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Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human "ome" and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation., Competing Interests: Declaration of interests S.G.D. is a consultant for Abbott, and S.G.D. and K.J.L. have industry research support from Novartis. R.V.S. has served as a consultant for Amgen, Cytokinetics, and Thryv Therapeutics (with options ownership in Thryv). R.V.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling and a pending patent on proteomic signatures of fitness and lung and liver diseases. R.V.S. also has stock options with Thryv Therapeutics. A.S.P. is a co-inventor on a pending patent for proteomic signatures of fitness, lung, and liver diseases. K.A. does ad hoc consulting for Tegus and Guidepoint and serves on a DSMB for Fortrea. M.N. has received speaking honoraria from Cytokinetics. K.J.L. serves as a consultant for Medtronic, Implicit Biosciences, Kiniksa Pharmaceuticals, and Cytokinetics. K.J.L. receives grant support from Amgen, Novartis, Kiniksa Pharmaceuticals, and Implicit Biosciences. S.D. is a co-founder and has equity in Thryv therapeutics and Switch Therapeutics. S.D. has received grant support from Abbot Laboratories and Bristol Myers Squib. S.D. is a co-inventor on a patent on tissue-specific EV-RNAs. R.K. has received personal fees from GSK, Astrazeneca, Boehringer Ingelheim, and CVS Caremark. S.J.S. has received consulting fees from 35Pharma, Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, BaroPace, Bayer, Boehringer-Ingelheim, Boston Scientific, BridgeBio, Bristol Myers Squibb, Corvia, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, eMyosound, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, SalubriusBio, Sardocor, Shifamed, Tectonic, Tenax, Tenaya, Ulink, and Ultromics. J.M.A. was employed by Amgen. J.W. reports consulting/scientific advisory board for Abiomed, Abbott, Astra Zeneca, Boehringer Ingelheim, and Cytokinetics within the last 24 months., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The association between microRNAs (miRNAs) and established cardiac biomarkers is largely unknown. We aimed to measure the association between plasma miRNAs and N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin I, soluble urokinase-type plasminogen activator receptor (suPAR), and galectin-3 with cardiac structure and function and clinical outcomes., Methods and Results: We quantified 32 plasma miRNAs using the FirePlex miRNA assay and measured biomarkers in 139 individuals with symptomatic heart failure (HF). We used principal component (PC) analysis and linear regression to evaluate the association between miRNAs and biomarkers with ventricular size and function by echocardiography and Cox modelling for the incidence of a first composite event of HF hospitalization, heart transplant, left ventricular assist device implant, or death. The mean (standard deviation) age at baseline was 64.3 (12.4) years, 33 (24%) were female, and 122 (88%) were White. A total of 45 events occurred over a median follow-up of 368 (interquartile range 234, 494) days. Baseline NT-proBNP (β = -2.0; P = 0.001) and miRNA PC2 (β = 2.6; P = 0.002) were associated with baseline left ventricular ejection fraction. NT-proBNP (β = 20.6; P = 0.0004), suPAR (β = -39.6; P = 0.005), and PC4 (β = 21.1; P = 0.02) were associated with baseline left ventricular end-diastolic volumes. NT-proBNP [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.28-2.18, P = 0.0002], galectin-3 (HR 2.02, 95% CI 1.05-3.91, P = 0.036), PC3 (HR 1.75, 95% CI 1.23-2.49, P = 0.002), and PC4 (HR 1.67, 95% CI 1.1-2.52, P = 0.016) were independently associated with incident events., Conclusions: Biomarkers and miRNA PCs are associated with cardiac structure and function and incident cardiovascular outcomes. Combining information from miRNAs provides prognostic information beyond biomarkers in HF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

BACKGROUNDCardiorenal syndrome (CRS) - renal injury during heart failure (HF) - is linked to high morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear.METHODSWe investigated the role of circulating EVs from patients with CRS on renal epithelial/endothelial cells using a microfluidic kidney-on-chip (KOC) model. The small RNA cargo of circulating EVs was regressed against serum creatinine to prioritize subsets of functionally relevant EV-miRNAs and their mRNA targets investigated using in silico pathway analysis, human genetics, and interrogation of expression in the KOC model and in renal tissue. The functional effects of EV-RNAs on kidney epithelial cells were experimentally validated.RESULTSRenal epithelial and endothelial cells in the KOC model exhibited uptake of EVs from patients with HF. HF-CRS EVs led to higher expression of renal injury markers (IL18, LCN2, HAVCR1) relative to non-CRS EVs. A total of 15 EV-miRNAs were associated with creatinine, targeting 1,143 gene targets specifying pathways relevant to renal injury, including TGF-β and AMPK signaling. We observed directionally consistent changes in the expression of TGF-β pathway members (BMP6, FST, TIMP3) in the KOC model exposed to CRS EVs, which were validated in epithelial cells treated with corresponding inhibitors and mimics of miRNAs. A similar trend was observed in renal tissue with kidney injury. Mendelian randomization suggested a role for FST in renal function.CONCLUSIONPlasma EVs in patients with CRS elicit adverse transcriptional and phenotypic responses in a KOC model by regulating biologically relevant pathways, suggesting a role for EVs in CRS.TRIAL REGISTRATIONClinicalTrials.gov NCT03345446.FUNDINGAmerican Heart Association (AHA) (SFRN16SFRN31280008); National Heart, Lung, and Blood Institute (1R35HL150807-01); National Center for Advancing Translational Sciences (UH3 TR002878); and AHA (23CDA1045944).

Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high-impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital-University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.

Background: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed., Methods: The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d., Findings: miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes., Interpretation: Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy., Funding: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li)., Competing Interests: Declaration of interests Dr. Das is a founder of Switch Therapeutics, which did not play any role in this study and has consulted for Amgen. The other authors have declared that no conflict of interest exists., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this study, we investigated the baseline characteristics and "trajectories" of clinical response in men and women after cardiac resynchronization therapy (CRT) implantation. Although women enjoy improved echocardiographic response after CRT compared with men, the kinetics of this response and its relation to functional performance and outcomes are less clear. We identified 592 patients who underwent CRT implantation at our center between 2004 and 2017 and were serially followed in a multidisciplinary clinic. Longitudinal linear mixed effects regression for cardiac response was specified, including interaction terms between time after CRT and sex , and Cox regression models were used to assess differences in all-cause mortality by gender after CRT. Women in our cohort were younger than men, had less frequent ischemic etiology of heart failure (24% vs 60% in men), a shorter QRS (151 vs 161 ms) and more frequent left bundle branch block (77% vs 52%) at baseline. Women had a greater improvement in left ventricular ejection fraction that was evident starting at approximately 1-month after CRT. We did not observe effect modification by gender in New York Heart Association class or 6-minute walk distance after CRT. Although women had improved mortality after CRT, after adjustment for potential confounders, gender was not associated with mortality after CRT. In conclusion, women were more likely to have CRT implantation for left bundle branch block and exhibited improved echocardiographic but not functional response within the first year after CRT. Clinical outcomes after CRT were not associated with gender in adjusted analysis., Competing Interests: Disclosures Dr. Das is a founding member and holds equity for LQT Therapeutics and Switch Therapeutics and receives research grant from Abbott. Dr. Singh has consulted for Abbott, Boston Scientific, Biotronik, CVRx, Cardiologs, Medtronic, Microport, EBR, Impulse Dynamics, Nopras Inc, National Century Health, Sanofi Inc., and Toray Inc. Dr. Heist has consulted for Boston Scientific, Pfizer, Medtronic, and Abbott; has equity in Oracle Health and receives research grant from Biotronik. The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis., Methods: RNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice., Results: We identified exercise-regulated cardiac lncRNAs, called lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure; lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis., Conclusions: These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.

Background: Current guidelines recommend measuring natriuretic peptide biomarkers to establish prognosis in patients with chronic heart failure with reduced ejection fraction (HFrEF). We assessed whether a combination biomarkers approach improve prognostication in patients with stable HFrEF., Methods and Results: An observational cohort study recruited 202 patients with stable HFrEF at a single center, tertiary care hospital undergoing elective cardiac resynchronization therapy device placement from 2013 to 2015. Twenty-four biomarkers were analyzed individually and in combination using Cox proportion hazard regression model for major adverse cardiac events (ie, death, cardiac transplant, left ventricular assist device placement), and major adverse cardiac events plus HF hospitalizations. The single best biomarker for predicting major adverse cardiac events is peripheral mid-regional pro-adrenomedullin (C statistic = 0.771 ± 0.045) compared to current guideline recommended N-terminal pro b-type natriuretic peptide (C=0.668 ± 0.046). The best combined biomarkers for predicting major adverse cardiac events are blood urea nitrogen, coronary sinus C-reactive protein, peripheral mid-regional pro-atrial natriuretic peptide and peripheral soluble IL-1 receptor-like 1 (C = 0.767 ± 0.036)., Conclusions: In this observational cohort, the combined biomarkers (blood urea nitrogen, C-reactive protein, mid-regional pro-atrial natriuretic peptide and soluble IL-1 receptor-like 1) or the single biomarker (mid-regional pro-adrenomedullin) was superior to N-terminal pro B-type natriuretic peptide, the current guideline recommended biomarker in predicting cardiovascular outcomes in patients with HFrEF. Larger studies are needed to validate these findings and examine whether single or combined biomarkers improve HFrEF prognostication., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs) mediate intercellular signaling by transferring their cargo to recipient cells, but the functional consequences of signaling are not fully appreciated. RBC-derived EVs are abundant in circulation and have been implicated in regulating immune responses. Here, we use a transgenic mouse model for fluorescence-based mapping of RBC-EV recipient cells to assess the role of this intercellular signaling mechanism in heart disease. Using fluorescent-based mapping, we detected an increase in RBC-EV-targeted cardiomyocytes in a murine model of ischemic heart failure. Single cell nuclear RNA sequencing of the heart revealed a complex landscape of cardiac cells targeted by RBC-EVs, with enrichment of genes implicated in cell proliferation and stress signaling pathways compared with non-targeted cells. Correspondingly, cardiomyocytes targeted by RBC-EVs more frequently express cellular markers of DNA synthesis, suggesting the functional significance of EV-mediated signaling. In conclusion, our mouse model for mapping of EV-recipient cells reveals a complex cellular network of RBC-EV-mediated intercellular communication in ischemic heart failure and suggests a functional role for this mode of intercellular signaling., (© 2021 Valkov et al.)

