Vaccination-Associated Myocarditis and Myocardial Injury.

SARS-CoV-2 vaccine-associated myocarditis/myocardial injury should be evaluated in the contexts of COVID-19 infection, other types of viral myocarditis, and other vaccine-associated cardiac disorders. COVID-19 vaccine-associated myocardial injury can be caused by an inflammatory immune cell infiltrate, but other etiologies such as microvascular thrombosis are also possible. The clinical diagnosis is typically based on symptoms and cardiac magnetic resonance imaging. Endomyocardial biopsy is confirmatory for myocarditis, but may not show an inflammatory infiltrate because of rapid resolution or a non-inflammatory etiology. Myocarditis associated with SARS-COVID-19 vaccines occurs primarily with mRNA platform vaccines, which are also the most effective. In persons aged >16 or >12 years the myocarditis estimated crude incidences after the first 2 doses of BNT162b2 and mRNA-1273 are approximately 1.9 and 3.5 per 100 000 individuals, respectively. These rates equate to excess incidences above control populations of approximately 1.2 (BNT162b2) and 1.9 (mRNA-1273) per 100 000 persons, which are lower than the myocarditis rate for smallpox but higher than that for influenza vaccines. In the studies that have included mRNA vaccine and SARS-COVID-19 myocarditis measured by the same methodology, the incidence rate was increased by 3.5-fold over control in COVID-19 compared with 1.5-fold for BNT162b2 and 6.2-fold for mRNA-1273. However, mortality and major morbidity are less and recovery is faster with mRNA vaccine-associated myocarditis compared to COVID-19 infection. The reasons for this include vaccine-associated myocarditis having a higher incidence in young adults and adolescents, typically no involvement of other organs in vaccine-associated myocarditis, and based on comparisons to non-COVID viral myocarditis an inherently more benign clinical course.

Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart.

BACKGROUND: Organ fibrosis due to excessive production of extracellular matrix by resident fibroblasts is estimated to contribute to >45% of deaths in the Western world, including those due to cardiovascular diseases such as heart failure. Here, we screened for small molecule inhibitors with a common ability to suppress activation of fibroblasts across organ systems. METHODS: High-content imaging of cultured cardiac, pulmonary, and renal fibroblasts was used to identify nontoxic compounds that blocked induction of markers of activation in response to the profibrotic stimulus, transforming growth factor-ß1. SW033291, which inhibits the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase, was chosen for follow-up studies with cultured adult rat ventricular fibroblasts and human cardiac fibroblasts (CF), and for evaluation in mouse models of cardiac fibrosis and diastolic dysfunction. Additional mechanistic studies were performed with CFs treated with exogenous eicosanoids. RESULTS: Nine compounds, including SW033291, shared a common ability to suppress transforming growth factor-ß1-mediated activation of cardiac, pulmonary, and renal fibroblasts. SW033291 dose-dependently inhibited transforming growth factor-ß1-induced expression of activation markers (eg, α-smooth muscle actin and periostin) in adult rat ventricular fibroblasts and normal human CFs, and reduced contractile capacity of the cells. Remarkably, the 15-hydroxyprostaglandin dehydrogenase inhibitor also reversed constitutive activation of fibroblasts obtained from explanted hearts from patients with heart failure. SW033291 blocked cardiac fibrosis induced by angiotensin II infusion and ameliorated diastolic dysfunction in an alternative model of systemic hypertension driven by combined uninephrectomy and deoxycorticosterone acetate administration. Mechanistically, SW033291-mediated stimulation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling was required for the compound to block CF activation. Of the 12 exogenous eicosanoids that were tested, only 12(S)-hydroxyeicosatetraenoic acid, which signals through the G protein-coupled receptor, GPR31, recapitulated the suppressive effects of SW033291 on CF activation. CONCLUSIONS: Inhibition of degradation of eicosanoids, arachidonic acid-derived fatty acids that signal through G protein-coupled receptors, is a potential therapeutic strategy for suppression of pathological organ fibrosis. In the heart, we propose that 15-hydroxyprostaglandin dehydrogenase inhibition triggers CF-derived autocrine/paracrine signaling by eicosanoids, including 12(S)-hydroxyeicosatetraenoic acid, to stimulate extracellular signal-regulated kinase 1/2 and block conversion of fibroblasts into activated cells that secrete excessive amounts of extracellular matrix and contribute to heart failure pathogenesis.

