), and NIH/NIA (R01AG075834). PC is supported by George Mines Travelling Fellowship by the Canadian Heart Rhythm Society. PC is also the recipient of the Alan K. Laws Clinician Scientist grant (Mentorship Merit award) from the Department of Anesthesiology and Pain Medicine, University of Toronto. The remaining author has nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although major pathogenesis mechanisms of heart failure (HF) are well established, the significance of early (mal)adaptive structural changes of cardiomyocytes preceding symptomatic ischemic HF remains ambiguous. The aim of this study is to present the morphological characterization of changes in cardiomyocytes and their reorganization of intermediate filaments during remodeling preceding symptomatic ischemic HF in an adult human heart. A total of 84 myocardial tissue samples from middle-left heart ventricular segments were analyzed histomorphometrically and immunohistochemically, observing the cardiomyocyte's size, shape, and desmin expression changes in the remodeling process: Stage A of HF, Stage B of HF, and Stages C/D of HF groups (ACC/AHA classification). Values p < 0.05 were considered significant. The cellular length, diameter, and volume of Stage A of HF increased predominantly by the diameter vs. the control group ( p < 0.001) and continued to increase in Stage B of HF in a similar pattern ( p < 0.001), increasing even more in the C/D Stages of HF predominantly by length ( p < 0.001). Desmin expression was increased in Stage A of HF vs. the control group ( p < 0.001), whereas it was similar in Stages A and B of HF ( p > 0.05), and most intense in Stages C/D of HF ( p < 0.001). Significant morphological changes of cardiomyocytes and their cytoskeletal reorganization were observed during the earliest remodeling events preceding symptomatic ischemic HF.

Aim: To determine the effect of dapagliflozin therapy on myocardial remodeling and fibrosis according to magnetic resonance imaging (MRI) with contrast in patients with chronic heart failure (CHF) and atrial fibrillation (AF)., Materials and Methods: In the group of 22 patients with a combination of CHF and AF we analyzed the dynamics of remodeling parameters and assessed myocardial fibrosis during 6-month therapy with dapagliflozin according to cardiac MRI with contrast., Results:   After 6 months of dapagliflozin therapy there was a statistically significant increase in LVEF (27 [23-32]-32 [26.5-36.5] p-0.04) and a tendency to decrease volume and linear dimensions of LV, LP. There was no progression of myocardial fibrosis according to the results of cardiac MRI with contrast in patients with HFrFV and AF., Conclusions: Dapagliflozin therapy in patients with HFrEF and AF led to favorable myocardial remodeling changes.

Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death. There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats. Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin. Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

For years, females were thought of as smaller men with complex hormonal cycles; as a result, females have been largely excluded from preclinical and clinical research. However, in the last ten years, with the increased focus on sex as a biological variable, it has become clear that this is not the case, and in fact, male and female cardiovascular biology and cardiac stress responses differ substantially. Premenopausal women are protected from cardiovascular diseases, such as myocardial infarction and resultant heart failure, having preserved cardiac function, reduced adverse remodeling, and increased survival. Many underlying biological processes that contribute to ventricular remodeling differ between the sexes, such as cellular metabolism; immune cell responses; cardiac fibrosis and extracellular matrix remodeling; cardiomyocyte dysfunction; and endothelial biology; however, it is unclear how these changes afford protection to the female heart. Although many of these changes are dependent on protection provided by female sex hormones, several of these changes occur independent of sex hormones, suggesting that the nature of these changes is more complex than initially thought. This may be why studies focused on the cardiovascular benefits of hormone replacement therapy in post-menopausal women have provided mixed results. Some of the complexity likely stems from the fact that the cellular composition of the heart is sexually dimorphic and that in the setting of MI, different subpopulations of these cell types are apparent. Despite the documented sex-differences in cardiovascular (patho)physiology, the underlying mechanisms that contribute are largely unknown due to inconsistent findings amongst investigators and, in some cases, lack of rigor in reporting and consideration of sex-dependent variables. Therefore, this review aims to describe current understanding of the sex-dependent differences in the myocardium in response to physiological and pathological stressors, with a focus on the sex-dependent differences that contribute to post-infarction remodeling and resultant functional decline., Competing Interests: Declaration of competing interest The author has no conflicts of interest and/or disclosures to declare. The author has no competing interests., (Copyright © 2023 The Author. Published by Elsevier B.V. All rights reserved.)