Aims: Up to 30% of selected heart failure patients do not benefit clinically from cardiac resynchronization therapy (CRT). Left ventricular (LV) wall thickness (WT) analysed using computed tomography (CT) has rarely been evaluated in response to CRT and mitral regurgitation (MR) improvement. We examined the association of LVWT and the ability to reverse LV remodelling and MR improvement after CRT., Methods and Results: Fifty-four patients scheduled for CRT underwent pre-procedural CT. Reduced LVWT was defined as WT <6 mm and quantified as a percentage of total LV area. Endpoints were 6-month clinical and echocardiographic response to CRT [New York Heart Association (NYHA) class, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV)], MR improvement and 2-year major adverse cardiac events (MACE). Patients were divided into three groups according to the percentage of LVWT <6 mm area: ≤20%, 20-50%, and ≥50%. At 6 months, 75%, 71%, and 42% of the patients experienced NYHA improvement in the ≤20%, 20-50%, and ≥50% group, respectively. Additionally, ≤20% group presented higher LVEF, LVEDV, and LVESV positive response rate (86%, 59%, and 83%, respectively). Both 20-50% and ≥50% groups exhibited a lower LVEF, LVEDV, and LVESV positive response rate (52% and 42%; 47% and 45%; and 53% and 45%, respectively). Additionally, ≥25% of LVWT <6 mm inclusive of at least one papillary muscle insertion was the only predictor of lack of MR improvement. Lastly, ≥50% group experienced significantly lower 2-year MACE survival free probability., Conclusion: WT evaluated using CT could help to stratify the response to CRT and predict MR improvement and outcomes., Clinical Trial Registration: NCT01097733., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Depression independently predicts poor outcomes in heart failure (HF) patients, including increased mortality, morbidity and 30-day re-hospitalization. In this network meta-analysis, we compared different interventions designed to treat depression in HF., Materials and Methods: Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and PsycINFO up to November 2016. Included randomized clinical trials (RCTs) compared interventions (Exercise therapy (ET), cognitive behavioral therapy (CBT) or antidepressant (AD) medications) for depression in heart failure patients. The primary outcome was change in depressive symptoms based on validated measures of depression. Network meta-analysis based on random effects model estimating standardized mean difference (SMD) with 95% confidence interval (CI), compared the effects of the 3 classes of interventions with respect to usual care or placebo control conditions., Results: A total of 21 RCTs (including 4563 HF patients) reporting the effects of treating depression in HF patients were included in the analysis. In comparison to placebo or usual standard of care, ET (SMD -0.38; 95% CI -0.54 to -0.22) and CBT (SMD -0.29; 95% CI -0.58 to -0.01) were associated with reduction in depressive symptoms whereas AD (SMD -0.16; 95% CI -0.44 to 0.11) was less effective., Conclusions: This meta-analysis is suggestive of therapeutic benefit of ET and CBT in comparison to usual standard of care in treating depression in HF patients. However, comparison among the three interventions was not conclusive. Future randomized clinical trials are warranted to compare the therapeutic effects of ET, CBT and AD in such patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Mortality is high among patients heart failure (HF) who are receiving treatment, and therefore identifying new pathways rooted in preclinical cardiac remodeling phenotypes may afford novel biomarkers and therapeutic avenues. Circulating extracellular RNAs (ex-RNAs) are an emerging class of biomarkers with target-organ epigenetic effects relevant to myocardial biology, although large human investigations remain limited., Objective: To measure the association of highly expressed circulating ex-RNAs with left ventricular remodeling and incident HF in a community-based cohort., Design, Setting, and Participants: This is a prospective observational cohort study of individuals who were included in the eighth examination of the Framingham Offspring Cohort (2005-2008). Collected data include measurements of the left ventricle via electrocardiography, determination of circulating ex-RNAs in plasma, and incidence of heart failure. Data analysis was completed from December 2016 to June 2018., Exposures: A total of 398 circulating ex-RNA molecules in plasma were measured by reverse transcription polymerase chain reaction; disease ontology analysis was also performed., Main Outcomes and Measures: Echocardiographic indices of left ventricular (LV) remodeling and incident heart failure., Results: A total of 2763 participants of the Framingham Heart Study with measured ex-RNAs (mean [SD] age, 66.3 [9.0] years; 1499 [54.3%] female) were included in this study. Of this sample, 2429 to 2432 individuals had echocardiographic measures recorded (depending on the measurement). A total of 2681 individuals had HF status determined, of whom 116 (4.3%) experienced HF (median [interquartile range] follow-up, 7.7 [6.6-8.6] years). We identified 12 ex-RNAs associated with LV mass and at least 1 other echocardiographic phenotype (LV end-diastolic volume or left atrial dimension). Of these 12 ex-RNAs, 3 micro RNAs (miR-17, miR-20a, and miR-106b) were associated with a 15% reduction in long-term incident HF per 2-fold increase in circulating level during the follow-up period, after adjustments for age, sex, established HF risk factors, and prevalent or interim myocardial infarction. These 3 RNAs shared sequence homology and targeted a shared group of messenger RNAs that specified pathways relevant to HF (eg, transforming growth factor-β signaling, growth/cell cycle, and apoptosis), and shared a disease association with hypertension in disease ontology analysis., Conclusions and Relevance: This study identifies a group of circulating, noncoding RNAs associated with echocardiographic phenotypes, long-term incident HF, and pathways relevant to myocardial remodeling in a large community-based sample. Further investigations into the functional biology of these ex-RNAs are warranted for surveillance for HF prevention.

