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Background: The impact of tricuspid regurgitation (TR) on cardiac remodeling has not been thoroughly studied in a randomized controlled trial using advanced imaging., Objectives: The goal of this analysis was to provide comparative longitudinal changes in right heart remodeling using cardiac magnetic resonance and time-resolved functional computed tomography (4D-CT) in patients with symptomatic severe TR randomized to TriClip vs medical therapy (control)., Methods: TRILUMINATE Pivotal (Clinical Trial to Evaluate Cardiovascular Outcomes In Patients Treated With the Tricuspid Valve Repair System Pivotal) is an international randomized controlled trial in symptomatic patients with severe TR. A prospective imaging substudy was performed on TRILUMINATE Pivotal subjects at 10 sites. Cardiac magnetic resonance and 4D-CT were performed following dedicated imaging protocols at baseline and at 30 days, and a final 4D-CT at 1 year (all assessed by an imaging core lab)., Results: Sixty-nine randomized subjects (31 TriClip, 38 control) were enrolled. TR volume significantly decreased with TriClip at 30 days (P < 0.0001; 70% reduction). A strong association (r = 0.90; P < 0.0001) was observed between changes in TR volume and right ventricular end-diastolic volume at 30 days. Significant reductions in right ventricular end-diastolic volume (12% reduction; P < 0.001) and tricuspid annular area (11% reduction; P < 0.0001) were seen at 30 days and sustained through 1 year with TriClip. No meaningful changes were observed in the control group., Conclusions: Advanced imaging from the TRILUMINATE Pivotal imaging substudy demonstrated that TriClip effectively reduced TR. Significant cardiac remodeling was observed at 30 days and sustained at 1 year. With TriClip, the extent of cardiac remodeling was associated with the degree of TR reduction. (Clinical Trial to Evaluate Cardiovascular Outcomes In Patients Treated With the Tricuspid Valve Repair System Pivotal; NCT03904147)., Competing Interests: Funding Support and Author Disclosures This study was funded by Abbott. Dr Cavalcante has received consulting fees from 4C Medical, Abbott, Alleviant, Anteris, Boston Scientific, Circle Cardiovascular Imaging, Edwards Lifesciences, JenaValve, JC Medical, Medtronic, Novo Nordisk, Pie Medical, Siemens Healthineers, Shockwave, and Zoll; and has received research grant support from Abbott Structural, Allina Health Foundation, JenaValve, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI). Dr Scherer has received consulting/speaker fees/honoraria from Abbott, Boston Scientific, Edwards Lifesciences, HeartFlow, Philips, and Siemens; and has received institutional grant/research support from Boston Scientific and HeartFlow. Dr Fukui has served as a consultant for Edwards Lifesciences and Anteris. Dr Harb has served as a speaker for Edwards Lifesciences; and has served as a consultant and speaker for Abbott, Boston Scientific, and TeraRecon. Dr Schwartz has served as a consultant for Abbott, Boston Scientific, Cordis, Edwards Lifesciences, Medtronic, and Phillips. Dr Ricciardi has received consultant and speaker fees from Abbott. Dr Khalique has received consulting fees from Siemens, Philips, Edwards, Croivalve, Triflo, and Restore Medical. Dr Kodali has received grant/research support from Boston Scientific, Edwards Lifesciences, and Medtronic; has received consulting fees/honoraria from Ancora Heart Inc, Aria CV Inc, Dura Biotech, Thubrikar Aortic Valve Inc, and Valfix Medical; and has owned equity from Admedus Regen Pty Ltd., Dura Biotech, Supira Medical, and Trisol Medical. Dr Whisenant has received consulting fees/honoraria from Abbott and Edwards Lifesciences. Dr Yadav is a consultant/speaker for Edwards Lifesciences, Abbott Vascular, Boston Scientific, and Medtronic; is on the Medical Advisory Board of Dasi Simulations, Trisol, and Opus; and has equity in Dasi Simulations and Opus. Dr Emaminia has received consultant fees from Abbott. Dr Batchelor has consulted for Abbott, Edwards, Boston Scientific, and Medtronic; and has received research support from Abbott and Boston Scientific. Dr Lin is an employee of Abbott. Dr Trusty is an employee of Abbott. Dr Hahn has served as a speaker for Abbott, Baylis Medical, Edwards Lifesciences, and Philips. Dr Adams has served as the national coprincipal investigator of Abbott TRILUMINATE Pivotal Trial, Medtronic APOLLO U.S. Pivotal Trial, ReChord U.S. Pivotal Trial, and Medtronic CoreValve U.S. Pivotal Trial. Dr Sorajja has served as a consultant for Boston Scientific, Edwards Lifesciences, Evolution Medical, Medtronic, Shifamed, TriFlo, and WL Gore; has served as a member of the advisory board for VDyne and Anteris; and has served as the principal investigator of clinical trials for Abbott and HighLife. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Aortic stenosis (AS) and mitral regurgitation (MR) result in different patterns of left ventricular remodeling and hypertrophy., Objectives: We characterized left ventricular wall stress (LVWS) profiles in pressure and volume-overloaded systems, examined the relationship between baseline LVWS and cardiac remodeling, and assessed the acute effects of valve intervention on LVWS using invasive pressures combined with cardiac magnetic resonance (CMR) imaging measures of left ventricular volumes/mass., Methods: A total of 47 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) and 15 patients with severe MR undergoing MitraClip (MC) underwent a 6-minute walk test (6MWT), transthoracic echocardiogram, and CMR before their procedures. Catheters in the left ventricle were used to record hemodynamic changes before and after valve/clip deployment. This was integrated with CMR data to calculate LVWS before and after intervention., Results: The TAVR group demonstrated significant reductions in systolic LVWS post procedure (median 24.7 Pa [IQR: 14 Pa] pre vs median 17.3 Pa [IQR: 