Search

Introduction:Reflex-mediated syncope occurs in 15% of children and young adults. In rare instances, pacemakers are required to treat syncopal episodes associated with transient sinus pauses or atrioventricular block. This study describes a single centre experience in the use of permanent pacemakers to treat syncope in children and young adults.Materials and methods:Patients with significant pre-syncope or syncope and pacemaker implantation from 1978 to 2018 were reviewed. Data collected included the age of presentation, method of diagnosis, underlying rhythm disturbance, age at implant, type of pacemaker implanted, procedural complications and subsequent symptoms.Results:Fifty patients were identified. Median age at time of the first syncopal episode was 10.2 (range 0.3–20.4) years, with a median implant age of 14.9 (0.9–34.3) years. Significant sinus bradycardia/pauses were the predominant reason for pacemaker implant (54%), followed by high-grade atrioventricular block (30%). Four (8%) patients had both sinus pauses and atrioventricular block documented. The majority of patients had dual-chamber pacemakers implanted (58%), followed by ventricular pacemakers (38%). Median follow-up was 6.7 (0.4–33.0) years. Post-implant, 4 (8%) patients continued to have syncope, 7 (14%) had complete resolution of their symptoms, and the remaining reported a decrease in their pre-syncopal episodes and no further syncope. Twelve (24%) patients had complications, including two infections and eight lead malfunctions.Conclusions:Paediatric patients with reflex-mediated syncope can be treated with pacing. Complication rates are high (24%); as such, permanent pacemakers should be reserved only for those in whom asystole from sinus pauses or atrioventricular block has been well documented.

Background: Mutations in tafazzin ( TAZ ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. Methods: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells and cardiac-specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca 2+ handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca 2+ handling and contractility. Results: A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias, including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared with wild-type controls, BTHS-induced pluripotent stem cell–derived cardiomyocytes had increased diastolic Ca 2+ and decreased Ca 2+ transient amplitude. BTHS-induced pluripotent stem cell–derived cardiomyocytes had higher levels of mitochondrial and cellular reactive oxygen species than wild-type controls, which activated CaMKII (Ca 2+ /calmodulin-dependent protein kinase II). Activated CaMKII phosphorylated the RYR2 (ryanodine receptor 2) on serine 2814, increasing Ca 2+ leak through RYR2. Inhibition of this reactive oxygen species–CaMKII–RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca 2+ handling in BTHS-induced pluripotent stem cell–derived cardiomyocytes and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca 2+ and decreased Ca 2+ transient amplitude. These abnormalities were ameliorated by Ca 2+ /calmodulin-dependent protein kinase II or reactive oxygen species inhibition. Conclusions: This study identified a molecular pathway that links TAZ mutation with abnormal Ca 2+ handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial reactive oxygen species production.

Background: Truncating variants in the desmosomal gene PKP2 (PKP2 tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity. Methods: We identified individuals with PKP2 tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The PKP2 tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI [Illumina, Inc.]) were assessed. Results: PKP2 tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique PKP2 tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with PKP2 tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10 −4 ). The ARVC cohort included 487 ARVC probands with 144 distinct PKP2 tv, with 25 PKP2 tv common to both cohorts. The odds ratio for ARVC for the 25 common PKP2 tv was 0.047 (95% CI, 0.001–0.268; P= 2.43×10 −6 ), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiate PKP2 tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with PKP2 tv (7.9% versus 4.3%; odds ratio, 2.11; P =0.005). Conclusions: PKP2 tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how PKP2 tv cause ARVC in combination with associated genetic and environmental risk factors.

Current drug development efforts for the treatment of atrial fibrillation are hampered by the fact that many preclinical models have been unsuccessful in reproducing human cardiac physiology and its response to medications. In this study, we demonstrated an approach using human induced pluripotent stem cell‐derived atrial and ventricular cardiomyocytes (hiPSC‐aCMs and hiPSC‐vCMs, respectively) coupled with a sophisticated optical mapping system for drug screening of atrial‐selective compounds in vitro. We optimized differentiation of hiPSC‐aCMs by modulating the WNT and retinoid signaling pathways. Characterization of the transcriptome and proteome revealed that retinoic acid pushes the differentiation process into the atrial lineage and generated hiPSC‐aCMs. Functional characterization using optical mapping showed that hiPSC‐aCMs have shorter action potential durations and faster Ca2+ handling dynamics compared with hiPSC‐vCMs. Furthermore, pharmacological investigation of hiPSC‐aCMs captured atrial‐selective effects by displaying greater sensitivity to atrial‐selective compounds 4‐aminopyridine, AVE0118, UCL1684, and vernakalant when compared with hiPSC‐vCMs. These results established that a model system incorporating hiPSC‐aCMs combined with optical mapping is well‐suited for preclinical drug screening of novel and targeted atrial selective compounds., Chamber‐specific differentiation of hiPSC‐derived cardiomyocytes allowed for the development of an atrial cardiomyocyte‐based drug screening platform. In‐depth characterization of hiPSC‐derived atrial and ventricular cardiomyocytes revealed chamber‐specific phenotypes in molecular signatures and functional profiles. Drug screening with high‐content optical mapping system captured atrial‐selective pharmacology which demonstrated the utility of hiPSC‐derived atrial cardiomyocytes as an in vitro drug screening model.