Background: Plasma extracellular RNAs have recently garnered interest as biomarkers in heart failure (HF). Most studies in HF focus on single extracellular RNAs related to phenotypes and outcomes, and few describe their functional roles. We hypothesized that clusters of plasma microRNAs (miRNAs) associated with left ventricular (LV) remodeling in human HF would identify novel subsets of genes involved in HF in animal models., Methods and Results: We prospectively measured circulating miRNAs in 64 patients with systolic HF (mean age, 64.8 years; 91% men; median LV ejection fraction, 26%) with serial echocardiography (10 months apart) during medical therapy. We defined LV reverse remodeling as a 15% reduction in LV end-systolic volume index. Using principal components analysis, we identified a component associated with LV reverse remodeling (odds ratio=3.99; P =0.01) that provided risk discrimination for LV reverse remodeling superior to a clinical model (C statistic, 0.58 for a clinical model versus 0.71 for RNA-based model). Using network bioinformatics, we uncovered genes not previously widely described in HF regulated simultaneously by >2 miRNAs. We observed increased myocardial expression of these miRNAs during HF development in animals, with downregulation of target gene expression, suggesting coordinate miRNA-mRNA regulation. Target mRNAs were involved in autophagy, metabolism, and inflammation., Conclusions: Plasma miRNAs associated with LV reverse remodeling in humans are dysregulated in animal HF and target clusters of genes involved in mechanisms implicated in HF. A translational approach integrating human HF, bioinformatics, and model systems may uncover novel pathways involved in HF., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00351390., (© 2018 American Heart Association, Inc.)

Background: The lifetime risk of heart failure (HF) is higher in the black population than in other racial groups in the United States., Methods and Results: We measured the Life's Simple 7 ideal cardiovascular health metrics in 4195 blacks in the JHS (Jackson Heart Study; 2000-2004). We evaluated the association of Simple 7 metrics with incident HF and left ventricular structure and function by cardiac magnetic resonance (n=1188). Mean age at baseline was 54.4 years (65% women). Relative to 0 to 2 Simple 7 factors, blacks with 3 factors had 47% lower incident HF risk (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39-0.73; P <0.0001); and those with ≥4 factors had 61% lower HF risk (HR, 0.39; 95% CI, 0.24-0.64; P =0.0002). Higher blood pressure (HR, 2.32; 95% CI, 1.28-4.20; P =0.005), physical inactivity (HR, 1.65; 95% CI, 1.07-2.55; P =0.02), smoking (HR, 2.04; 95% CI, 1.43-2.91; P <0.0001), and impaired glucose control (HR, 1.76; 95% CI, 1.34-2.29; P <0.0001) were associated with incident HF. The age-/sex-adjusted population attributable risk for these Simple 7 metrics combined was 37.1%. Achievement of ideal blood pressure, ideal body mass index, ideal glucose control, and nonsmoking was associated with less likelihood of adverse cardiac remodeling by cardiac magnetic resonance., Conclusions: Cardiovascular risk factors in midlife (specifically elevated blood pressure, physical inactivity, smoking, and poor glucose control) are associated with incident HF in blacks and represent targets for intensified HF prevention., (© 2017 American Heart Association, Inc.)

Background/aims: Identification of novel biomarkers to identify acute heart failure (AHF) patients at high risk of mortality is an area of unmet clinical need. Recently, we reported that the baseline level of circulating miR-30d was associated with left ventricular remodeling in response to cardiac resynchronization therapy in advanced chronic heart failure patients. However, the role of circulating miR-30d as a prognostic marker of survival in patients with AHF has not been explored., Methods: Patients clinically diagnosed with AHF were enrolled and followed up for 1 year. Quantitative reverse transcription polymerase chain reactions were used to determine serum miR-30d levels. The univariate logistic regression analysis and multivariate logistic regression analysis were used to determine the predictors for all-cause mortality in AHF patients. Kaplan-Meier survival analysis was used to analyze the role of miR-30d in prediction of survival., Results: A total of 96 AHF patients were enrolled and followed up for 1 year. Serum miR-30d was significantly lower in AHF patients who expired in the one year follow-up period compared to those who survived. Univariate logistic regression analysis yielded 18 variables that were associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 4 variables including heart rate, hemoglobin, serum sodium, and serum miR-30d level associated with mortality. ROC curve analysis showed that hemoglobin, heart rate and serum sodium displayed poor prognostic value for AHF (AUCs not higher than 0.700) compared to miR-30d level (AUC = 0.806). Kaplan-Meier survival analysis confirmed that patients with higher serum miR-30d levels had significantly lower mortality (P=0.001)., Conclusion: In conclusion, this study shows evidence for the predictive value of circulating miR-30d as 1-year all-cause mortality in AHF patients. Large multicentre studies are further needed to validate our findings and accelerate the transition to clinical utilization., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