Background: Pacing at sites of longest interventricular delay has been associated with greater reverse remodeling in cardiac resynchronization therapy (CRT). However, the effects of pacing at such sites on clinical outcomes is less well studied., Objective: The purpose of this study was to assess the association between interventricular delay and clinical outcomes in CRT patients implanted with quadripolar left ventricular (LV) leads., Methods: RALLY-X4 was a registry study of the Acuity X4 quadripolar LV leads. Interventricular delay was measured during unpaced basal rhythm from the right ventricular (RV) lead to the LV lead electrode (E1 to E4) chosen for CRT pacing. Patients were stratified by median RV-LV delay (80 ms) into short and long delay groups; they also were analyzed by multivariable modeling. The primary composite outcome measure was all-cause mortality and heart failure hospitalization (HFH) at 18 months., Results: A total of 581 patients had complete RV-LV delay data. Mean LV ejection fraction was 27%, and 73% had typical left bundle branch block. Predictors of long RV-LV delay included female sex, left bundle branch block, and QRS duration >150 ms. Survival free of the primary outcome at 18-month follow-up was 87% in the long activation delay group compared with 77% in the short delay group (P = .0042). Multivariate analysis showed that RV-LV delay was an independent predictor of survival free of HFH (P = .028)., Conclusion: Among CRT patients with quadripolar LV pacing leads, longer baseline interventricular activation delay was significantly associated with the composite endpoint of all-cause mortality and HFH., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) response stratified by left ventricular (LV) remodeling revealed differing mortality profiles for distinct patient cohorts. Measuring functional end points, as well as mortality, may better assess CRT efficacy and inform patient management. However, the association between LV remodeling and functional outcomes after CRT is not well understood., Objective: The purpose of this study was to evaluate long-term CRT outcomes by extent of LV remodeling., Methods: REsynchronization reVErses Remodeling in Systolic Left vEntricular dysfunction (ClinicalTrials.gov identifier NCT00271154) was a prospective, double-blind, randomized trial of CRT. Subjects were classified on the basis of LV end-systolic volume (LVESV) change from baseline to 6 months post-CRT: worsened (increase), stabilized (0%-≤15% reduction), responder (>15%-<30% reduction), and super-responder (≥30% reduction). Subjects were evaluated annually for 5 years., Results: The analyses included 353 subjects randomized to CRT-ON arm. All-cause mortality was higher in the worsened group than in the other 3 response groups (29.8% vs 8.0%; P < .0001), with no difference in survival among those groups (P = .87). A significant interaction between the LVESV group and time was observed for health status and quality of life (P = .02 for both). The interaction was not significant for 6-minute hall walk (P = .79); however, super-responders had increased walk distance compared with the other 3 response groups (P = .03)., Conclusion: Preventing further increase in LVESV with CRT was associated with reduced mortality, whereas functional measure improvement was associated with LV remodeling magnitude. These results support the consideration of functional and mortality end points to assess CRT efficacy and provide further evidence that the dichotomous "responder and nonresponder" classification should be modified., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background Heart failure with recovered ejection fraction (HFrecEF) has been a newly recognized entity since 2020. However, the concept has primarily focused on left ventricular ejection fraction improvement, with less focus on the recovery of the left atrium. In this study, we investigated changes in left atrial (LA) echocardiographic indices in HFrecEF. Methods and Results An inpatient cohort with heart failure with reduced ejection fraction (HFrEF) was identified retrospectively and followed up prospectively in a single tertiary hospital. The enrolled patients were classified into HFrecEF and persistent HFrEF groups. Alternations in LA parameters by echocardiography were calculated. The primary outcome was a composite of cardiovascular death or heart failure rehospitalization. A total of 699 patients were included (HFrecEF: n=228; persistent HFrEF: n=471). Compared with persistent HFrEF, the HFrecEF group had greater reductions in LA diameter, LA transverse diameter, LA superior-inferior diameter, LA volume, and LA volume index but not in LA sphericity index. Cox regression analysis showed that the HFrecEF group experienced lower risks of prespecified end points than the persistent HFrEF group after adjusting for confounders. Additionally, 136 (59.6%) and 62 (13.0%) patients showed LA reverse remodeling (LARR) for the HFrecEF and persistent HFrEF groups, respectively. Among the HFrecEF subgroup, patients with LARR had better prognosis compared with those without LARR. Multivariate logistic analysis demonstrated that age and coronary heart disease were 2 independent negative predictors for LARR. Conclusions In HFrecEF, both left ventricular systolic function and LA structure remodeling were improved. Patients with HFrecEF with LARR had improved clinical outcomes, indicating that the evaluation of LA size provides a useful biomarker for risk stratification of heart failure.

Introduction: Ventricular remodeling is a mal-adaptive process. Both angiotensin-converting enzyme inhibitors and sacubitril/valsartan have been shown to reverse remodeling in mostly uncontrolled observational studies. There is a lack of head-to-head studies. Methods: This cohort study compares the remodeling effects of angiotensin receptor blockers combined with a neprilysin inhibitor (ARNI) and perindopril in heart failure with reduced ejection fraction (HFrEF) patients between January 2017 and December 2020. Inclusion criteria: (i) age > 18 years, (ii) recent diagnosis of de-novo HFrEF (EF < 40%), (iii) baseline echocardiography performed not more than 2 months prior to treatment onset, and (iv) follow-up echocardiography performed not earlier than 6 months and not later than 18 months posttreatment onset. No prior treatment with renin-angiotensin-aldosterone system inhibitors was permitted in the ARNI group. Left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) were analyzed. A two-way repeated measure ANOVA (for normally distributed) and generalized estimating equation test for nonnormally distributed interval dependent variables. Mean comparison between and within groups was performed using the Bonferroni test. Results: Following an average treatment period of 9 months, LVEF improved from 24.9% to 36.4% for ARNI and from 28.7% to 40.5% for perindopril, increments of 11.5% and 11.8% resp. (Bonferroni test [ P  ≤ .05]). LVEDV was reduced by 8.4 mL and 3.2 mL, and LVESV by 17.9 mL and 10.8 mL for ARNI and perindopril resp. Only the reduction of LVESV for ARNI was statistically significant ( P  = .007). Conclusion: Both ARNI and perindopril yielded a significant improvement in the LVEF within 9 months. The remodeling effect of ARNI seems stronger because of the greater improvements in left ventricular volumes.

Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose of Review: Ischemic cardiomyopathy refers to systolic left ventricular dysfunction in the setting of obstructive coronary artery disease and represents the most common cause of heart failure worldwide. It is often the combination of an irreversible loss of viable mass following an acute myocardial infarction (AMI) with a dysfunctional, but still viable, myocardium in the context of a chronically reduced myocardial blood flow and reduced coronary reserve. Medical treatments aiming at modulating neurohumoral response and restoring blood flow to the ischemic cardiomyocytes were shown to dramatically abate the occurrence of ventricular dysfunction and adverse remodeling in ischemic cardiomyopathy., Recent Findings: Novel therapeutic approaches, such as mechanical unloading and modulation of the inflammatory response, appear to be promising. Furthermore, the understanding of the mechanisms by which, despite optimal treatment, heart failure ensues after AMI, with or without adverse remodeling and systolic dysfunction, is a critical step in the search for novel ways to tackle heart failure risk beyond preservation of left ventricular volumes and systolic function. In this review article, we explore the principal pathophysiological mechanisms and pathways of heart failure in ischemic cardiomyopathy, therapeutic opportunities, and knowledge gaps in this area., (© 2022. The Author(s).)

Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre to postpuberty. Rat pups ( n = 57, 3 wk old, 30-45 g) were subjected to PAB or sham surgery. Animals were euthanized either before or after puberty (4 and 8 wk postsurgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 wk, whereas females did not. After 8 wk, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 wk in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared with males ( P = 0.055). Histology showed significantly less RV myocardial fibrosis in female compared with male PAB rats 8 wk after surgery. Myosin heavy chain 7-to-6 ratio switch and calcineurin signaling were less pronounced in female PAB rats compared with males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure compared with males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones. NEW & NOTEWORTHY In this study, we describe sex differences in our unique weanling rat model of increased RV pressure load by pulmonary artery banding. We are the first to assess temporal sex-related differences in RV adaptation during pubertal development. Female rats show superior RV function and less diastolic dysfunction and fibrosis compared with male rats. These differences are already present before puberty, indicating that the differences in RV adaptation are not only determined by sex hormones.