OBJECTIVE To determine the impact of provocative electrophysiology testing in postoperative congenital heart disease (CHD) patients on the management of supraventricular tachycardia (SVT) and clinical outcomes. METHODS This is a retrospective study including patients

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell–derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.

Inherited arrhythmias are disorders caused by one or more genetic mutations that increase the risk of arrhythmia, which result in life-long risk of sudden death. These mutations either primarily perturb electrophysiological homeostasis (e.g. long QT syndrome and catecholaminergic polymorphic ventricular tachycardia), cause structural disease that is closely associated with severe arrhythmias (e.g. hypertrophic cardiomyopathy), or cause a high propensity for arrhythmia in combination with altered myocardial structure and function (e.g. arrhythmogenic cardiomyopathy). Currently available therapies offer incomplete protection from arrhythmia and fail to alter disease progression. Recent studies suggest that gene therapies may provide potent, molecularly targeted options for at least a subset of inherited arrhythmias. Here, we provide an overview of gene therapy strategies, and review recent studies on gene therapies for catecholaminergic polymorphic ventricular tachycardia and hypertrophic cardiomyopathy caused by MYBPC3 mutations.

Objectives: To describe a single institutional experience managing fetuses with supraventricular tachycardia (SVT) and to identify associations between patient characteristics and fetal and postnatal outcomes. Background: Sustained fetal SVT is associated with significant morbidity and mortality if untreated, yet the optimal management strategy remains unclear. Methods: Retrospective cohort study including fetuses diagnosed with sustained SVT (>50% of the diagnostic echocardiogram) between 1985 and 2018. Fetuses with congenital heart disease were excluded. Results: Sustained SVT was diagnosed in 65 fetuses at a median gestational age of 30 weeks (range, 14-37). Atrioventricular re-entrant tachycardia and atrial flutter were the most common diagnoses, seen in 41 and 16 cases, respectively. Moderate/severe ventricular dysfunction was present in 20 fetuses, and hydrops fetalis was present in 13. Of the 57 fetuses initiated on transplacental drug therapy, 47 received digoxin first-line, yet 39 of 57 (68%) required advanced therapy with sotalol, flecainide, or amiodarone. Rate or rhythm control was achieved in 47 of 57 treated fetuses. There were no cases of intrauterine fetal demise. Later gestational age at fetal diagnosis (odds ratio [OR], 1.1, 95% confidence interval [CI], 1.01-1.2, P = .02) and moderate/severe fetal ventricular dysfunction (OR, 6.1, 95% CI, 1.7-21.6, P = .005) were associated with postnatal SVT. Two postnatal deaths occurred. Conclusions: Fetuses with structurally normal hearts and sustained SVT can be effectively managed with transplacental drug therapy with minimal risk of intrauterine fetal demise. Treatment requires multiple antiarrhythmic agents in over half of cases. Later gestational age at fetal diagnosis and the presence of depressed fetal ventricular function, but not hydrops, predict postnatal arrhythmia burden.

Background: Current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells (iPSCs) are capable of generating highly pure cardiomyocyte populations as determined by expression of cardiac troponin T. However, these cardiomyocytes remain immature, more closely resembling the fetal state, with a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared with adult cardiomyocytes. Immaturity of iPSC-derived cardiomyocytes may be a significant barrier to clinical translation of cardiomyocyte cell therapies for heart disease. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of rapamycin (mTOR)–signaling pathway plays a key role in nutrient sensing and growth. We hypothesized that transient inhibition of the mTOR-signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation. Methods: Cardiomyocytes were differentiated from 3 human iPSC lines using small molecules to modulate the Wnt pathway. Torin1 (0 to 200 nmol/L) was used to inhibit the mTOR pathway at various time points. We quantified contractile, metabolic, and electrophysiological properties of matured iPSC-derived cardiomyocytes. We utilized the small molecule inhibitor, pifithrin-α, to inhibit p53 signaling, and nutlin-3a, a small molecule inhibitor of MDM2 (mouse double minute 2 homolog) to upregulate and increase activation of p53. Results: Torin1 (200 nmol/L) increased the percentage of quiescent cells (G 0 phase) from 24% to 48% compared with vehicle control ( P Conclusions: Transient treatment of human iPSC-derived cardiomyocytes with Torin1 shifts cells to a quiescent state and enhances cardiomyocyte maturity.