Novel Tissue Factor Inhibition for Thromboprophylaxis in COVID-19: Primary Results of the ASPEN-COVID-19 Trial.

BACKGROUND: Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown. METHODS: ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days. RESULTS: Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was -16.8% (interquartile range, -45.7 to 36.8; P=0.41) with rNAPc2 treatment and -11.2% (-36.0 to 34.4; P=0.91) with heparin (Pintergroup=0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% [-14.9 to 145.2]; P=0.02) than the rNAPc2 group (median, 25.9% [-49.1 to 136.4]; P=0.14; Pintergroup=0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, -32.7% [-44.7 to 4.3]; P=0.007 and heparin median, -16.8% [-36.0 to 0.5]; P=0.008, Pintergroup=0.34). CONCLUSIONS: rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04655586.

Cardiomyocyte-Specific Long Noncoding RNA Regulates Alternative Splicing of the Triadin Gene in the Heart.

BACKGROUND: Abnormalities in Ca2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive. METHODS: We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as, a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart. RESULTS: We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA. CONCLUSIONS: These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.

lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth.

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.

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

Rationale and design of a study to assess the safety and efficacy of rNAPc2 in COVID-19: the Phase 2b ASPEN-COVID-19 trial.

BACKGROUND: The interaction between thrombosis and inflammation appears central to COVID-19-associated coagulopathy and likely contributes to poor outcomes. Tissue factor is a driver of disordered coagulation and inflammatory signaling in viral infections and is important for viral replication; therefore, tissue factor may be an important therapeutic target in COVID-19. STUDY DESIGN: ASPEN-COVID-19 (NCT04655586) is a randomized, prospective open-label blinded endpoint (PROBE), active comparator Phase 2b trial to evaluate the safety and efficacy of recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent tissue factor inhibitor, in patients hospitalized with COVID-19 with elevated D-dimer levels. This report describes the design of the Phase 2b dose ranging and proof of concept study. Participants are randomly assigned, in a 1:1:2 ratio, to lower or higher dose rNAPc2 by subcutaneous injection on days 1, 3, and 5 or to heparin according to local standard of care; randomization is stratified by baseline D-dimer level (at 2X upper limit of normal). The primary efficacy endpoint for Phase 2b is proportional change in D-dimer concentration from baseline to Day 8 or day of discharge, whichever is earlier. The primary safety endpoint is major or non-major clinically relevant bleeding through Day 8. Phase 2b enrollment began in December 2020 and is projected to complete ∼160 participants by Q4 2021. CONCLUSIONS: ASPEN-COVID-19 will provide important data on a novel therapeutic approach that may improve outcomes in hospitalized COVID-19 patients beyond available anticoagulants by targeting tissue factor, with potential effects on not only thrombosis but also inflammation and viral propagation.

An LMNA synonymous variant associated with severe dilated cardiomyopathy: Case report.