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling., (© 2022 European Society of Cardiology.)

Background: Despite interest in left ventricular (LV) recovery, there is an absence of data on the relationship between intrinsic LV hemodynamics and both reverse remodeling on a continuous flow LV assist device (CF-LVAD) therapy. We hypothesized that the markers of intrinsic LV function would be associated with remodeling, optimization, and outcomes., Methods and Results: Patients with continuous flow LVADs between 2015 and 2019 who underwent combined left and right heart catheterization ramp protocol at a single institution were enrolled. Patients were stratified by response to continuous flow LV assist device therapy: full responders, partial responders, or nonresponders per the Utah-Inova criteria. Hemodynamic data, including LV hemodynamics of peak LV dP/dt and tau (τ) were obtained at each phase. The 1-year heart failure hospitalization-free survival was the primary end point. Among 61 patients included in the current study 38 (62%) were classified as nonresponders, 14 as partial responders (23%), and 9 as full responders (15%). The baseline LV dP/dt and τ varied by response status (P ≤ .02) and generally correlated with reverse remodeling on linear regression. Biventricular filling pressures varied with τ and there was an interaction effect of speed on the relationship between τ and pulmonary capillary wedge pressure (P = .04). Last, τ was a prognostic marker and associated with 1-year HF hospital-free survival (odds ratio 1.04, 95% confidence interval 1.00-1.07, P = .02 per millisecond increase)., Conclusions: Significant correlations between τ and LV dP/dt and reverse remodeling were noted, with τ serving as a prognostic marker. A higher LVAD speed was associated with a greater reliance on LVAD for unloading. Future work should focus on defining the optimal level of LVAD support in relation to LV recovery., Competing Interests: Disclosures: Conflicts of Interest A.N.R., J.B.G, J.M.S., S.S.K, and A.L.C. have no financial relationships with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. A.B. has no conflicts of interest but would like to declare he is a cofounder of Rion, LLC. He has received grant funding and serves on the scientific advisory board of HCYTE., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) reduces mortality and improves outcomes in appropriately selected patients with heart failure (HF); however, response may vary., Objective: We sought to correlate 6-month CRT response assessed by clinical composite score (CCS) and left ventricular end-systolic volume index (LVESVi) with longer-term mortality and HF-related hospitalizations., Methods: Individual patient data from 5 prospective CRT studies-Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD), InSync III Marquis, predictors of response to cardiac resynchronization therapy (PROSPECT), and Adaptive CRT-were pooled. Classification of CRT response status using CCS and LVESVi were made at 6 months. Kaplan-Meier analyses were used to assess time to mortality. Cox proportional hazards regression models were used to compute hazard ratios (HRs) for the 3 levels of CRT response: improved, stabilized, and worsened. Adjusted models controlled for baseline factors known to influence both CRT response and mortality. HF-related hospitalization was compared between CRT response categories using incidence rate ratios., Results: Among a total of 1603 patients, 1426 and 1165 were evaluated in the CCS and LVESVi outcome assessments, respectively. Mortality was significantly lower for patients in the improved (CCS: HR 0.22; 95% confidence interval [CI] 0.15-0.31; LVESVi: HR 0.40; 95% CI 0.27-0.60) and stabilized (CCS: HR 0.38; 95% CI 0.24-0.61; LVESVi: HR 0.41; 95% CI 0.25-0.68) groups than in the worsened group for both measures after adjusting for potential confounders., Conclusion: Patients with a worsened CRT response status have a high mortality rate and HF-related hospitalizations. Stabilized patients have a more favorable prognosis than do worsened patients and thus should not be considered CRT nonresponders., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: It has been known that ventricular conduction delays play a key role in the cardiac resynchronization therapy (CRT) response of patients with advanced heart failure (HF). However, no study to our knowledge has yet evaluated the serial changes in conduction times measured between different electrodes of CRT devices., Methods and Results: The Reduction or Extension of Conduction Time with Ventricular Electromechanical Remodeling (RECOVER) study (NCT04397224) was designed to investigate serial changes in interelectrode conduction times and to elucidate their prognostic value. We plan to enroll 100 patients implanted with CRT systems with endocardial quadripolar left ventricular leads. Patients will be scheduled for follow-up every 3 months over a period of 2 years, where they will undergo measurement of interelectrode conduction times to evaluate their serial changes. The primary outcome of the RECOVER study is the correlation between the degree of conduction time changes and the CRT response as defined by echocardiography. The time course and prognostic value of the serial changes in conduction times will be investigated as well., Conclusion: The RECOVER study is investigating whether serial changes in interelectrode conduction times can be useful parameters in predicting the CRT response or detecting worsening HF at an early stage., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Oncostatin M (OSM), a member of the interleukin-6 family, functions as a major mediator of cardiomyocyte remodeling under pathological conditions. Its involvement in a variety of human cardiac diseases such as aortic stenosis, myocardial infarction, myocarditis, cardiac sarcoidosis, and various cardiomyopathies make the OSM receptor (OSMR) signaling cascades a promising therapeutic target. However, the development of pharmacological treatment strategies is highly challenging for many reasons. In mouse models of heart disease, OSM elicits opposing effects via activation of the type II receptor complex (OSMR/gp130). Short-term activation of OSMR/gp130 protects the heart after acute injury, whereas chronic activation promotes the development of heart failure. Furthermore, OSM has the ability to integrate signals from unrelated receptors that enhance fetal remodeling (dedifferentiation) of adult cardiomyocytes. Because OSM strongly stimulates the production and secretion of extracellular proteins, it is likely to exert systemic effects, which in turn, could influence cardiac remodeling. Compared with the mouse, the complexity of OSM signaling is even greater in humans because this cytokine also activates the type I leukemia inhibitory factor receptor complex (LIFR/gp130). In this article, we provide an overview of OSM-induced cardiomyocyte remodeling and discuss the consequences of OSMR/gp130 and LIFR/gp130 activation under acute and chronic conditions.