12 Pa] post; P < 0.001). The MC group demonstrated significant reductions in diastolic LVWS (median 6.4 Pa [IQR: 5 Pa] pre vs median 4.3 Pa [IQR: 4.1 Pa] post; P = 0.021) with no significant change in systolic LVWS (30.6 ±1.61 pre vs 33 ±2.47 Pa post; P = 0.16). There was an inverse correlation between baseline systolic LVWS and 6MWT in the TAVR group (r = -0.31; P = 0.04)., Conclusions: TAVR results in significant reductions in systolic LVWS acutely. MC results in significant reductions in diastolic LVWS. Higher baseline systolic LVWS in TAVR is associated with shorter 6MWT suggesting that in AS, LVWS may be a useful marker of early decompensation., Competing Interests: Funding Support and Author Disclosures Prof Taylor is supported by an National Health and Medical Research Council (NHMRC) Leadership Investigator grant and A/Professor Dion Stub is supported by National Heart Foundation and NHMRC Research Fellowships. All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice., Objectives: The purpose of this study was to investigate associations among Sac/Val doses and changes in prognostic biomarkers, health status, and cardiac remodeling among individuals with HFrEF through 12 months of treatment with Sac/Val administered per usual care., Methods: A total of 794 persons with HFrEF (ejection fraction [EF] ≤40%) were categorized according to average daily doses of Sac/Val divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e') were assessed., Results: The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories., Conclusions: Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val doses. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183., Competing Interests: Funding Support and Author Disclosures The PROVE-HF study was funded by Novartis Pharmaceuticals. Dr Mohebi is supported by a Barry fellowship. Dr Piña has participated on advisory boards for Vifor and AstraZeneca; and has served as a steering committee member for Novartis. Drs Prescott and Ward are employees of Novartis Pharmaceuticals. Dr Butler is a consultant for Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide, and Vifor. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, Merck, Cytokinetics, and Myokardia; has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, and Sequana; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Prevencio, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, Takeda and Vifor. Dr Liu has reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR)., Objectives: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology., Methods: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals., Results: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals., Conclusions: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR., Competing Interests: Funding Support and Author Disclosures This work has been funded by the Canadian Institutes for Health Research (CIHR—grant #399323). Dr Clavel is supported by a New National Investigator from the Heart and Stroke Foundation of Canada and an Early Carrier Investigator Award from the CIHR. Dr Beaudoin is supported by the Fonds de Recherche du Québec-Santé (FRQS). The other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Mature B lymphocytes alter the recovery of cardiac function after acute myocardial infarction (MI) in mice. Follicular B cells and marginal zone B (MZB) cells are spatially distinct mature B-cell populations in the spleen, and they exert specific functional properties. microRNA-21 (miR21)/hypoxia-inducible factor-α (HIF-α)-related pathways have been shown to govern B-cell functions., Objectives: The goal of this study was to unravel the distinct role of MZB cells and that of endogenous activation of miR21/HIF-α signaling in MZB cells during post-ischemic injury., Methods: Acute MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Cardiac function and remodeling were assessed by using echocardiography and immunohistochemistry. To determine the specific role of MZB cells, the study used mice with B-cell lineage-specific conditional deletion of Notch signaling, which leads to selection deficiency of MZB cells. To evaluate the role of the HIF-1α isoform, mice were generated with MZB-cell lineage-specific conditional deletion of Hif1a., Results: Acute MI prompted an miR21-dependent increase in HIF-1α, particularly in splenic MZB cells. MZB cell deficiency and MZB cell-specific deletion of miR21 or Hif1a improved cardiac function after acute MI. miR21/HIF-1α signaling in MZB cells was required for Toll-like receptor dependent expression of the monocyte chemoattractant protein CCL7, leading to increased mobilization of inflammatory monocytes to the ischemic myocardium and to adverse post-ischemic cardiac remodeling., Conclusions: This work reveals a novel function for the miR21/HIF-1α pathway in splenic MZB cells with potential major implications for the modulation of cardiac function after acute MI., Competing Interests: Funding Support and Author Disclosures This work was supported by Fondation pour la Recherche Médicale (DEQ20160334910, Prof Silvestre; FDT20160435312, Prof Zlatanova), Fondation de France (FDF 00066471, Profs Silvestre and Pinto), Fédération Française de Cardiologie (Profs Silvestre and Sun) China Scholarship Council (No. 201708310220, Prof Sun) French National Research Agency (ANR to Prof Silvestre), and institutional grants from Université de Paris and the French National Institute for Health and Medical Research. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This paper aims to provide an important update on the recent preclinical and clinical trials using cell therapy strategies and engineered heart tissues for the treatment of postinfarction left ventricular remodeling and heart failure. In addition to the authors' own works and opinions on the roadblocks of the field, they discuss novel approaches for cardiac remuscularization via the activation of proliferative mechanisms in resident cardiomyocytes or direct reprogramming of somatic cells into cardiomyocytes. This paper's main mindset is to present current and future strategies in light of their implications for the design of future patient trials with the ultimate objective of facilitating the translation of discoveries in regenerative myocardial therapies to the clinic., Competing Interests: Funding Support and Author Disclosures This work was supported in part by the NIH UO1 HL134764. Dr Garry is the cofounder of NorthStar Genomics with no compensation. Dr Marbán has significant equity in Capricor Inc. Dr Zimmermann is founder and advisor of Repairon GmbH with no compensation. Dr Kamp has received modest compensation as a consultant for FujifilmCDI. Dr Wu is cofounder and advisor of Khloris Biosciences. Dr Dzau served on the Medtronic board until 2014, and received deferred compensation until 2018. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertensive disorders of pregnancy (HDP) are associated with short-term cardiac structure and function abnormalities, but later life changes are not well studied., Objectives: This study aimed to determine if HDP history is associated with echocardiographic differences 8 to 10 years after delivery, and if subgroups with placental maternal vascular malperfusion (MVM) lesions or current hypertension may be particularly affected., Methods: Women with pregnancies delivered from 2008 to 2009 were selected from a clinical cohort with abstracted pregnancy and placental pathology data to undergo transthoracic echocardiography (2017 to 2020). Medical history, blood pressure, and weight were measured at the study visit., Results: The authors enrolled 132 women (10 ± 1 years post-delivery, age 38 ± 6 years): 102 with normotensive pregnancies and 30 with HDP: pre-eclampsia (n = 21) or gestational hypertension (n = 9). Compared with women with normotensive pregnancies, those with HDP history were more likely to have current hypertension (63% vs. 26%; p < 0.001). After adjusting for age, race, MVM lesions, body mass index, current hypertension, and hemoglobin A1c, women with HDP history had higher interventricular septal thickness (β = 0.08; p = 0.04) and relative wall thickness (β = 0.04; p = 0.04). In subgroup analyses, those with both HDP history and current hypertension had a higher proportion of left ventricular remodeling (79.0%) compared with all other groups (only HDP [36.4%; p = 0.01], only current hypertension [46.2%; p = 0.02], and neither HDP nor hypertension [38.2%; p < 0.001]), and lower mitral inflow E/A and annular e'. Accounting for placental MVM lesions did not impact results., Conclusions: Women with both HDP history and current hypertension have pronounced differences in left ventricular structure and function a decade after pregnancy, warranting continued surveillance and targeted therapies for cardiovascular disease prevention., Competing Interests: FUNDING SUPPORT AND Author Disclosures This study was funded by an AHA Go Red for Women Grant (16SFRN28930000) and a University of Pittsburgh Medical Center Heart and Vascular Institute Fellow Research Grant. Dr. Countouris was funded by the National Institutes of Health (NHLBI T32 Training Grant HL129964). 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. Published by Elsevier Inc. All rights reserved.)

Myocardial ischemia and infarction, both in the acute and chronic phases, are associated with cardiomyocyte loss and dramatic changes in the cardiac extracellular matrix (ECM). It has long been appreciated that these changes in the cardiac ECM result in altered mechanical properties of ischemic or infarcted myocardial segments. However, a growing body of evidence now clearly demonstrates that these alterations of the ECM not only affect the structural properties of the ischemic and post-infarct heart, but they also play a crucial and sometimes direct role in mediating a range of biological pathways, including the orchestration of inflammatory and reparative processes, as well as the pathogenesis of adverse remodeling. This final part of a 4-part JACC Focus Seminar reviews the evidence on the role of the ECM in relation to the ischemic and infarcted heart, as well as its contribution to cardiac dysfunction and adverse clinical outcomes., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown., Objectives: This study aimed to characterize cardiac sympathovagal balance and proarrhythmia in a canine model of PVC-CM., Methods: In 12 canines, the investigators implanted epicardial pacemakers and radiotelemetry units to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA), and arterial blood pressure. Bigeminal PVCs (200 ms coupling) were applied for 12 weeks to induce PVC-CM in 7 animals then disabled for 4 weeks to allow complete recovery of left ventricular ejection fraction (LVEF), versus 5 sham controls., Results: After 12 weeks of PVCs, LVEF (p = 0.006) and dP/dT (p = 0.007) decreased. Resting SNA (p = 0.002) and VNA (p = 0.04), exercise SNA (p = 0.01), SNA response to evoked PVCs (p = 0.005), heart rate (HR) at rest (p = 0.003), and exercise (p < 0.04) increased, whereas HR variability (HRV) decreased (p = 0.009). There was increased spontaneous atrial (p = 0.02) and ventricular arrhythmias (p = 0.03) in PVC-CM. Increased SNA preceded both atrial (p = 0.0003) and ventricular (p = 0.009) arrhythmia onset. Clonidine suppressed SNA and abolished all arrhythmias. After disabling PVC for 4 weeks, LVEF (p = 0.01), dP/dT (p = 0.047), and resting VNA (p = 0.03) recovered to baseline levels. However, SNA, resting HR, HRV, and atrial (p = 0.03) and ventricular (p = 0.03) proarrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p = 0.02) but not ventricles (p = 0.2) of PVC-CM and recovered animals versus sham controls., Conclusions: Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympathovagal balance is an important trigger and substrate for atrial and ventricular proarrhythmia., (Published by Elsevier Inc.)