Introduction: Arrhythmogenic cardiomyopathy (ACM) resulting from variants in the desmosomal gene desmoplakin (DSP) is typically an adult onset disorder. Here, we describe penetrance, expression and outcomes of DSP-associated ACM in children. Methods: Patients aged ≤21 years with pathogenic/likely pathogenic variants in DSP were included. Penetrance was defined by:(i) ECG: T-wave inversion V4-V6; mean QRS amplitude 500 VPBs/24 hours, non-sustained or sustained ventricular arrhythmia (VA)(iii) LV dysfunction (EF Results: We identified 24 patients (67% female) inclusive of 8 probands and 16 family members. Variants were truncating in 22 and missense in 2; a second variant occurred in 4. Presenting symptoms were cardiac arrest (1); myocardial inflammation (3) with cardiac arrest (1), sustained VA (1), dyspnea (2), syncope (1), palpitations (1). ACM was penetrant in 17 (71%), with expression first evident at 15.2±3.3 years. The cardiac phenotype was left dominant (12) and biventricular (5). Isolated RV disease was not seen. Penetrant features were:(i) ECG: transient T-wave inversion in 1 (6%) and QRS amplitude Conclusions: DSP-mediated ACM may be fully penetrant in children affecting both probands and family members. VA and subepicardial LGE are prominent early features of disease and pediatric surveillance should reflect these findings.

Fasciculoventricular fibers (FVFs) are responsible for 1%-5% of cases of asymptomatic preexcitation on the surface electrocardiogram (ECG). Unlike ventricular preexcitation seen in Wolff-Parkinson-White (WPW) syndrome, FVFs are not associated with sudden cardiac death from preexcited atrial fibrillation.The purpose of this study was to identify surface ECG variables that differentiate FVFs from true WPW syndrome.This is a retrospective case-control study comparing surface ECG characteristics of patients diagnosed with FVFs (cases) with those of patients with WPW syndrome and anteroseptal accessory pathways (controls) via intracardiac electrophysiology testing at a single institution from 2005 to 2017.Twenty-four cases of FVFs confirmed by intracardiac electrophysiology testing were identified and compared with 48 consecutive controls with WPW syndrome and anteroseptal accessory pathways. Patients with WPW syndrome were found to have significantly higher delta wave amplitudes (4.8 ± 2.0 mm vs 1.9 ± 1.3 mm; P.001), shorter PR intervals (94.6 ± 12.5 ms vs 106.8 ± 13.2 ms; P.001), and longer QRS intervals (133.6 ± 19.0 ms vs 118.7 ± 24.7 ms; P = .006) than did those with FVFs. Multivariable logistic regression analysis identified the delta wave amplitude as the only independent predictor of WPW syndrome (odds ratio 3.1 per 1-mm increase; bootstrapped 95% confidence interval 1.5-6.4; c statistic 0.90; P = .002).The etiology of preexcitation in patients with an anteroseptal preexcitation pattern, whether because of a benign FVF or because of potentially serious WPW syndrome, can be noninvasively deduced using the surface ECG. A higher delta wave amplitude is an independent risk factor for the presence of WPW syndrome and can accurately distinguish WPW syndrome from a FVF with good test accuracy characteristics.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a variably penetrant disease increasingly identified in young patients. OBJECTIVES: This study sought to describe the diverse phenotype, genotype, and outcomes in pediatric and adolescent patients. METHODS: Records from 1999 to 2016 were reviewed for individuals age