Background: Heart failure with reduced ejection fraction (HFrEF) is a heterogeneous syndrome. In heart failure (HF) classifications, right ventricle (RV) function was for a long time unrecognized in favor of left ventricular ejection fraction (LVEF). The response to sacubitril/valsartan might differ according to phenotypes and the impact of right ventricular characteristics on this response remains controversial., Objectives: First, we applied clustering analysis in a HFrEF population undergoing sacubitril/valsartan treatment according to guidelines, to identify phenotypes and their associated clinical outcomes. Secondly, we evaluated RV-remodeling., Material and Methods: It is a prospective, observational, single-center study conducted on 108 symptomatic patients (mean age 66 ±12.8 years, 22.2% women). First, the clustering analysis was applied in a HFrEF population undergoing sacubitril/valsartan treatment, according to the guidelines, in order to identify phenotypes and clinical outcomes associated with them. Secondly, we evaluated RV-remodeling., Results: Two distinct clusters were identified. Among the differences between phenotypes, RV (tricuspid annular plane systolic excursion (TAPSE) 16 ±4 mm compared to 19 ±4 mm, p < 0.001; RV free wall strain -19 ±5% compared to -21 ±4%, p = 0.046; RV fraction area change (FAC) 31 ±9% compared to 38 ±9%, p < 0.001), LV-filling pressure (E-wave deceleration time 138 (median: 41) ms compared to 180 (median: 94) ms, p < 0.001; E/e' 16.7 (median: 8.0) ms compared to 13.0 (median: 9.7) ms, p = 0.02) and creatinine level (106 ±34 μmol/L compared to 90 ±19 μmol/L, p = 0.002) were substantially different at the initiation of therapy. Major adverse cardiac events (MACEs) or death occurred in 38 out of 107 patients: 51.1% in cluster 1 compared to 24.2% in cluster 2 (p = 0.0074). A significant improvement in RV-functional parameters was observed under treatment. The TAPSE improved and correlated with the change in left ventricular (LV) function. Yet, it did not correlate with systolic pulmonary artery pressure (sPAP) and LV end-diastolic diameter., Conclusions: The HFrEF phenotype characterized by more severe RV dysfunction has a worse prognosis during sacubitril/valsartan therapy. Both RVand LV functions significantly improve when the patient is treated with sacubitril/valsartan.

Purpose: Hyperpolarized [1- 13 C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1- 13 C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long-term left ventricular effects of heart failure medication, and could identify responders to treatment., Methods: Thirty-five rats were scanned with hyperpolarized [1- 13 C]pyruvate MRS 3 days after MI or sham surgery. The animals were re-examined after 30 days of therapy with β-blockers and ACE-inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high-resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point., Results: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P < .001). Cardiac metabolism, measured by both hyperpolarized [1- 13 C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow-up. Three days post MI, low bicarbonate + CO 2 /pyruvate ratio was associated with low LVEF. At follow-up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO 2 /pyruvate ratio, as measured by hyperpolarized MRS., Conclusion: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1- 13 C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism., (© 2021 International Society for Magnetic Resonance in Medicine.)

Heart Failure (HF) is among the major causes of global morbidity as well as mortality. Increased prevalence, frequent and prolonged hospitalization, rehospitalization, long-term consumption of healthcare resources, absenteeism, and death upsurge the economic burden linked to HF. For decades, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Blockers (ARBs), Beta-Blockers (BBs), and mineralocorticoid receptor antagonists (MRA), have remained the mainstay of the standard of care for HF management. Despite their proven efficacy and cost-effectiveness, HF remains a global pandemic and is still increasing in prevalence. Sacubitril/ Valsartan (SAC/VAL) is an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) that proved out to be a game-changer drug in HF treatment. Recent data indicated that SAC/VAL is more efficient and can improve the overall quality of life of HF patients with reduced ejection fraction (HFrEF) with fewer side effects. It is now incorporated in the guidelines as an alternative to ACEIs or ARBs to lower morbidity in addition to mortality in HFrEF patients. This review article will discuss the current guidelines-approved indications and highlight the potential emerging indications, in addition to the currently ongoing clinical trials that will expand the use of SAC/VAL., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chronic heart failure is a clinical syndrome with multiple etiologies, associated with significant morbidity and mortality. Cardiac arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, are common in heart failure. A number of cardiac diseases including heart failure alter the expression and regulation of ion channels and transporters leading to arrhythmogenic electrical remodeling. Myocardial hypertrophy, fibrosis and scar formation are key elements of arrhythmogenic structural remodeling in heart failure. In this article, the mechanisms responsible for increased arrhythmia susceptibility as well as the underlying changes in ion channel, transporter expression and function as well as alterations in calcium handling in heart failure are discussed. Understanding the mechanisms of arrhythmogenic remodeling is key to improving arrhythmia management and the prevention of sudden cardiac death in patients with heart failure.