Congestive heart failure (CHF) is a major cause of hospitalizations, morbidity, and mortality in Western societies. In addition to optimal medical and device therapy, exercise training is an important adjunct treatment option for CHF patients. MicroRNAs (miRNAs, miRs) participate in a variety of physiological and pathological processes. Dynamic regulation of circulating miRNAs during exercise in healthy persons and athletes has recently been documented, however, the response of circulating miRNAs to exercise in CHF patients is undetermined. Twenty-eight CHF patients underwent a symptom-limited incremental cardiopulmonary exercise test on a bicycle ergometer using a standardized exercise protocol of revised Ramp10 programs at Shanghai Tongji Hospital. Blood samples were collected before and immediately after an acute exercise session. RNA was extracted from the serum and selected miRNAs were determined using quantitative polymerase chain reactions. Moreover, inflammatory and muscle damage markers were determined by enzyme linked immunosorbent assays. We found that serum miR-21, miR-378 and miR-940 levels were significantly up-regulated immediately following an acute exercise while the rest were not changed. In addition, no robust correlation was identified between changes of these miRNAs and exercise capacity, muscle damage or inflammation. In conclusion, serum miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in CHF patients. Further studies are needed to clarify the potential use of circulating miRNAs as biomarkers of exercise adaptation in CHF patients, and if they have any use as prognostic markers of cardiovascular outcomes.

Background: Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined., Methods and Results: Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as an increase in left ventricular ejection fraction ≥10%). MiR-30d was enriched in coronary sinus blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. In HFDYS patients, miR-30d plasma levels inversely correlated with high-sensitivity troponin T, a marker of myocardial necrosis., Conclusions: Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling., (© 2015 American Heart Association, Inc.)

Background: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications., Methods and Results: We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations., Conclusions: SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease.

Aims: Although cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure, a significant minority of patients do not respond adequately to this therapy. The objective of this study was to examine the impact of a 'multidisciplinary care' (MC) approach on the clinical outcome in CRT patients., Methods and Results: The clinical outcome in patients prospectively receiving MC (n = 254) was compared with a control group of patients who received conventional care (CC, n = 173). The MC group was followed prospectively in an integrated clinic setting by a team of subspecialists from the heart failure, electrophysiology, and echocardiography service at 1-, 3-, and 6-months post-implant. All patients had echocardiographic-guided optimization at their 1-month visit. The proportional hazards model (adjusting for all covariates) and Kaplan-Meier time to first event curves were compared between the two groups, over a 2-year follow-up. The long-term outcome was measured as a combined endpoint of heart failure hospitalization, cardiac transplantation, or all-cause mortality. The clinical characteristics between the MC and CC groups at baseline were comparable (age, 68 ± 13 vs. 69 ± 12; NYHA III, 90 vs. 82%; ischaemic cardiomyopathy 55 vs. 64%, P = NS, respectively). The event-free survival was significantly higher in the multidisciplinary vs. the CC group (P = 0.0015). A significant reduction in clinical events was noted in the MC group vs. the CC group (hazard ratio: 0.62, 95% CI: 0.46-0.83, P = 0.001)., Conclusion: Integrated MC may improve 2-year event-free survival in patients receiving cardiac resynchronization therapy. Prospective randomized studies are needed to validate our findings.

Background: The optimal pacing site for cardiac resynchronization therapy (CRT) is along the left ventricle (LV) lateral or posterolateral wall. However, little is known about the impact of segmental pacing site on outcomes., Objective: We assessed the impact of segmental LV lead position on CRT outcomes., Methods: Patients (n = 115) undergoing CRT were followed prospectively. Segmental LV lead position along the longitudinal axis (apical, midventricle, or basal) was determined retrospectively by examining coronary sinus (CS) venograms and chest X-rays. The primary outcome was a combined endpoint of heart failure hospitalization, cardiac transplantation, or all-cause mortality. Secondary outcomes included change in New York Heart Association (NYHA) functional class and degree of LV reverse remodeling., Results: Patients were divided into two groups based on LV lead position: apical (n = 25) and basal/midventricle (n = 90). The apical group was older (72.9 +/- 8.9 vs. 66.5 +/- 13.3 years; P = .010) and more likely to have ischemic cardiomyopathy (77% vs. 52%, P <.001). During a mean follow-up of 15.1 +/- 9.0 months, event-free survival was significantly lower in the apical group: 52% vs. 79%, hazard ratio [HR] 2.7 (95% confidence interval [CI] 1.5-5.5, P = .006). The adverse impact of apical lead placement remained significant after adjusting for clinical covariates: HR 2.3 (95% CI 1.1-4.8, P = .03). The apical group also experienced less improvement in NYHA functional class and less LV reverse remodeling., Conclusions: Apical LV lead placement is associated with worse CRT outcomes. Preferential positioning of LV leads in the basal/midventricle segments may improve outcomes., (Copyright 2010. Published by Elsevier Inc.)