Dilated cardiomyopathy (DCM) is one of the most common cardiac phenotypes caused by mutations of lamin A/C (LMNA) gene in humans. In our study, a cohort of 57 patients who underwent heart transplant for dilated cardiomyopathy was screened for variants in LMNA. We identified a synonymous variant c.936G>A in the last nucleotide of exon 5 of LMNA in a DCM family. Clinically, the LMNA variant carriers presented with severe familial DCM, conduction disease, and high creatine-kinase level. The LMNA c.936G>A variant is novel and has not been reported in current genetic variant databases. Sanger sequencing results showed the presence of LMNA c.936G>A variant in the genomic DNA but not in the cDNA derived from one family member's heart tissue. Real-time quantitative polymerase chain reaction showed significantly lower LMNA mRNA levels in the patient's heart compared to the controls, suggesting that the c.936G>A LMNA variant resulted in reduced mRNA and possibly lower protein expression of LMNA. These findings expand the understanding on the association between synonymous variant of LMNA and the molecular pathogenesis in DCM patients.

Integrated analysis of miRNA-mRNA interaction in pediatric dilated cardiomyopathy.

BACKGROUND: MicroRNAs (miRNAs) are short single-stranded nucleotides that can regulate gene expression. Although we previously evaluated the expression of miRNAs in pediatric dilated cardiomyopathy (DCM) by miRNA array, pathway prediction based on changes in mRNA expression has not been previously analyzed in this population. The current study aimed to determine the regulation of miRNA expression by miRNA-sequencing (miRNA-seq) and, through miRNA-sequencing (mRNA-seq), analyze their putative target genes and altered pathways in pediatric DCM hearts. METHODS: miRNA expression was determined by miRNA-seq [n = 10 non-failing (NF), n = 20 DCM]. Expression of a subset of miRNAs was evaluated in adult DCM patients (n = 11 NF, n = 13 DCM). miRNA-mRNA prediction analysis was performed using mRNA-seq data (n = 7 NF, n = 7 DCM) from matched samples. RESULTS: Expression of 393 miRNAs was significantly different (p < 0.05) in pediatric DCM patients compared to NF controls. TargetScan-based miRNA-mRNA analysis revealed 808 significantly inversely expressed genes. Functional analysis suggests upregulated pathways related to the regulation of stem cell differentiation and cardiac muscle contraction, and downregulated pathways related to the regulation of protein phosphorylation, signal transduction, and cell communication. CONCLUSIONS: Our results demonstrated a unique age-dependent regulation of miRNAs and their putative target genes, which may contribute to distinctive phenotypic characteristics of DCM in children. IMPACT: This is the first study to compare miRNA expression in the heart of pediatric DCM patients to age-matched healthy controls by RNA sequencing. Expression of a subset of miRNAs is uniquely dysregulated in children. Using mRNA-seq and miRNA-seq from matched samples, target prediction was performed. This study underscores the importance of pediatric-focused studies.

Development and application of an electronic synoptic report for reporting and management of low-dose computed tomography lung cancer screening examination.

BACKGROUND: Interpretation of Low Dose CT scans and protocol driven management of findings is a key aspect of lung cancer screening program performance. Reliable and reproducible methods are needed to communicate radiologists' interpretation to the screening program or clinicians driving management decision. METHODS: We performed an audit of a subset of dictated reports from the PANCAN study to assess for omissions. We developed an electronic synoptic reporting tool for radiologists embedded in a clinical documentation system software. The tool was then used for reporting as part of the Alberta Lung Cancer Screening Study and McGill University Health Centre Pilot Lung Cancer Screening Program. RESULTS: Fifty reports were audited for completeness. At least one omission was noted in 30 (70%) of reports, with a major omission (missing lobe, size, type of nodule in report or actionable incidental finding in recommendation section of report) in 24 (48%). Details of the reporting template and functionality such as automated nodule cancer risk assessment, Lung-RADS category assignment, auto-generated narrative type report as well as personalize participant results letter is provided. A description of the system's performance in its application in 2815 CT reports is then summarized. CONCLUSIONS: We found that narrative type radiologist reports for lung cancer screening CT examinations frequently lacked specific discrete data elements required for management. We demonstrate the successful implementation of a radiology synoptic reporting system for use in lung cancer screening, and the use of this information to drive program management and communications.

Serum response factor deletion 5 regulates phospholamban phosphorylation and calcium uptake.