Objectives: This study sought to assess the impact of a more detailed classification of response on survival., Background: Cardiac resynchronization therapy (CRT) improves functional status and outcomes in selected populations with heart failure (HF). However, approximately 30% of patients do not improve with CRT by various metrics, and they are traditionally classified as nonresponders., Methods: REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) was a randomized trial of CRT among patients with mild HF. Patients were classified as Improved, Stabilized, or Worsened using prespecified criteria based on the clinical composite score (CCS) and change in left ventricular end-systolic volume index (LVESVi). All-cause mortality across CRT ON subgroups at 5 years was compared., Results: Of the 406 subjects surviving 1 year, 5-year survival differed between CCS subgroups (p = 0.03), with increased mortality in the Worsened response group. Of the 353 subjects with adequate echocardiograms, survival differed significantly between response groups (p < 0.001), also due to increased mortality in the Worsened group. When combining CCS and LVESVi results, the lowest survival was observed among subjects who worsened for both measures, whereas the highest survival occurred in subjects who did not worsen by either endpoint. Multivariate analysis showed that LVESVi worsening with CRT at 6 months, baseline LVESVi, and gender were independent predictors of survival., Conclusions: For both CCS and reverse remodeling, patients who worsen with CRT have a high mortality, although remodeling was the more important endpoint. Patients who stabilize early with CRT have a much better prognosis than previously recognized, suggesting that the current convention of nonresponder classification should be modified. (REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction]; NCT00271154)., Competing Interests: Funding Support and Author Disclosures The REVERSE trial was supported by Medtronic, Inc., Minneapolis, Minnesota. Drs. Gold, Linde, and Daubert have served as consultants to and received research grants from Medtronic. Dr. Gold has served as a consultant and receives research grants from Boston Scientific. Dr. Rickard has received a research grant from Abbott; and has been a consultant for Medtronic. Dr. Daubert has received research grants, speaker honoraria, and consulting fees from Medtronic and St. Jude Medical. Dr. Zimmerman has been an employee of Medtronic. Dr. Linde has received honoraria payments from Medtronic, Abbott, and Impulse Dynamics; and has been supported by grants from the Swedish Heart Lung Foundation and Stockholm City Council., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dilated cardiomyopathy (DCM) is increasingly recognized as a heterogenous disease with distinct phenotypes on late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging. While mid-wall striae (MWS) fibrosis is a widely recognized phenotypic risk marker, other fibrosis patterns are prevalent but poorly defined. Right ventricular (RV) insertion (RVI) site fibrosis is commonly seen, but without objective criteria has been considered a non-specific finding. In this study we developed objective criteria for RVI fibrosis and studied its clinical relevance in a large cohort of patients with DCM., Methods: We prospectively enrolled 645 DCM patients referred for LGE-CMR. All underwent standardized imaging protocols and baseline health evaluations. LGE images were blindly scored using objective criteria, inclusive of RVI site and MWS fibrosis. Associations between LGE patterns and CMR-based markers of adverse chamber remodeling were evaluated. Independent associations of LGE fibrosis patterns with the primary composite clinical outcome of heart failure admission or death were determined by multivariable analysis., Results: The mean age was 56 ± 14 (28% female) with a mean left ventricular (LV) ejection fraction (LVEF) of 37%. At a median of 1061 days, 129 patients (20%) experienced the primary outcome. Any abnormal LGE was present in 306 patients (47%), inclusive of 274 (42%) meeting criteria for RVI site fibrosis and 167 (26%) for MWS fibrosis. All with MWS fibrosis showed RVI site fibrosis. Solitary RVI site fibrosis was associated with higher bi-ventricular volumes [LV end-systolic volume index (78 ± 39 vs. 66 ± 33 ml/m 2 , p = 0.01), RV end-diastolic volume index (94 ± 28 vs. 84 ± 22 ml/m 2 (p < 0.01), RV end-systolic volume index (56 ± 26 vs. 45 ± 17 ml/m 2 , p < 0.01)], lower bi-ventricular function [LVEF 35 ± 12 vs. 39 ± 10% (p < 0.01), RV ejection fraction (RVEF) 43 ± 12 vs. 48 ± 10% (p < 0.01)], and higher extracellular volume (ECV). Patient with solitary RVI site fibrosis experienced a non-significant 1.4-fold risk of the primary outcome, increasing to a significant 2.6-fold risk when accompanied by MWS fibrosis., Conclusions: RVI site fibrosis in the absence of MWS fibrosis is associated with bi-ventricular remodelling and intermediate risk of heart failure admission or death. Our study findings suggest RVI site fibrosis to be pre-requisite for the incremental development of MWS fibrosis, a more advanced phenotype associated with greater LV remodeling and risk of clinical events.

Background Withdrawal of optimal medical therapy has been reported to relapse cardiac dysfunction in patients with dilated cardiomyopathy (DCM) whose cardiac function had improved. However, it is unknown whether beta-blockers can prevent deterioration of cardiac function in those patients. We examined the effect of beta-blockers on left ventricular ejection fraction (LVEF) in recovered DCM. Methods and Results We analyzed the clinical personal record of DCM, a national database of the Japanese Ministry of Health, Labor and Welfare, between 2003 and 2014. Recovered DCM was defined as a previously documented LVEF <40% and a current LVEF ≥40%. Patients with recovered DCM were divided into 2 groups according to the use of beta-blockers. A one-to-one propensity case-matched analysis was used. The primary outcome was defined as a decrease in LVEF >10% at 2 years of follow-up. Of 5370 eligible patients, 4104 received beta-blockers. Propensity score matching yielded 1087 pairs. Mean age was 61.9 years, and 1619 (74.5%) were men. Mean LVEF was 49.3±8.2%, and median B-type natriuretic peptide was 46.6 (interquartile range, 18.0-118.1) pg/mL. The primary outcome was observed less frequently in the beta-blocker group than in the no-beta-blocker group (19.6% versus 24.0%; odds ratio [OR], 0.77; 95% CI, 0.63-0.95; P =0.013). Subgroup analysis demonstrated that female patients (women: OR, 0.54; 95% CI, 0.36-0.81; men: OR, 0.88; 95% CI, 0.69-1.12; P for interaction=0.040) were benefited by beta-blockers. Conclusions Beta-blocker use could prevent deterioration of left ventricular systolic function in patients with recovered DCM.