This study sought to determine the practical use of the recently introduced LINQ implantable loop recorder (LINQ-ILR) in a cohort of pediatric and adult congenital arrhythmia patients.Correlating symptoms to a causative arrhythmia is a key aspect of diagnosis and management in clinical electrophysiology.Retrospective review of clinical data, implantation indications, findings, and therapeutic decisions in patients who underwent LINQ-ILR implantation from April 1st, 2014 to January 30th, 2017 at Boston Children's Hospital.A total of 133 patients were included, of which 76 (57%) were male. The mean age at implantation was 15.7 ± 9.1 years with a duration of follow-up of 11.8 months. Congenital heart disease was present in 34 patients (26%), a confirmed genetic diagnosis in 50 (38%), and cardiomyopathy in 22 (26%), and the remainder were without a previous diagnosis. Syncope was the most common indication for LINQ-ILR implantation, occurring in 59 patients (44%). The median time to diagnosis was 4.5 months, occurring in 78 patients (59%). Cardiac device placement occurred in 17 patients (22%), a medication change in 9 (12%), electrophysiology study/ablation in 5 (6%), or LINQ-ILR explantation in 42 (54%). Infection or erosion occurred in 5 patients. Syncope was correlated with a diagnostic transmission (54% vs. 31%, p = 0.01).The LINQ-ILR is an important diagnostic tool, providing useful data in more than one-half of patients in 6 months. Adverse events are low. Patient selection is critical and undiagnosed syncope represents an important presenting indication for which a LINQ-ILR implant should be considered.

BACKGROUND: Mutations in tafazzin (TAZ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. METHODS: We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) and cardiac specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca(2+) handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca(2+) handling and contractility. RESULTS: A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared to WT, BTHS iPSC-CMs had increased diastolic Ca(2+) and decreased Ca(2+) transient amplitude. BTHS iPSC-CMs had higher levels of mitochondrial and cellular ROS than WT, which activated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Activated CaMKII phosphorylated the cardiac ryanodine receptor (RYR2) on serine 2814, increasing Ca(2+) leak through RYR2. Inhibition of this ROS-CaMKII-RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca(2+) handling in BTHS iPSC-CMs and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca(2+) and decreased Ca(2+) transient amplitude. These abnormalities were ameliorated by CaMKII or ROS inhibition. CONCLUSIONS: This study identified a molecular pathway that links TAZ mutation to abnormal Ca(2+) handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial ROS production.

Background: Atrioventricular reentrant tachycardia is common in children. Catheter ablation is increasingly used as a first-line therapy with a high acute success rate, but recurrence during follow-up remains a concern. The aim of this study was to identify risk factors for recurrence after accessory pathway (AP) ablation. Methods: Retrospective cohort study including patients who underwent AP ablation between 2013 and 2018. Cox proportional hazards model was used to examine the association between patient and procedural characteristics and recurrence during follow-up. Results: From 558 AP ablation procedure, 542 (97%) were acutely successful. During a median follow-up of 0.4 (interquartile range, 0.1–1.4) years, there were 42 (8%) patients with documented recurrence. On univariate analysis, early recurrence was associated with younger age, congenital heart disease, multiple AP, AP location (right sided and posteroseptal versus left sided), cryoablation (versus radiofrequency), empirical ablation, the lack of full power radiofrequency lesions ( Conclusions: In our institutional experience, radiofrequency consolidation time

Producing excellent physician scientists starts with the active discovery of talent and dedication, supported by the strong belief that physician involvement in biomedical research is essential to make fundamental discoveries that improve human health. The revolution of surgical and interventional therapy of structural heart disease has had 'profoundly positive effects on survival and quality of life over the decades. (…) Small increments in clinical improvement will still be possible in the future, but for the most part, the potential for major advancement using these techniques has been exhausted' (Frank Hanley, MD; Stanford). Personalized medicine, rapid genetic diagnostics, RNA and extracellular vesicle biology, epigenetics, gene editing, gene and stem cell-derived therapy are exemplary areas where specialized training for paediatric/congenital cardiology physician scientists will be increasingly needed to further advance the field. About a decade ago, a series in Circulation discussed academic career models and highlighted the major challenges facing the cardiovascular 'clinician scientist' (syn. physician scientist), which have not abated since. To develop the skills and expertise in both clinical congenital cardiology and basic research, the training of fellows must be focused and integrated. The current pandemic COVID-19 puts additional pressure and hurdles on fellows-in-training (FIT) and early career investigators (ECI) who aim to establish, consolidate or expand their own research group. Here, we discuss the major challenges, opportunities and necessary changes for academic institutions to sustain and recruit physician scientists in paediatric/congenital cardiology in the years to come.

Rationale:Cardiac CITED4 is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown.Objective:To investigate the role of CITED4 in murine models of exercise and pressure overload.Methods and Results:We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mammalian target of rapamycin (mTOR) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a pro-fibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC.Conclusions:CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.