Aims: Up to 30% of selected heart failure patients do not benefit clinically from cardiac resynchronization therapy (CRT). Left ventricular (LV) wall thickness (WT) analysed using computed tomography (CT) has rarely been evaluated in response to CRT and mitral regurgitation (MR) improvement. We examined the association of LVWT and the ability to reverse LV remodelling and MR improvement after CRT.Methods and Results: Fifty-four patients scheduled for CRT underwent pre-procedural CT. Reduced LVWT was defined as WT <6 mm and quantified as a percentage of total LV area. Endpoints were 6-month clinical and echocardiographic response to CRT [New York Heart Association (NYHA) class, LV ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV)], MR improvement and 2-year major adverse cardiac events (MACE). Patients were divided into three groups according to the percentage of LVWT <6 mm area: ≤20%, 20-50%, and ≥50%. At 6 months, 75%, 71%, and 42% of the patients experienced NYHA improvement in the ≤20%, 20-50%, and ≥50% group, respectively. Additionally, ≤20% group presented higher LVEF, LVEDV, and LVESV positive response rate (86%, 59%, and 83%, respectively). Both 20-50% and ≥50% groups exhibited a lower LVEF, LVEDV, and LVESV positive response rate (52% and 42%; 47% and 45%; and 53% and 45%, respectively). Additionally, ≥25% of LVWT <6 mm inclusive of at least one papillary muscle insertion was the only predictor of lack of MR improvement. Lastly, ≥50% group experienced significantly lower 2-year MACE survival free probability.Conclusion: WT evaluated using CT could help to stratify the response to CRT and predict MR improvement and outcomes.Clinical Trial Registration: NCT01097733. [ABSTRACT FROM AUTHOR]

Physiological cardiac hypertrophy, in response to stimuli such as exercise, is considered adaptive and beneficial. In contrast, pathological cardiac hypertrophy that arises in response to pathological stimuli such as unrestrained high blood pressure and oxidative or metabolic stress is maladaptive and may precede heart failure. We found that the transcript encoding DNA damage-inducible transcript 4-like (DDiT4L) was expressed in murine models of pathological cardiac hypertrophy but not in those of physiological cardiac hypertrophy. In cardiomyocytes, DDiT4L localized to early endosomes and promoted stress-induced autophagy through a process involving mechanistic target of rapamycin complex 1 (mTORC1). Exposing cardiomyocytes to various types of pathological stress increased the abundance of DDiT4L, which inhibited mTORC1 but activated mTORC2 signaling. Mice with conditional cardiac-specific overexpression of DDiT4L had mild systolic dysfunction, increased baseline autophagy, reduced mTORC1 activity, and increased mTORC2 activity, all of which were reversed by suppression of transgene expression. Genetic suppression of autophagy also reversed cardiac dysfunction in these mice. Our data showed that DDiT4L may be an important transducer of pathological stress to autophagy through mTOR signaling in the heart and that DDiT4L could be therapeutically targeted in cardiovascular diseases in which autophagy and mTOR signaling play a major role. [ABSTRACT FROM AUTHOR]

Background A recent genome-wide association study identified a susceptibility locus for atrial fibrillation at the KCNN3 gene. Since the KCNN3 gene encodes for a small conductance calcium-activated potassium channel, we hypothesized that overexpression of the SK3 channel increases susceptibility to cardiac arrhythmias. Methods and results We characterized the cardiac electrophysiological phenotype of a mouse line with overexpression of the SK3 channel. We generated homozygote (SK3T/T) and heterozygote (SK3+/T) mice with overexpression of the channel and compared them with wild-type (WT) controls. We observed a high incidence of sudden death among SK3T/T mice (7 of 19 SK3T/T mice). Ambulatory monitoring demonstrated that sudden death was due to heart block and bradyarrhythmias. SK3T/T mice displayed normal body weight, temperature, and cardiac function on echocardiography; however, histological analysis demonstrated that these mice have abnormal atrioventricular node morphology. Optical mapping demonstrated that SK3T/T mice have slower ventricular conduction compared with WT controls (SK3T/T vs. WT; 0.45 ± 0.04 vs. 0.60 ± 0.09 mm/ms, P = 0.001). Programmed stimulation in 1-month-old SK3T/T mice demonstrated inducible atrial arrhythmias (50% of SK3T/T vs. 0% of WT mice) and also a shorter atrioventricular nodal refractory period (SK3T/T vs. WT; 43 ± 6 vs. 52 ± 9 ms, P = 0.02). Three-month-old SK3T/T mice on the other hand displayed a trend towards a more prolonged atrioventricular nodal refractory period (SK3T/T vs. WT; 61 ± 1 vs. 52 ± 6 ms, P = 0.06). Conclusion Overexpression of the SK3 channel causes an increased risk of sudden death associated with bradyarrhythmias and heart block, possibly due to atrioventricular nodal dysfunction. [ABSTRACT FROM AUTHOR]