AIMS: Pediatric dilated cardiomyopathy (pDCM) is characterized by unique age-dependent molecular mechanisms that include myocellular responses to therapy. We previously showed that pDCM, but not adult DCM patients respond to phosphodiesterase 3 inhibitors (PDE3i) by increasing levels of the second messenger cAMP and consequent phosphorylation of phospholamban (PLN). However, the molecular mechanisms involved in the differential pediatric and adult response to PDE3i are not clear. METHODS AND RESULTS: Quantification of serum response factor (SRF) isoforms from the left ventricle of explanted hearts showed that PDE3i treatment affects expression of SRF isoforms in pDCM hearts. An SRF isoform lacking exon 5 (SRFdel5) was highly expressed in the hearts of pediatric, but not adult DCM patients treated with PDE3i. To determine the functional consequence of expression of SRFdel5, we overexpressed full length SRF or SRFdel5 in cultured cardiomyocytes with and without adrenergic stimulation. Compared to a control adenovirus, expression of SRFdel5 increased phosphorylation of PLN, negatively affected expression of the phosphatase that promotes dephosphorylation of PLN (PP2Cε), and promoted faster calcium reuptake, whereas expression of full length SRF attenuated calcium reuptake through blunted phosphorylation of PLN. CONCLUSIONS: Taken together, these data indicate that expression of SRFdel5 in pDCM hearts in response to PDE3i contributes to improved function through regulating PLN phosphorylation and thereby calcium reuptake.

Transcriptome signature of ventricular arrhythmia in dilated cardiomyopathy reveals increased fibrosis and activated TP53.

AIMS: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT. METHODS AND RESULTS: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT. CONCLUSIONS: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.

Left atrial vortex size and velocity distributions by 4D flow MRI in patients with paroxysmal atrial fibrillation: Associations with age and CHA2 DS2 -VASc risk score.

BACKGROUND: Characterization of left atrial (LA) hemodynamics in paroxysmal atrial fibrillation (PAF) may provide valuable insights for thromboembolic risk. PURPOSE: To evaluate LA vortex formation and velocity distributions by 4D flow MRI and identify associations with age, LA/LV (left ventricle) function, and established risk scores. STUDY TYPE: Prospective clinical. POPULATION: Patients with PAF (n = 45, 46 ± 14 years) and healthy controls (n = 15, 54 ± 9 years) were enrolled. MRI SEQUENCES: 3T standardized cardiac MRI protocol inclusive of 4D flow MRI. ASSESSMENT: Flow analysis planes were prescribed at each pulmonary vein. Velocity distribution analysis and vortex size quantification by the Lambda2 (λ2 ) method were performed in the LA. STATISTICS: Pearson or Spearman's correlation coefficients, r, were calculated to identify relationships between 4D flow-derived LA parameters and age, LA/LV function, and CHA2 DS2 -VASc stroke risk score. Univariate and multivariate determinants of stroke risk were assessed using linear regressions. To compare parameters within multiple groups, one-way analysis of variance or Kruskal-Wallis was used. RESULTS: LA vortice sizes were observed in all subjects using λ2 showing inverse correlations with peak pulmonary vein inflow velocities (P < 0.05), and positive correlations with LA volume (P < 0.05). Vortex size was elevated in PAF at all phases of the cardiac cycle, being most prominent at end early diastole (3.98 ± 1.84 cm3 vs. 6.93 ± 3.11 cm3 , P = 0.001). Velocity distribution analysis showed a greater incidence of flow stasis among patients with PAF (P < 0.05). In univariate regression, vortex size was associated with the CHA2 DS2 -VASc risk score at peak systole (0.457 ± 0.038, P ≤ 0.001). However, in multivariate regression age was the dominant determinant of stroke risk (0.348 ± 0.012, P = 0.006). DATA CONCLUSION: This study demonstrated that LA vortex size is increased among low-risk patients with PAF and is associated with the CHA2 DS2 -VASc risk score. Age remained the dominant determinant of stroke risk. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:871-884.