Background: The impact of aging on cardiac function is not fully elucidated. Speckle-tracking echocardiography can unmask subclinical cardiac dysfunction., Objectives: This study investigated the impact of healthy aging on left ventricular (LV), right ventricular (RV), and left atrial (LA) performance and their relationship with serum B-type natriuretic peptide (BNP) levels in a sample of the general population without prevalent cardiovascular risk factors and structural heart disease., Methods: Speckle-tracking echocardiography was performed to assess LV global longitudinal strain (LVGLS), RV free wall strain, and LA phasic strain in 481 normal weight healthy participants who underwent extensive cardiovascular examination. Elevated BNP was defined as BNP >37.82 pg/ml for men and >50.86 pg/ml for women, which was the 90th percentile of BNP value distribution in the study population., Results: Mean age was 60 ± 12 years (range: 24 to 86 years), and 46% of the participants were men. The earliest alteration of age-related cardiac performance was observed in LA reservoir and conduit strain starting from decade 5, followed by elevated E/e' from decade 6. LVGLS decreased starting from decade 7, whereas there were no significant differences in RV strain, LV ejection fraction, or LV mass index across the decades. In the multivariable linear regression analyses, age was an independent predictor of decreased LVGLS (standardized β = 0.21; p < 0.001) and decreased LA phasic strain (standardized β = -0.40 and -0.61 for reservoir and conduit strain; both p < 0.001). Age and LA strain were significantly associated with elevated BNP values (adjusted odds ratios: 1.10 and 0.93; both p < 0.05, respectively), independent of ventricular morphology and function., Conclusions: Decreases in LA reservoir and conduit strain are the earliest markers of age-related cardiac remodeling, and LA reservoir strain is an independent predictor of elevated serum BNP level, with both possibly being markers of increased risk of heart failure in older adults., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The combination of cardiomyocyte (CM) and vascular cell (VC) fetal reprogramming upon stress culminates in end-stage heart failure (HF) by mechanisms that are not fully understood. Previous studies suggest KLF15 as a key regulator of CM hypertrophy., Objectives: This study aimed to characterize the impact of KLF15-dependent cardiac transcriptional networks leading to HF progression, amenable to therapeutic intervention in the adult heart., Methods: Transcriptomic bioinformatics, phenotyping of Klf15 knockout mice, Wnt-signaling-modulated hearts, and pressure overload and myocardial ischemia models were applied. Human KLF15 knockout embryonic stem cells and engineered human myocardium, and human samples were used to validate the relevance of the identified mechanisms., Results: The authors identified a sequential, postnatal transcriptional repression mediated by KLF15 of pathways implicated in pathological tissue remodeling, including distinct Wnt-pathways that control CM fetal reprogramming and VC remodeling. The authors further uncovered a vascular program induced by a cellular crosstalk initiated by CM, characterized by a reduction of KLF15 and a concomitant activation of Wnt-dependent transcriptional signaling. Within this program, a so-far uncharacterized cardiac player, SHISA3, primarily expressed in VCs in fetal hearts and pathological remodeling was identified. Importantly, the KLF15 and Wnt codependent SHISA3 regulation was demonstrated to be conserved in mouse and human models., Conclusions: The authors unraveled a network interplay defined by KLF15-Wnt dynamics controlling CM and VC homeostasis in the postnatal heart and demonstrated its potential as a cardiac-specific therapeutic target in HF. Within this network, they identified SHISA3 as a novel, evolutionarily conserved VC marker involved in pathological remodeling in HF., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previously, we have shown that radiofrequency (RF) renal denervation (RDN) reduces myocardial infarct size in a rat model of acute myocardial infarction (MI) and improves left ventricular (LV) function and vascular reactivity in the setting of heart failure following MI., Objectives: The authors investigated the therapeutic efficacy of RF-RDN in a clinically relevant normotensive swine model of heart failure with reduced ejection fraction (HFrEF)., Methods: Yucatan miniswine underwent 75 min of left anterior descending coronary artery balloon occlusion to induce MI followed by reperfusion (R) for 18 weeks. Cardiac function was assessed pre- and post-MI/R by transthoracic echocardiography and every 3 weeks for 18 weeks. HFrEF was classified by an LV ejection fraction <40%. Animals who met inclusion criteria were randomized to receive bilateral RF-RDN (n = 10) treatment or sham-RDN (n = 11) at 6 weeks post-MI/R using an RF-RDN catheter., Results: RF-RDN therapy resulted in significant reductions in renal norepinephrine content and circulating angiotensin I and II. RF-RDN significantly increased circulating B-type natriuretic peptide levels. Following RF-RDN, LV end-systolic volume was significantly reduced when compared with sham-treated animals, leading to a marked and sustained improvement in LV ejection fraction. Furthermore, RF-RDN improved LV longitudinal strain. Simultaneously, RF-RDN reduced LV fibrosis and improved coronary artery responses to vasodilators., Conclusions: RF-RDN provides a novel therapeutic strategy to reduce renal sympathetic activity, inhibit the renin-angiotensin system, increase circulating B-type natriuretic peptide levels, attenuate LV fibrosis, and improve left ventricular performance and coronary vascular function. These cardioprotective mechanisms synergize to halt the progression of HFrEF following MI/R in a clinically relevant model system., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Ejection fraction (EF) reflects both cardiac function and remodeling, and is widely recognized as a valuable diagnostic and prognostic tool. Its use in a variety of settings, ranging from heart failure and myocardial infarction to valvular heart disease, has made it a cornerstone of modern cardiology, pervading guidelines and practice. However, the development of the test was in another era, with younger patients and a lower prevalence of heart failure with preserved EF. The performance expectations of EF in the current era are also demanding-in relation to detection of subclinical LV dysfunction, and especially relating to recognition of changes in LV function on sequential testing-for example in patients taking cardiotoxic drugs. This review discusses whether the impressive evidence base for EF justifies its ongoing use in the context of newer markers of LV function, and the sophisticated questions posed by modern