Coronary Venous Geometry in Patients Undergoing CRT. Introduction: The coronary sinus (CS) is often distorted in patients with advanced cardiomyopathy, making CS cannulation difficult. The objective of this study was to examine the impact of the underlying cardiac pathology on the variability of the CS anatomy, using rotational coronary venous angiography (RCVA). Methods and Results: Seventy-nine patients undergoing RCVA for cardiac resynchronization therapy (CRT) were evaluated: age 63 ± 15 years, 43% with prior coronary artery bypass grafting (CABG). Aspects of the CS anatomy which could impact cannulation were examined: the CS ostial angle, the posterior displacement of the CS away from the atrioventricular groove, a measure of CS curvature, and the presence of stenoses and aneurysmal dilatations. The CS ostial angle was variable (65–151°, mean 119 ± 19°, <90° in 8 patients) and decreased significantly (P = 0.0022) with increasing severity of tricuspid regurgitation (TR), reaching 94 ± 18° in patients with severe TR. The posterior displacement of the CS was significantly more accentuated in patients with prior CABG when compared with the patients without CABG (7.1 ± 3.7 vs 4.5 ± 2.8 mm; P = 0.0246). The decrease in luminal diameter at the CS–great cardiac vein (GCV) junction was 2.0 ± 1.0 mm, being more pronounced in patients with prior CABG versus nonCABG (26 vs 20%; P = 0.042). Stenoses and aneurysmal dilatations of the CS–GCV were encountered in 4 (5%) and 6 (8%) of patients, respectively, all of them with prior CABG, representing 12% and 18% of the CABG group. Conclusion: The CS anatomy in patients undergoing CRT is variable, and is impacted by the severity of the underlying TR and history of a prior CABG. (J Cardiovasc Electrophysiol, Vol. 21, pp. 436–440, April 2010) [ABSTRACT FROM AUTHOR]

Regulation of sodium flux across the cell membrane plays a vital role in the generation of action potentials and regulation of membrane excitability in cells such as cardiomyocytes and neurons. Alteration of sodium channel function has been implicated in diseases such as epilepsy, long QT syndrome, and heart failure. However, single cell imaging of sodium dynamics has been limited due to the narrow selection of fluorescent sodium indicators available to researchers. Here we report, the detection of spatially defined sodium activity during action potentials. Fluorescent nanosensors that measure sodium in real-time, are reversible and are completely selective over other cations such as potassium that were used to image sodium. The use of the nanosensors in vitro was validated by determining drug-induced activation in heterologous cells transfected with the voltage-gated sodium channel Navi .7. Spatial information of sodium concentrations during action potentials will provide insight at the cellular level on the role of sodium and how slight changes in sodium channel function can affect the entirety of an action potential. [ABSTRACT FROM AUTHOR]

The authors present insights on the genetic and epigenetic basis of arrhythmia and heart failure. Topics discussed include the increasing incidence of cardiac arrhythmia and heart failure, the arrhythmogenic KCNE gene variants and their roles in arrhythmia and heart failure, and the epigenetic mechanisms associated with heart failure including DNA methylation and histone remodeling. Also mentioned is the proposed Quantum Biophysics Semeiotics (QBS) microcirculatory theory of atherosclerosis.

An abstract of the article "Cellular hypertrophy occurs before interstitial fibrosis in pressure-overload heart failure," by Ravi Shah, Otavio R. Coelho-Filho, Richard N. Mitchell, Raymond Y. Kwong, Saumya Das, Anthony Rosenzweig and Michael Jerosch-Herold is presented.

In a multicenter randomized double-blind study we demonstrated that Qiliqiangxin (QLQX), a traditional Chinese medicine, had a protective effect in heart failure patients. However, whether and via which mechanism QLQX attenuates cardiac remodeling after acute myocardial infarction (AMI) is still unclear. AMI was created by ligating the left anterior descending coronary artery in mice. Treating the mice in the initial 3 days after AMI with QLQX did not change infarct size. However, QLQX treatment ameliorated adverse cardiac remodeling 3 weeks after AMI including better preservation of cardiac function, decreased apoptosis and reduced fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) was down-regulated in control animals after AMI and up-regulated by QLQX administration. Interestingly, expression of AKT, SAPK/JNK, and ERK was not altered by QLQX treatment. Inhibition of PPARγ reduced the beneficial effects of QLQX in AMI remodeling, whereas activation of PPARγ failed to provide additional improvement in the presence of QLQX, suggesting a key role for PPARγ in the effects of QLQX during cardiac remodeling after AMI. This study indicates that QLQX attenuates cardiac remodeling after AMI by increasing PPARγ levels. Taken together, QLQX warrants further investigation as as a therapeutic intervention to mitigate remodeling and heart failure after AMI. [ABSTRACT FROM AUTHOR]