Imaging limitations in evaluating blunt cardiac trauma: A case report.

A 20-year old male presented with life-threatening polytrauma secondary to a motor vehicle accident. He had sustained injuries to the chest, including blunt cardiac trauma. On a short-term follow-up imaging, it was determined the patient had an injury to the main pulmonary artery and possible pericardial rupture. Given these imaging findings, he was taken to the operating room for emergent surgical intervention. Surgery revealed intracardiac injury; however, the pulmonary artery was intact. This case report is significant for the following two learning points: (a) The potential limitations of computed tomography when assessing intrathoracic injury, and (b) unique constellation of injuries secondary to trauma.

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure.

BACKGROUND: Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures. RESULTS: RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets. CONCLUSIONS: Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.

A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial.

BACKGROUND: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials. METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).

MicroRNAs in Heart Failure, Cardiac Transplantation, and Myocardial Recovery: Biomarkers with Therapeutic Potential.

PURPOSE OF REVIEW: Heart failure is increasing in prevalence with a lack of recently developed therapies that produce major beneficial effects on its associated mortality. MicroRNAs are small non-coding RNA molecules that regulate gene expression, are differentially regulated in heart failure, and are found in the circulation serving as a biomarker of heart failure. RECENT FINDINGS: Data suggests that microRNAs may be used to detect allograft rejection in cardiac transplantation and may predict the degree of myocardial recovery in patients with a left ventricular assist device or treated with beta-blocker therapy. Given their role in regulating cellular function, microRNAs are an intriguing target for oligonucleotide therapeutics, designed to mimic or antagonize (antagomir) their biological effects. We review the current state of microRNAs as biomarkers of heart failure and associated conditions, the mechanisms by which microRNAs control cellular function, and how specific microRNAs may be targeted with novel therapeutics designed to treat heart failure.

AKAP-Lbc mobilizes a cardiac hypertrophy signaling pathway.

Elevated catecholamines in the heart evoke transcriptional activation of the Myocyte Enhancer Factor (MEF) pathway to induce a cellular response known as pathological myocardial hypertrophy. We have discovered that the A-Kinase Anchoring Protein (AKAP)-Lbc is upregulated in hypertrophic cardiomyocytes. It coordinates activation and movement of signaling proteins that initiate MEF2-mediated transcriptional reprogramming events. Live-cell imaging, fluorescent kinase activity reporters, and RNA interference techniques show that AKAP-Lbc couples activation of protein kinase D (PKD) with the phosphorylation-dependent nuclear export of the class II histone deacetylase HDAC5. These studies uncover a role for AKAP-Lbc in which increased expression of the anchoring protein selectively amplifies a signaling pathway that drives cardiac myocytes toward a pathophysiological outcome.

Visual analysis of biological data-knowledge networks.

BACKGROUND: The interpretation of the results from genome-scale experiments is a challenging and important problem in contemporary biomedical research. Biological networks that integrate experimental results with existing knowledge from biomedical databases and published literature can provide a rich resource and powerful basis for hypothesizing about mechanistic explanations for observed gene-phenotype relationships. However, the size and density of such networks often impede their efficient exploration and understanding. RESULTS: We introduce a visual analytics approach that integrates interactive filtering of dense networks based on degree-of-interest functions with attribute-based layouts of the resulting subnetworks. The comparison of multiple subnetworks representing different analysis facets is facilitated through an interactive super-network that integrates brushing-and-linking techniques for highlighting components across networks. An implementation is freely available as a Cytoscape app. CONCLUSIONS: We demonstrate the utility of our approach through two case studies using a dataset that combines clinical data with high-throughput data for studying the effect of ß-blocker treatment on heart failure patients. Furthermore, we discuss our team-based iterative design and development process as well as the limitations and generalizability of our approach.