cardiology., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sacubitril/valsartan (SAC/VAL) is approved by the U.S. Food and Drug Administration for heart failure with reduced ejection fraction (HFrEF)., Objectives: This study investigated the effects of SAC/VAL on acute myocardial infarction (MI) and cardiac remodeling in a translational rabbit model of MI., Methods: New Zealand White rabbits were sedated and underwent conscious MI (45-min ischemia) by balloon inflation (previously implanted surgically) followed by 72 h (acute protocol) or 10 weeks (chronic protocols) of reperfusion. "Infarct-sparing" protocol: SAC/VAL, VAL, or placebo were randomly allocated and administered at reperfusion. "HFrEF-treatment" protocol: rabbits were randomized, and treatment commenced after echocardiography-confirmed left ventricular ejection fraction (LVEF) ≤40%. "HFrEF-prevention" protocol: treatment started at reperfusion and continued daily throughout the study., Results: Compared with placebo, SAC/VAL and VAL significantly reduced infarct size (TTC staining) and plasma troponin levels; however, only SAC/VAL preserved LVEF at 72 h post-MI. In the HFrEF-treatment protocol, LVEF improvement was observed with SAC/VAL compared with both placebo and VAL starting 2 weeks post-treatment, a benefit that persisted throughout study duration. In the HFrEF-prevention protocol, SAC/VAL and VAL attenuated the decline in LVEF post-MI, although SAC/VAL offered better functional protection. The functional improvement observed in both treatment protocols was paralleled by significant reduction in left ventricular (LV) scar size (Picrosirius red staining) in the SAC/VAL groups., Conclusions: Reperfusion therapy with SAC/VAL or VAL offers robust acute infarct-sparing benefits; however, SAC/VAL treatment offered superior short-term and long-term benefits in preventing MI-induced LV dysfunction compared with VAL. SAC/VAL also significantly attenuated LV scar size following MI compared with placebo, whereas VAL did not reach statistical significance in scar reduction., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Alcohol-induced cardiotoxicity is incompletely understood. Specifically, the long-term impact of alcohol use on ventricular remodeling or dysfunction, its modulators, and effect thresholds among young adults remain controversial., Objectives: The authors sought to evaluate a potential relationship between alcohol intake and cardiac remodeling, assessed by echocardiography, over 20 years of follow-up., Methods: Among the CARDIA (Coronary Artery Risk Development in Young Adults) study cohort, the authors studied all subjects without baseline heart disorders who provided adequate information on their drinking habits and underwent echocardiographic evaluation at years 5 and 25 of the study. The echocardiographic outcomes were left ventricular (LV) ejection fraction, indexed LV end-diastolic volume and LV mass, and left atrial diameter. Participants were grouped according to their weighted-average weekly drinking habits. An additional analysis used the estimated cumulative alcohol consumption. Regression models and multivariable fractional polynomials were used to evaluate the association between alcohol consumption and the outcomes., Results: Among the 2,368 participants, alcohol consumption was an independent predictor of higher indexed LV mass (p = 0.014) and indexed LV end-diastolic volume (p = 0.037), regardless of sex. No significant relationship between alcohol intake and LV ejection fraction was found. Drinking predominantly wine was associated with less cardiac remodeling and there was a nonsignificant trend for a harmful effect of binge drinking., Conclusions: After 20 years of follow-up, alcohol intake was associated with adverse cardiac remodeling, although it was not related with LV systolic dysfunction in this initially healthy young cohort. Our results also suggest that drinking predominantly wine associates with less deleterious findings in cardiac structure., (Copyright © 2018 American College of Cardiology Foundation. All rights reserved.)

Myocardial injury induces significant changes in ventricular structure and function at both the cellular and anatomic level, leading to ventricular remodeling and subsequent heart failure. Unloading left ventricular pressure has been studied in both the short-term and long-term settings, as a means of preventing or reversing cardiac remodeling. In acute myocardial infarction, cardiac unloading is used to reduce oxygen demand and limit infarct size. Research has demonstrated the benefits of short-term unloading with mechanical circulatory support devices before reperfusion in the context of acute myocardial infarction with cardiogenic shock, and a confirmatory trial is ongoing. In chronic heart failure, ventricular unloading using mechanical circulatory support can reverse many of the cellular and anatomic changes that accompany ventricular remodeling. Ongoing research is evaluating the ability of left ventricular assist devices to promote myocardial recovery and remission from clinical heart failure., (Copyright © 2018. Published by Elsevier Inc.)

Background: Left ventricular (LV) hypertrophy, a key process in human cardiac disease, results from cellular (hypertrophy) and extracellular matrix expansion (interstitial fibrosis)., Objectives: This study sought to investigate whether human myocardial interstitial fibrosis in aortic stenosis (AS) is plastic and can regress., Methods: Patients with symptomatic, severe AS (n = 181; aortic valve area index 0.4 ± 0.1 cm 2 /m 2 ) were assessed pre-aortic valve replacement (AVR) by echocardiography (AS severity, diastology), cardiovascular magnetic resonance (CMR) (for volumes, function, and focal or diffuse fibrosis), biomarkers (N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T), and the 6-min walk test. CMR was used to measure the extracellular volume fraction (ECV), thereby deriving matrix volume (LV mass × ECV) and cell volume (LV mass × [1 - ECV]). Biopsy excluded occult bystander disease. Assessment was repeated at 1 year post-AVR., Results: At 1 year post-AVR in 116 pacemaker-free survivors (age 70 ± 10 years; 54% male), mean valve gradient had improved (48 ± 16 mm Hg to 12 ± 6 mm Hg; p < 0.001), and indexed LV mass had regressed by 19% (88 ± 26 g/m 2 to 71 ± 19 g/m 2 ; p < 0.001). Focal fibrosis by CMR late gadolinium enhancement did not change, but ECV increased (28.2 ± 2.9% to 29.9 ± 4.0%; p < 0.001): this was the result of a 16% reduction in matrix volume (25 ± 9 ml/m 2 to 21 ± 7 ml/m 2 ; p < 0.001) but a proportionally greater 22% reduction in cell volume (64 ± 18 ml/m 2 to 50 ± 13 ml/m 2 ; p < 0.001). These changes were accompanied by improvement in diastolic function, N-terminal pro-B-type natriuretic peptide, 6-min walk test results, and New York Heart Association functional class., Conclusions: Post-AVR, focal fibrosis does not resolve, but diffuse fibrosis and