Background: The benefits of exercise training in the cardiovascular system have been well accepted; however, the underlying mechanism remains to be explored. Here, we report the initial functional characterization of an exercise-induced cardiac physiological hypertrophy-associated novel long noncoding RNA (lncRNA).Methods: Using lncRNA microarray profiling, we identified lncRNAs in contributing the modulation of exercise-induced cardiac growth that we termed cardiac physiological hypertrophy-associated regulator (CPhar). Mice with adeno-associated virus serotype 9 driving CPhar overexpression and knockdown were used in in vivo experiments. Swim training was used to induce physiological cardiac hypertrophy in mice, and ischemia reperfusion injury surgery was conducted to investigate the protective effects of CPhar in mice. To investigate the mechanisms of CPhar's function, we performed various analyses including quantitative reverse transcription polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), functional rescue experiments, mass spectrometry, in vitro RNA transcription, RNA pulldown, RNA immunoprecipitation, chromatin immunoprecipitation assay, luciferase reporter assay, and coimmunoprecipitation assays.Results: We screened the lncRNAs in contributing the modulation of exercise-induced cardiac growth through lncRNA microarray profiling and found that CPhar was increased with exercise and was necessary for exercise-induced physiological cardiac growth. The gain and loss of function of CPhar regulated the expression of proliferation markers, hypertrophy, and apoptosis in cultured neonatal mouse cardiomyocytes. Overexpression of CPhar prevented myocardial ischemia reperfusion injury and cardiac dysfunction in vivo. We identified DDX17 (DEAD-Box Helicase 17) as a binding partner of CPhar in regulating CPhar downstream factor ATF7 (activating transcription factor 7) by sequestering C/EBPβ (CCAAT/enhancer binding protein beta).Conclusions: Our study of this lncRNA CPhar provides new insights into the regulation of exercise-induced cardiac physiological growth, demonstrating the cardioprotective role of CPhar in the heart, and expanding our mechanistic understanding of lncRNA function, as well. [ABSTRACT FROM AUTHOR]

Background--Cardiomyocyte hypertrophy is a critical precursor to the development of heart failure. Methods to phenotype cellular hypertrophy noninvasively are limited. The goal was to validate a cardiac magnetic resonance-based approach for the combined assessment of extracellular matrix expansion and cardiomyocyte hypertrophy. Methods and Results--Two murine models of hypertension (n=18, with n=15 controls) induced by L-NG-nitroarginine methyl ester (L-NAME) and pressure overload (n=11) from transaortic constriction (TAC) were imaged by cardiac magnetic resonance at baseline and 7 weeks after L-NAME treatment or up to 7 weeks after TAC. T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water (τic), a cell size-dependent parameter, and extracellular volume fraction, a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Cardiomyocyte diameter and length were measured on FITC-wheat germ agglutinin-stained sections. The τic correlated strongly with histological cardiomyocyte volume-to-surface ratio (r=0.78, P<0.001) and cell volume (r=0.75, P<0.001). Histological cardiomyocyte diameters and cell volumes were higher in mice treated with L-NAME compared with controls (P<0.001). In the TAC model, cardiac magnetic resonance and histology showed cell hypertrophy at 2 weeks after TAC without significant fibrosis at this early time point. Mice exposed to TAC demonstrated a significant, longitudinal, and parallel increase in histological cell volume, volume-to-surface ratio, and τic between 2 and 7 weeks after TAC. Conclusion--The τic measured by contrast-enhanced cardiac magnetic resonance provides a noninvasive measure of cardiomyocyte hypertrophy. Extracellular volume fraction and τic can track myocardial tissue remodeling from pressure overload. [ABSTRACT FROM AUTHOR]

Patients with diabetes and heart failure (HF) have worse clinical outcomes compared to patients with HF without diabetes after cardiac resynchronization therapy (CRT). Patients with HF and diabetes represent a growing population at high risk for cardiovascular events and are increasingly treated with CRT. Although patients with diabetes and HF appear to benefit from CRT, their clinical outcomes are worse than those of patients without diabetes after CRT. The aim of this study was to identify clinical predictors that explain the differential hazard in patients with diabetes. We studied 442 patients (169 with diabetes) with systolic HF referred to the Massachusetts General Hospital CRT clinic from 2003 to 2010 to identify predictors of outcomes after CRT in patients with HF and diabetes. Patients with diabetes were more likely to have ischemic causes of HF than those without diabetes, but there was no difference in the left ventricular ejection fraction or HF classification at implantation. Patients with diabetes had poorer event-free survival (death or HF hospitalization) compared to those without diabetes (log-rank p = 0.04). The presence of diabetes was the most important independent predictor of differential outcomes in the entire population (hazard ratio 1.65, 95% confidence interval 1.10 to 2.51). Patients with diabetes receiving insulin therapy had poorer survival, whereas those not receiving insulin therapy had similar survival to patients without diabetes. Patients with peri-implantation glycosylated hemoglobin >7% had worse outcomes, whereas patients with glycosylated hemoglobin ≤7% had improved survival (hazard ratio 0.36, 95% confidence interval 0.15 to 0.86) equivalent to that of patients without diabetes. In conclusion, although the presence of diabetes, independent of other variables, increases the hazard of worse outcomes after CRT, there is additional risk conferred by insulin use and suboptimal peri-implantation glycemic control. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study" by Y.F. Melman along with the author's response to the same.