Background: The mechanisms of improvement of left ventricular (LV) function with cardiac resynchronization therapy (CRT) are not yet elucidated. The aim of this study was to characterize CRT responder profiles through clustering analysis, on the basis of clinical and echocardiographic preimplantation data, integrating automatic quantification of longitudinal strain signals., Methods: This was a multicenter observational study of 250 patients with chronic heart failure evaluated before CRT device implantation and followed up to 4 years. Clinical, electrocardiographic, and echocardiographic data were collected. Regional longitudinal strain signals were also analyzed with custom-made algorithms in addition to existing approaches, including myocardial work indices. Response was defined as a decrease of ≥15% in LV end-systolic volume. Death and hospitalization for heart failure at 4 years were considered adverse events. Seventy features were analyzed using a clustering approach (k-means clustering)., Results: Five clusters were identified, with response rates between 50% in cluster 1 and 92.7% in cluster 5. These five clusters differed mainly by the characteristics of LV mechanics, evaluated using strain integrals. There was a significant difference in event-free survival at 4 years between cluster 1 and the other clusters. The quantitative analysis of strain curves, especially in the lateral wall, was more discriminative than apical rocking, septal flash, or myocardial work in most phenogroups., Conclusions: Five clusters are described, defining groups of below-average to excellent responders to CRT. These clusters demonstrate the complexity of LV mechanics and prediction of response to CRT. Automatic quantitative analysis of longitudinal strain curves appears to be a promising tool to improve the understanding of LV mechanics, patient characterization, and selection for CRT., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Few studies have investigated right atrial (RA) remodeling in heart failure (HF) with preserved ejection fraction (HFpEF). This study sought to characterize the RA remodeling in HFpEF and to determine its prognostic significance., Methods and Results: Patients with HFpEF were classified based on the presence of RA enlargement (RA volume index >39 mL/m 2 in men and >33 mL/m 2 in women). Compared with patients with normal RA size (n = 234), patients with RA dilation (n = 67) showed a higher prevalence of atrial fibrillation (AF), worse right ventricular systolic function, more severe pulmonary hypertension, and a greater prevalence of mild tricuspid regurgitation, as well as impaired RA reservoir function, with increased hepatobiliary enzyme levels. AF was strongly associated with the presence of RA dilation (odds ratio [OR] 10.2, 95% confidence interval [CI] 4.00-26.1 in current AF vs no AF and odds ratio 3.38, 95% CI 1.26-9.07, earlier AF vs no AF). Patients with RA dilation had more than a two-fold increased risk of composite outcomes of all-cause mortality or HF hospitalization (adjusted hazard ratio 2.01, 95% CI 1.09-3.70, P = .02). The presence of RA dilation also displayed an additive prognostic value over left atrial dilation alone., Conclusions: These data demonstrate that HFpEF with RA remodeling is associated with distinct echocardiographic features characterizing advanced right heart dysfunction with an increased risk of adverse outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Heart failure (HF) and atrial fibrillation (AF) are two major life-threatening diseases worldwide. Causes and mechanisms are incompletely understood, yet current therapies are unable to stop disease progression. In this review, we focus on the contribution of the transcriptional modulator, Jun dimerization protein 2 (JDP2), and on HF and AF development. In recent years, JDP2 has been identified as a potential prognostic marker for HF development after myocardial infarction. This close correlation to the disease development suggests that JDP2 may be involved in initiation and progression of HF as well as in cardiac dysfunction. Although no studies have been done in humans yet, studies on genetically modified mice impressively show involvement of JDP2 in HF and AF, making it an interesting therapeutic target.

Purpose of Review: To review reverse cardiac remodeling and guideline-directed medical and device therapy (GDMT) within the context of recent data on combined angiotensin receptor/neprilysin inhibitor (ARNI) therapy., Recent Findings: Preliminary data suggested that ARNI therapy led to significant reversal of deleterious cardiac remodeling. More definitive data regarding impact of ARNI therapy on remodeling parameters are now available from two prospective trials, PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure) and EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction). Both studies demonstrated marked improvements in biomarker and echocardiographic parameters of reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Much of the observed clinical benefit of sacubitril/valsartan therapy in patients with HFrEF is likely related to significant reverse cardiac remodeling. Ongoing trials will assess the role for ARNI therapy in patients with heart failure with preserved ejection fraction (HFpEF) and in the post-myocardial infarction setting. Future studies should comprehensively assess predictors of response to ARNI therapy.

Objectives: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT)., Background: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs., Methods: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection., Results: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups., Conclusions: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain., Competing Interests: Funding Support and Author Disclosures This study was funded by an unrestricted grant from Novartis and The St. Vincent’s Clinic Foundation, Australia. Dr. Keogh has conducted clinical trial research for Actelion, Pfizer, United Therapeutics, Arena, Acceleron, Bayer, Respira, GlaxoSmithKline, and Gilead. Dr. Macdonald has received an institutional research grant from Novartis; has been on the advisory boards of Novartis and AstraZeneca; has received speaker honoraria from Servier; and has received travel support from Transmedics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Inflammatory activation during acute ST-elevation myocardial infarction (STEMI) can contribute to post-infarct heart failure (HF). This study aimed to determine prognostic value of high-sensitivity C-reactive protein concentration (CRP) for HF over a long-term follow-up in 204 patients with a first STEMI undergoing guideline-based therapies including percutaneous coronary intervention. CRP was measured at admission, 24 h (CRP 24 ), discharge (CRP DC ), and one month (CRP 1M ) after index hospitalization for STEMI. Within a median period of 5.6 years post-index hospitalization for STEMI, hospitalization for HF (HFH) which is a primary endpoint, occurred in 24 patients (11.8%, HF+ group). During the study, 8.3% of HF+ patients died vs. 1.7% of patients without HFH (HF- group) ( p = 0.047). CRP 24 , CRP DC , and CRP 1M were significantly higher in HF+ compared to HF- group. The median CRP 1M in HF+ group was 2.57 mg/L indicating low-grade systemic inflammation, in contrast to 1.54 mg/L in HF- group. CRP 1M ≥ 2 mg/L occurred in 58.3% of HF+ vs. 42.8% of HF- group ( p = 0.01). Kaplan-Meier analysis showed decreased probability of survival free from HFH in patients with CRP 24 ( p < 0.001), CRP DC ( p < 0.001), and CRP 1M ( p = 0.03) in quartile IV compared to lower quartiles. In multivariable analysis, CRP DC significantly improved prediction of HFH over a multi-year period post-STEMI. Persistent elevation in CRP post STEMI aids in risk stratification for long-term HF and suggests that ongoing cardiac and low-grade systemic inflammation promote HF development despite guideline-based therapies.

Objective: The aim: To increase the treatment effectiveness of CHF patients after MI with stenting by using magnesium and potassium salts of gluconic acid, eplerenone, and rivaroxaban in complex therapy., Patients and Methods: Materials and methods: The research was performed at the premises of Ivano-Frankivsk Regional Clinical Cardiology Centre, Ukraine. 84 patients with CHF after past MI were examined., Results: Results and conclusions: A more pronounced anti-ischemic effect has been linked to the use of combination therapy with rivaroxaban on the background of basic therapy (BT) in patients with CHF after MI, compared with the use of magnesium and potassium salts of gluconic acid or eplerenone. The use of eplerenone in the complex treatment of these patients on the background of BT has been proven to provide a pronounced reverse remodeling of the left myocardium in the postinfarction period.

Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood. To address this question, we first used a murine coronary artery ligation MI model to reveal that an intact gut microbiome is important for cardiac repair. Specifically, gut microbiome disruption impairs normal inflammatory responses in infarcted myocardium, elevates adverse cardiac gene biomarkers, and leads to worse HF outcomes. Conversely, reconstituting the microbiome post-MI in mice with prior gut microbiome disruption improves healing, consistent with the notion that normal gut physiology contributes to cardiac repair. To investigate a role for the circadian system, we initially utilized circadian mutant Clock ∆19/∆19 mice, revealing that a functional circadian mechanism is necessary for gut microbiome benefits on post-MI cardiac repair and HF. Finally, we demonstrate that circadian-mediated gut responses that benefit cardiac repair can be conferred by time-restricted feeding, as wake time feeding of MI mice improves HF outcomes, but these benefits are not observed in MI mice fed during their sleep time. In summary, gut physiology is important for cardiac repair, and the circadian system influences the beneficial gut responses to improve post-MI and HF outcomes., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent data demonstrate promising effects on left ventricular dysfunction and left ventricular ejection fraction (LVEF) improvement following ablation for atrial fibrillation (AF) in patients with heart failure. We sought to study the relationship between LVEF, New York Heart Association class on presentation, and the end points of mortality and heart failure admissions in the CASTLE-AF study (Catheter Ablation for Atrial Fibrillation With Heart Failure) population. Furthermore, predictors for LVEF improvement were examined., Methods: The CASTLE-AF patients with coexisting heart failure and AF (n=363) were randomized in a multicenter prospective controlled fashion to ablation (n=179) versus pharmacological therapy (n=184). Left ventricular function and New York Heart Association class were assessed at baseline (after randomization) and at each follow-up visit., Results: In the ablation arm, a significantly higher number of patients experienced an improvement in their LVEF to >35% at the end of the study (odds ratio, 2.17; P <0.001). Compared with the pharmacological therapy arm, both ablation patient groups with severe (<20%) or moderate/severe (≥20% and <35%) baseline LVEF had a significantly lower number of composite end points (hazard ratio [HR], 0.60; P =0.006), all-cause mortality (HR, 0.54; P =0.019), and cardiovascular hospitalizations (HR, 0.66; P =0.017). In the ablation group, New York Heart Association I/II patients at the time of treatment had the strongest improvement in clinical outcomes (primary end point: HR, 0.43; P <0.001; mortality: HR, 0.30; P =0.001)., Conclusions: Compared with pharmacological treatment, AF ablation was associated with a significant improvement in LVEF, independent from the severity of left ventricular dysfunction. AF ablation should be performed at early stages of the patient's heart failure symptoms.

Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge about the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To identify the mechanism of action, we examined previously unobtainable measurements of cardiac function from in vivo, ex vivo, and in silico states of clinically relevant heart failure (HF) in large animals. High-resolution ex vivo magnetic resonance imaging and histological data were used along with state-of-the-art subject-specific computational model simulations. Ex vivo data were incorporated in detailed geometric computational models for swine hearts in health (n = 5), ischemic HF (n = 5), and ischemic HF treated with alginate hydrogel injection therapy (n = 5). Hydrogel injection therapy mitigated elongation of sarcomere lengths (1.68 ± 0.10μm [treated] vs. 1.78 ± 0.15μm [untreated], p<0.001). Systolic contractility in treated animals improved substantially (ejection fraction = 43.9 ± 2.8% [treated] vs. 34.7 ± 2.7% [untreated], p<0.01). The in silico models realistically simulated in vivo function with >99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as an LV mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated HF controls without causing negative secondary outcomes to cardiac function. STATEMENT OF SIGNIFICANCE: Heart failure is considered a growing epidemic and hence an important health problem in the US and worldwide. Its high prevalence (5.8 million and 23 million, respectively) is expected to increase by 25% in the US alone by 2030. Heart failure is associated with high morbidity and mortality, has a 5-year mortality rate of 50%, and contributes considerably to the overall cost of health care ($53.1 billion in the US by 2030). Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge concerning the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To understand the mechanism of action, we combined high-resolution ex vivo magnetic resonance imaging and histological data in swine with state-of-the-art subject-specific computational model simulations. The in silico models realistically simulated in vivo function with >99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as a left ventricular mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated heart failure controls without causing negative secondary outcomes to cardiac function. Moreover, if the hydrogel can be delivered percutaneously rather than via the currently used open-chest procedure, this therapy may become routine for heart failure treatment. A minimally invasive procedure would be in the best interest of this patient population; i.e., one that cannot tolerate general anesthesia and surgery, and it would be significantly more cost-effective than surgery., (Copyright © 2020. Published by Elsevier Ltd.)

Despite major progress in interventional and medical treatments, myocardial infarction (MI) and subsequent development of heart failure (HF) are still associated with high mortality. Both during ischemia reperfusion (IR) in the acute setting of MI, as well as in the chronic remodeling process following MI, oxidative stress substantially contributes to cardiac damage. Reactive oxygen species (ROS) generated within mitochondria are particular drivers of mechanisms contributing to IR injury, including induction of mitochondrial permeability transition or oxidative damage of intramitochondrial structures and molecules. But even beyond the acute setting, mechanisms like inflammatory signaling, extracellular remodeling, or pro-apoptotic signaling that contribute to post-infarction remodeling are regulated by mitochondrial ROS. In the current review, we discuss both sources and consequences of mitochondrial ROS during IR and in the chronic setting following MI, thereby emphasizing the potential therapeutic value of attenuating mitochondrial ROS to improve outcome and prognosis for patients suffering MI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natriuretic peptides (NPs) have become important diagnostic and prognostic biomarkers in cardiovascular diseases, particularly in heart failure (HF). Diagnosis and management of coronary artery disease and atrial fibrillation (AF) can also be guided by NP levels. When interpreting NP levels, however, the caveat is that age, sex, body mass index, renal dysfunction, and race affect the clearance of NPs, resulting in different cut-off values in clinical practice. In AF, NP levels have been associated with incident AF in the general population, recurrences after catheter ablation, prediction of clinical prognosis, and the risk of stroke. In this article, we first review and summarize the current evidence and the roles of B-type NP and atrial NP in HF and coronary artery disease and then focus on the increasing utility of NPs in the diagnosis and management of and the research into AF.