Objectives This study sought to determine the long-term effect of dual-site ventricular pacing (i.e., cardiac resynchronization therapy [CRT]) versus single-site pacing in patients with Fontan physiology and high-grade atrioventricular block (AVB). Background Chronic single-site ventricular pacing in Fontan patients is associated with significant morbidity and mortality. Methods The study conducted a retrospective review of all Fontan patients with high-grade AVB who received pacemakers at a single institution between 1990 and 2016 with follow-up of 12 months or greater. The primary study outcome was a composite of death or heart transplantation. Results Nineteen patients received CRT devices and 43 patients received single-site ventricular pacemakers (SVPMs), with a median follow-up of 4.9 years (range 1.1 to 11.3 years) and 10.4 years (range 1.1 to 26.8 years), respectively. One (5.3%) CRT patient and 11 (25.6%) SVPM patients reached the composite endpoint of death or transplant (odds ratio: 0.16; 95% confidence interval: 0.02 to 1.36; p = 0.09). Kaplan-Meier analysis showed similar rates of freedom from death or transplant between the 2 study groups over a 5-year follow-up period (p = 0.08). The proportion of SVPM patients with abnormal ventricular systolic function before device implantation (9.5%) and at follow-up (33.3%) significantly increased (p=0.009). The CRT cohort had less change in their ventricular function (42.1% before device implant, 36.8% at follow-up; p = 1.00); however, a Kaplan-Meier analysis over a 5-year follow-up period found no difference in the presence of abnormal ventricular systolic function between groups (p = 0.27). Conclusions There was no significant difference in long-term outcomes between Fontan patients who were single- or dual-site paced for high-grade AVB.

Summary: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Nav1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain. : In this article, Isom, Parent, and colleagues show that the high risk of SUDEP in the developmental and epileptic encephalopathy, Dravet syndrome, may result from a predisposition to cardiac arrhythmias in addition to neuronal hyperexcitability, reflecting haploinsufficiency of SCN1A in heart and brain causing potential compensatory overexpression of other sodium-channel genes in those tissues. Keywords: epilepsy, cardiac arrhythmia, sodium channel, SUDEP, induced pluripotent stem cell (iPSC), developmental and epileptic encephalopathy

Objective This study evaluates the ability of experienced pediatric electrophysiologists (EPs) to reliably classify incomplete right bundle branch block (IRBBB) and assesses its clinical utility as an isolated ECG finding in a group of healthy outpatient children without prior cardiac evaluation. Design We performed a retrospective analysis of all electrocardiographic and echocardiographic records at Boston Children's Hospital between January 1, 2005, and December 31, 2014. Echocardiographic diagnoses were identified if registered between the date of the index electrocardiogram and the ensuing year. A selected subset of 473 ECGs was subsequently reanalyzed in a blinded manner by six pediatric EPs to determine the consistency with which the finding of IRBBB could be assigned. Results Of the 331 278 ECGs registered in the BCH database, 32 127 (9.7%) met inclusion criteria and were analyzed for the prevalence of isolated right bundle conduction disturbance findings. The mean age was 12.1 ± 4.0 years, and the population was 49% male. Of the 32 127 ECGs, 72.5% were coded normal, 3.0% were coded IRBBB, and 0.5% were coded complete right bundle branch block (CRBBB). A total of 7.3% of patients coded as normal had an ensuing echocardiogram, compared to 12.5% coded IRBBB. Echo findings were recorded in 0.1% of normal and 0.2% of IRBBB. Patients with ASD-secundum type were no more likely to have isolated IRBBB on previous ECG than the general population (2.5% vs 3.0%). Analysis of inter-reader variability in ECG findings and conduction disturbance identification was high (range of IRBBB prevalence 1-20% among readers). Reinterpretation of ECGs using explicit diagnostic criteria did not demonstrate consistent discrimination of IRBBB and Normal ECGs. Conclusions IRBBB is not uncommon in a healthy school age population and is observed to have high inter-reader variability. It was associated with increased use of echocardiographic exam but was not associated with increased rate of echocardiographic findings when compared with rates for normal ECGs.