myocardial cellular hypertrophy regress. Regression is accompanied by structural and functional improvements suggesting that human diffuse fibrosis is plastic, measurable by CMR and a potential therapeutic target. (Regression of Myocardial Fibrosis After Aortic Valve Replacement; NCT02174471)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The local inflammatory tissue response after acute myocardial infarction (MI) determines subsequent healing. Systemic interaction may induce neuroinflammation as a precursor to neurodegeneration., Objectives: This study sought to assess the influence of MI on cardiac and brain inflammation using noninvasive positron emission tomography (PET) of the heart-brain axis., Methods: After coronary artery ligation or sham surgery, mice (n = 49) underwent serial whole-body PET imaging of the mitochondrial translocator protein (TSPO) as a marker of activated macrophages and microglia. Patients after acute MI (n = 3) were also compared to healthy controls (n = 9)., Results: Infarct mice exhibited elevated myocardial TSPO signal at 1 week versus sham (percent injected dose per gram: 8.0 ± 1.6 vs. 4.8 ± 0.9; p < 0.001), localized to activated CD68 + inflammatory cells in the infarct. Early TSPO signal predicted subsequent left ventricular remodeling at 8 weeks (r partial = -0.687; p = 0.001). In parallel, brain TSPO signal was elevated at 1 week (1.7 ± 0.2 vs. 1.4 ± 0.2 for sham; p = 0.017), localized to activated microglia. After interval decline at 4 weeks, progressive heart failure precipitated a second wave of neuroinflammation (1.8 ± 0.2; p = 0.005). TSPO was concurrently up-regulated in remote cardiomyocytes at 8 weeks (8.8 ± 1.7, p < 0.001) without inflammatory cell infiltration, suggesting mitochondrial impairment. Angiotensin-converting enzyme inhibitor treatment lowered acute inflammation in the heart (p = 0.003) and brain (p = 0.06) and improved late cardiac function (p = 0.05). Patients also demonstrated elevation of cardiac TSPO signal in the infarct territory, paralleled by neuroinflammation versus controls., Conclusions: The brain is susceptible to acute MI and chronic heart failure. Immune activation may interconnect heart and brain dysfunction, a finding that provides a foundation for strategies to improve heart and brain outcomes., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Tenascin-C (TNC) is a highly conserved matricellular protein with a distinct expression pattern during development and disease. Remodeling of the left ventricle (LV) in response to pressure overload leads to the re-expression of the fetal gene program., Objectives: The aim of this study was to investigate the function of TNC in cardiac hypertrophy in response to pressure overload., Methods: Pressure overload was induced in TNC knockout and wild-type mice by constricting their abdominal aorta or by infusion of angiotensin II. Echocardiography, immunostaining, flow cytometry, quantitative real-time polymerase chain reaction, and reciprocal bone marrow transplantation were used to evaluate the effect of TNC deficiency., Results: Echocardiographic analysis of pressure overloaded hearts revealed that all LV parameters (LV end-diastolic and -systolic dimensions, ejection fraction, and fractional shortening) deteriorated in TNC-deficient mice compared with their wild-type counterparts. Cardiomyocyte size and collagen accumulation were significantly greater in the absence of TNC. Mechanistically, TNC deficiency promoted rapid accumulation of the CCR2 + /Ly6C hi monocyte/macrophage subset into the myocardium in response to pressure overload. Further, echocardiographic and immunohistochemical analyses of recipient hearts showed that expression of TNC in the bone marrow, but not the myocardium, protected the myocardium against excessive remodeling of the pressure-overloaded heart., Conclusions: TNC deficiency further impaired cardiac function in response to pressure overload and exacerbated fibrosis by enhancing inflammation. In addition, expression of TNC in the bone marrow, but not the myocardium, protected the myocardium against excessive remodeling in response to mild pressure overload., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Reproductive factors reflective of endogenous sex hormone exposure might have an effect on cardiac remodeling and the development of heart failure (HF)., Objectives: This study examined the association between key reproductive factors and the incidence of HF., Methods: Women from a cohort of the Women's Health Initiative were systematically evaluated for the incidence of HF hospitalization from study enrollment through 2014. Reproductive factors (number of live births, age at first pregnancy, and total reproductive duration [time from menarche to menopause]) were self-reported at study baseline in 1993 to 1998. We employed Cox proportional hazards regression analysis in age- and multivariable-adjusted models., Results: Among 28,516 women, with an average age of 62.7 ± 7.1 years at baseline, 1,494 (5.2%) had an adjudicated incident HF hospitalization during an average follow-up of 13.1 years. After adjusting for covariates, total reproductive duration in years was inversely associated with incident HF: hazard ratios (HRs) of 0.99 per year (95% confidence interval [CI]: 0.98 to 0.99 per year) and 0.95 per 5 years (95% CI: 0.91 to 0.99 per 5 years). Conversely, early age at first pregnancy and nulliparity were significantly associated with incident HF in age-adjusted models, but not after multivariable adjustment. Notably, nulliparity was associated with incident HF with preserved ejection fraction in the fully adjusted model (HR: 2.75; 95% CI: 1.16 to 6.52)., Conclusions: In post-menopausal women, shorter total reproductive duration was associated with higher risk of incident HF, and nulliparity was associated with higher risk for incident HF with preserved ejection fraction. Whether exposure to endogenous sex hormones underlies this relationship should be investigated in future studies., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function., Objectives: This study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM., Methods: In vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients., Results: In swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility ∼46°). E2A changes correlated with wall thickness changes (in vivo r 2  = 0.75; in situ r 2  = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was ∼17%. In healthy human control subjects, E2A increased from diastole (18°) to systole (65°; p < 0.001; E2A mobility = 45°). HCM patients showed significantly greater E2A in diastole than control subjects did (48°; p < 0.001) with impaired E2A mobility (23°; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40°; p < 0.001) with impaired E2A mobility (20°; p < 0.001)., Conclusions: Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans., (Published by Elsevier Inc.)