Background: Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of β 1 -adrenoceptor (β 1 -AA), a catecholamine-like substance with β 1 -adrenergic activity, in patients with heart failure. Although evidence demonstrates that this autoantibody may alter T cell proliferation and secretion, the role of T lymphocytes in heart failure induced by β 1 -AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by β 1 -AA., Methods and Results: β 1 -AA monoclonal antibodies (β 1 -AAmAb) produced using the hybridoma technique were administered in wild-type mice or T lymphocyte deficiency nudes for 12 weeks. T lymphocytes from heart failure patients and neonatal cardiomyocytes were utilized in vitro. Mouse protein antibody array analysis was employed to detect the cytokines responsible for β 1 -AAmAb-induced heart failure. Compared to wild-type mice, T lymphocyte deficiency mice prevented cardiac function from getting worse, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. As shown by protein array, the serum level of interleukin (IL)-6 was significantly lower in the nude group as compared to wild-type after β 1 -AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by β 1 -AAmAb caused direct damage in the cardiomyocytes, and β 1 -AAmAb promoted proliferation of T lymphocytes isolated from patients with heart failure and increased IL-6 release. IL-6-specific siRNA virtually abolished cardiomyocyte apoptosis, suggesting that IL-6 may be a key cytokine released by T lymphocytes and responsible for β 1 -AAmAb-induced cardiac remodeling., Conclusions: Collectively, we demonstrate that β 1 -AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.

Background: The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure., Methods: Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles., Results: In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p < 0.05) and an increased incidence of Early afterdepolarisations (+ 150%), while treatment with Entinostat in failing hearts could partially prevent this effect (from 250 ± 41 ms to 170 ± 53 ms, p < 0.05; reduction in EAD by 50%). Entinostat treatment partially restored KCNH2 and Cav1.3 gene expressions in failing hearts, and inhibited the development of cardiac fibrosis in vivo., Conclusion: In a rabbit model of heart failure, Entinostat diminishes heart failure related prolongation of repolarization and partially restores KCNH2 and Cav1.3 expression. In addition, Entinostat exerts antifibrotic properties both in vitro and in vivo. Thus, Entinostat might be an interesting candidate for the pharmaceutical therapy of heart failure directed against structural and electrical remodeling.

Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8 years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7 years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C-terminal telopeptide, matrix metalloproteinase-1) and high-sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (-14.2%) and increase in E/e' ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, -14.2%; C-terminal telopeptide, -16.4%; P≤0.029). An increase in E/e' ratio over time was borderline associated with lower matrix metalloproteinase-1 (+9.8%) and lower matrix metalloproteinase-1/tissue inhibitor of metalloproteinase-1 ratio (+11.9%; P≤0.041). Higher high-sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow-up ( P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation.

Background: Functional mitral regurgitation (FMR) and atrial fibrillation (AF) are frequent heart failure (HF) complications. Cardiac resynchronization therapy (CRT) can improve FMR; however, little is known about the influence of AF on FMR improvement., Objective: The purpose of this study was to investigate the mechanisms and impact of baseline AF on FMR improvement after CRT., Methods: CRT recipients with HF, AF, or sinus rhythm (SR) at baseline with moderate or severe FMR, were included from an ongoing registry. Left atrial (LA), mitral annular (MA), and left ventricular (LV) dimensions were evaluated echocardiographically. FMR improvement was defined as ≥1 grade decrease from baseline to 6-month follow-up. Clinical and echocardiographic measurements were performed at baseline and 6-month follow-up., Results: A total of 419 patients (age 66 ± 8 years; 73% male) were analyzed. At 6-month follow-up, FMR improved in 145 patients (45.6%) with SR vs 31 of AF patients (30.7%) (P = .011). Despite similar LV reverse remodeling at 6 months after CRT (LV end-systolic volume decreased by 32.1 ± 43.2 mL in the SR group and by 27.7 ± 6.3 mL in those with AF; P = .353), patients with SR exhibited smaller LA volumes (63.0 ± 26.5 mL vs 103.1 ± 41.0 mL; P <.001) and MA diameters (42.3 ± 5.6 mm vs 46.1 ± 5.8 mm; P <.001) compared to AF patients., Conclusion: FMR improvement is more common in CRT recipients in SR vs AF, despite a similar degree of LV remodeling. LA volume and MA diameter are greater in the AF group, causing the negative impact of AF on FMR improvement in CRT, as well as indicating a potential therapeutic target (ie, AF rhythm control)., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Professional guidelines are based on the best available evidence. However, patients treated in clinical practice may differ from those included in reference trials., Objective: The aim of this study was to evaluate the effects of cardiac resynchronization therapy (CRT) in a large population of patients implanted with a CRT device stratified in accordance with the 2016 European heart failure (HF) guidelines., Methods: We collected data on 930 consecutive patients from the Cardiac Resynchronization Therapy MOdular REgistry. The primary end point was a composite of death and HF hospitalization., Results: Five hundred sixty-three (60.5%) patients met class I indications, 145 (15.6%) class IIa, 108 (11.6%) class IIb, and 114 (12.3%) class III. After a median follow-up of 1001 days, 120 (14.7%) patients who had an indication to CRT had died and 71 (8.7%) had been hospitalized for HF. The time to the end point was longer in patients with a class I indication (hazard ratio 0.55; 95% confidence interval 0.39-0.76; P = .0001). After 12 months, left ventricular (LV) end-systolic volume had decreased by ≥15% in 61.5% (320/520) of patients whereas in 57.5% (389/676) of patients the absolute LV ejection fraction improvement was ≥5%. Adherence to class I was also associated with an absolute LV ejection fraction increase of >5% (P = .0142) and an LV end-systolic volume decrease of ≥15% (P = .0055)., Conclusion: In our population, ∼60% of patients underwent implantation according to the 2016 European HF guidelines class I indication. Adherence to class I was associated with a lower death and HF hospitalization rates and better LV reverse remodeling., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)