Background: High-level endurance training has been associated with right ventricular pathological remodeling and ventricular tachycardia (VT). Although overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been suggested, the arrhythmogenic substrate for VTs in athletes is unknown., Objectives: The goal of this study was to evaluate whether electroanatomic scar patterns related to sustained VT can distinguish exercise-induced arrhythmogenic remodeling from ARVC and post-inflammatory cardiomyopathies., Methods: In 57 consecutive patients (mean age 48 ± 16 years; 83% male) undergoing catheter ablation for scar-related right ventricular VT, 2 distinct scar distributions were identified: 1) scars involving the subtricuspid right ventricle in 46 patients (group A); and 2) scars restricted to the anterior subepicardial right ventricular outflow tract in 11 patients (group B)., Results: Definite ARVC or post-inflammatory cardiomyopathy was diagnosed in 40 (87%) of 46 group A patients but was not diagnosed in any patients in group B. All group B patients underwent intensive endurance training for a median of 15 h/week (interquartile range [IQR]: 10 to 20 h/week) for a median of 13 years (IQR: 10 to 18 years). The cycle lengths of scar-related VTs were significantly faster in group B patients (257 ± 34 ms vs. 328 ± 72 ms in group A; p = 0.003). Catheter ablation resulted in complete procedural success in 10 (91%) of 11 group B patients compared with 26 (57%) of 46 group A patients (p = 0.034). During a median follow-up of 27 months (IQR: 6 to 62 months), 50% of group A patients but none of the group B patients had a VT recurrence., Conclusions: This study describes a novel clinical entity of an isolated subepicardial right ventricular outflow tract scar serving as a substrate for fast VT in high-level endurance athletes that can be successfully treated by ablation. This scar pattern may allow distinguishing exercise-induced arrhythmogenic remodeling from ARVC and post-inflammatory cardiomyopathy., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Treatment of acute myocardial infarction (AMI) has improved significantly in recent years, but many patients have adverse left ventricular (LV) remodeling, a maladaptive change associated with progressive heart failure. Although this change is usually associated with large infarcts, some patients with relatively small infarcts have adverse remodeling, whereas other patients with larger infarcts (who survive the first several days after AMI) do not. This paper reviews the relevant data supporting the hypothesis that individual differences in the intensity of the post-AMI inflammatory response, involving 1 or more inflammatory-modulating pathways, may contribute to adverse LV remodeling. It concludes by outlining how individual variations in the inflammatory response could provide important novel therapeutic targets and strategies., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition., Objectives: The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation., Methods: Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets., Results: Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-β, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint., Conclusions: MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Physiological cardiac adaptation to regular exercise, including biventricular dilation and T-wave inversion (TWI), may create diagnostic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC)., Objectives: The goal of this study was to assess the accuracy of diagnostic criteria for ARVC when applied to athletes exhibiting electrocardiographic TWI and to identify discriminators between physiology and disease., Methods: The study population consisted of athletes with TWI (n = 45), athletes without TWI (n = 35), and ARVC patients (n = 35). Subjects underwent electrocardiography (ECG), signal-averaged electrocardiography (SAECG), echocardiography, cardiac magnetic resonance imaging (CMRI), Holter monitoring, and exercise testing., Results: There were no electrical, structural, or functional cardiac differences between athletes exhibiting TWI and athletes without TWI. When athletes were compared with ARVC patients, markers of physiological remodeling included early repolarization, biphasic TWI, voltage criteria for right ventricular (RV) or left ventricular hypertrophy, and symmetrical cardiac enlargement. Indicators of RV pathology included the following: syncope; Q waves or precordial QRS amplitudes <1.8 mV; 3 abnormal SAECG parameters; delayed gadolinium enhancement, RV ejection fraction ≤45%, or wall motion abnormalities at CMRI; >1,000 ventricular extrasystoles (or >500 non-RV outflow tract) per 24 h; and symptoms, ventricular tachyarrhythmias, or attenuated blood pressure response during exercise. Nonspecific parameters included the following: prolonged QRS terminal activation; ≤2 abnormal SAECG parameters; RV dilation without wall motion abnormalities; RV outflow tract ectopy; and exercise-induced T-wave pseudonormalization., Conclusions: TWI and balanced biventricular dilation are likely to represent benign manifestations of training in asymptomatic athletes without relevant family history. Diagnostic criteria for ARVC are nonspecific in such individuals. Comprehensive testing using widely available techniques can effectively differentiate borderline cases., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The role of patient age in the efficacy of mesenchymal stem cell (MSC) therapy in ischemic cardiomyopathy (ICM) is controversial., Objectives: This study sought to determine whether the therapeutic effect of culture-expanded MSCs persists, even in older subjects., Methods: Patients with ICM who received MSCs via transendocardial stem cell injection (TESI) as part of the TAC-HFT (Transendocardial Autologous Cells in Ischemic Heart Failure) (n = 19) and POSEIDON (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis) (n = 30) clinical trials were divided into 2 age groups: younger than 60 and 60 years of age and older. Functional capacity was measured by 6-min walk distance (6MWD) and quality of life using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) score, measured at baseline, 6 months, and 1 year post-TESI. Various cardiac imaging parameters, including absolute scar size, were compared at baseline and 1 year post-TESI., Results: The mean 6MWD was similar at baseline and increased at 1 year post-TESI in both groups: 48.5 ± 14.6 m (p = 0.001) for the younger and 35.9 ± 18.3 m (p = 0.038) for the older participants (p = NS between groups). The older group exhibited a significant reduction in MLHFQ score (-7.04 ± 3.54; p = 0.022), whereas the younger than 60 age group had a borderline significant reduction (-11.22 ± 5.24; p = 0.058) from baseline (p = NS between groups). Although there were significant reductions in absolute scar size from baseline to 1 year post-TESI, the effect did not differ by age., Conclusions: MSC therapy with TESI in ICM patients improves 6MWD and MLHFQ score and reduces myocardial infarction size. Importantly, older individuals did not have an impaired response to MSC therapy., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular risk factors are associated with left ventricular hypertrophy (LVH), but little is known regarding related impact of longitudinal measures of childhood adiposity and LV hemodynamic variables., Objectives: The aim of this study was to examine the impact of cumulative long-term burden and trends of excessive adiposity and elevated blood pressure (BP) during childhood on adulthood LVH and LV geometric remodeling patterns., Methods: This longitudinal study consisted of 1,061 adults, age 24 to 46 years, who had been examined 4 or more times for body mass index (BMI) and BP starting in childhood, with a mean follow-up of 28.0 years. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and BP from childhood to adulthood. Four LV geometric types were defined-normal, concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH)-all on the basis of LV mass indexed for body height (m(2.7)) and relative wall thickness., Results: Higher values of BMI and systolic and diastolic BP in childhood and adulthood, as well as total AUC and incremental AUC, were all significantly associated with higher LV mass index and LVH, adjusted for race, sex, and age. In addition, higher values of BMI and BP in childhood and adulthood, total AUC, and incremental AUC were significantly associated with EH and CH but not with CR. Importantly, all of these measures of BMI had a consistently and significantly greater influence on EH than did measures of BP., Conclusions: These findings indicate that the adverse influence of excessive adiposity and elevated BP levels on LVH begins in childhood., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiac resynchronization therapy (CRT) is an accepted treatment for patients with heart failure (HF), impaired left ventricular (LV) function, and a wide QRS complex. It has been revolutionary for patients with advanced HF whose only previous option was cardiac transplantation, and it is now a realistic option for patients with mild HF. The development of CRT also has united the previously disparate cardiological subspecialties of electrophysiology and HF. This review, written on the occasion of the 20th anniversary of the first clinical use of CRT for HF, takes a historical perspective on CRT's evolution from "bench to bedside." We also comment on the task faced by electrophysiologists and HF specialists as they make this life-saving therapy available to an increasing number of eligible patients., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Acute myocardial infarction (AMI) leads to molecular, structural, geometric, and functional changes in the heart in a process known as ventricular remodeling. An intense organized inflammatory response is triggered after myocardial ischemia and necrosis and involves all components of the innate immunity, affecting both cardiomyocytes and noncardiomyocyte cells. Inflammation is triggered by tissue injury; it mediates wound healing and scar formation and affects ventricular remodeling. Many therapeutic attempts aimed at reducing inflammation in AMI during the past 3 decades presented issues of impaired healing or increased risk of cardiac rupture or failed to show any additional benefit in addition to standard therapies. More recent strategies aimed at selectively blocking one of the key factors upstream rather than globally suppressing the response downstream have shown some promising results in pilot trials. We herein review the pathophysiological mechanisms of inflammation and ventricular remodeling after AMI and the results of clinical trials with anti-inflammatory strategies., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the incidence and predictors of recovery of normal echocardiographic function among children with idiopathic dilated cardiomyopathy (DCM)., Background: Most children with idiopathic DCM have poor outcomes; however, some improve., Methods: We studied children <18 years of age from the Pediatric Cardiomyopathy Registry who had both depressed left ventricular (LV) function (fractional shortening or ejection fraction z-score <-2) and LV dilation (end-diastolic dimension [LVEDD] z-score >2) at diagnosis and who had at least 1 follow-up echocardiogram 30 days to 2 years from the initial echocardiogram. We estimated the cumulative incidence and predictors of normalization., Results: Among 868 children who met the inclusion criteria, 741 (85%) had both echocardiograms. At 2 years, 22% had recovered normal LV function and size; 51% had died or undergone heart transplantation (median, 3.2 months), and 27% had persistently abnormal echocardiograms. Younger age (hazard ratio [HR]: 0.92; 95% confidence interval [CI]: 0.88 to 0.97) and lower LVEDD z-score (HR: 0.78; 95% CI: 0.70 to 0.87) independently predicted normalization. Nine children (9%) with normal LV function and size within 2 years of diagnosis later underwent heart transplantation or died., Conclusions: Despite marked LV dilation and depressed function initially, children with idiopathic DCM can recover normal LV size and function, particularly those younger and with less LV dilation at diagnosis. Investigations related to predictors of recovery, such as genetic associations, serum markers, and the impact of medical therapy or ventricular unloading with assist devices are important next steps. Longer follow-up after normalization is warranted as cardiac failure can recur. (Pediatric Cardiomyopathy Registry; NCT00005391)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to define the role of FMS-like tyrosine kinase 3 (FLT3) in the heart., Background: FLT3 is a prominent target of receptor tyrosine kinase inhibitors (TKIs) used for anticancer therapy. TKIs can cause cardiomyopathy but understanding of the mechanisms is incomplete, partly because the roles of specific TKI target receptors in the heart are still obscure., Methods: Myocardial infarction was induced in mice by permanent ligation of the left anterior descending coronary artery followed by intramyocardial injection of FLT3 ligand (FL) or vehicle into the infarct border zone. Cardiac morphology and function were assessed by echocardiography and histological analysis 1 week after infarction. In addition, FLT3 expression and regulation, as well as molecular mechanisms of FLT3 action, were examined in cardiomyocytes in vitro., Results: The intramyocardial injection of FL into the infarct border zone decreased infarct size and ameliorated post-myocardial infarction remodeling and function in mice. This beneficial effect was associated with reduced apoptosis, including myocytes in the infarct border zone. Cardiomyocytes expressed functional FLT3, and FLT3 messenger ribonucleic acid and protein were up-regulated under oxidative stress, identifying cardiomyocytes as FL target cells. FLT3 activation with FL protected cardiomyocytes from oxidative stress-induced apoptosis via an Akt-dependent mechanism involving Bcl-2 family protein regulation and inhibition of the mitochondrial death pathway., Conclusions: FLT3 is a cytoprotective system in the heart and a potential therapeutic target in ischemic cardiac injury. The protective mechanisms uncovered here may be further explored in view of potential cardiotoxic effects of FLT3-targeting anticancer therapy, particularly in patients with ischemic heart disease., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure., Background: In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling., Methods: The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy., Results: Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 ± 3.0 ml vs. -8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. -15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival., Conclusions: The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)