OBJECTIVE This quality improvement study was implemented to demonstrate consistent and reliable post procedure anticoagulation for patients undergoing left-sided ablations. We evaluated the safety and efficacy of anticoagulation practice during a transition from anticoagulation with overnight infusion of unfractionated heparin to a single subcutaneous injection of low molecular weight heparin. METHODS Outcomes for patients who received unfractionated heparin from January 2014 to October 2014, were compared with outcomes of patients who received low molecular weight heparin from October 2014 to October 2015. Complications prepractice and postpractice change were documented and compared to establish confidence in the practice change and confirm the safety of the anticoagulation therapy management. RESULTS There were no differences in the type or frequency of complications/adverse events demonstrated between the patients who had received unfractionated heparin for anticoagulation prophylaxis and those who received low molecular weight heparin. No thromboembolic events were reported or documented with either anticoagulation strategy. After confidence in the safety and efficacy of the practice change was established, a decision was made to discharge patients home the same day as there procedure, effectively reducing inpatient bed days and overall costs. CONCLUSION Administration of low molecular weight heparin provides predictable anticoagulation and equally safe as unfractionated heparin when administered to patients post left-sided ablation. A secondary gain has been reduction of procedural costs by elimination of the previously required inpatient observation stay.

Aims Conflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganized multiple-wavelet activation to organized rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism. Methods and results Optical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact fibrosis (CF), diffuse fibrosis (DiF), and patchy fibrosis (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum. Enhanced GJ coupling with rotigaptide (n = 10) progressively organized fibrillation in a concentration-dependent manner; increasing FDI (0 nM: 0.53 ± 0.04, 80 nM: 0.78 ± 0.03, P, Graphical Abstract

Background: Modeling of human arrhythmias with induced pluripotent stem cell–derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported. Methods: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell–derived cardiomyocyte–based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing. Results: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca 2+ levels and increased temporal and spatial dispersion of Ca 2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor–serine 2814 phosphorylation by Ca 2 + /calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues. Conclusions: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II–dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.

Sotalol is an important antiarrhythmic drug in the pediatric population. Given the risk of proarrhythmia, sotalol is initiated in inpatient settings, with adult studies as recent as 2015 supporting this practice.The purpose of this study was to determine the frequency of adverse events (AEs) during sotalol initiation for the management of atrial, supraventricular, or ventricular arrhythmias in pediatric patients.A retrospective cohort analysis of pediatric patients 21 years or younger initiated on oral sotalol for supraventricular tachycardia or ventricular tachycardia (VT) at Boston Children's Hospital from January 1, 2007, through July 1, 2016, was performed. The primary end point was an AE defined as significant bradycardia, new or increased ventricular arrhythmias, conduction block, or corrected QT interval (QTc) prolongation, resulting in dose reduction or cessation.There were 190 patients who met inclusion criteria, with 110 patients (58%) 6 months or younger. A total of 115 patients (60%) had congenital heart disease. Arrhythmias for which sotalol was initiated included atrioventricular reciprocating tachycardia/atrioventricular nodal reciprocating tachycardia (n = 105 [55%]), atrial flutter (n = 31 [16%]), ectopic atrial tachycardia (n = 26 [14%]), VT (n = 21 [11%]), and atrial fibrillation (n = 7 [4%]). The median pre-sotalol QTc was 438 ms (interquartile range 348-530 ms). Five patients (3%) (aged 0.1-18 years) had AEs including bradycardia40 beats/min (n = 2) and100 beats/min (n = 1) and QTc prolongation (n = 2). All 5 patients with AEs had repaired congenital heart disease.The incidence of AEs in pediatric patients initiating sotalol for atrial tachycardia, supraventricular tachycardia, or VT is low (3%), with no deaths or malignant rhythms reported in this series.

Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.

Atrial and ventricular arrhythmias are commonly seen with exercise stress testing (EST); these are almost always nonsustained, and the significance of those findings is, at best, modest. For patients with structurally normal hearts and combinations of isolated and repetitive ventricular ectopy, EST offers some mechanistic data and some marginal long-term prognostic data. Patients with increased ectopy during exercise or immediately post exercise deserve enhanced follow-up.

BACKGROUND Radiofrequency identification (RFID) detection systems are used to detect retained surgical sponges and may cause electromagnetic interference (EMI), altering intended function of cardiac pacing systems. Three pediatric patients requiring temporary pacing for postoperative atrioventricular block experienced transient inhibition of ventricular pacing during the use of RFID detection system. Bench testing was performed to evaluate the mechanism of pacemaker inhibition. METHODS Impedance of temporary pacing wires was obtained using a pacing system analyzer. Temporary pacemakers (Medtronic 5388, Medtronic 5392, and Biotronik Reocor D) at nominal settings (VVI 120 bpm, output 10 mA) were attached at the ventricular terminal to temporary pacing wires and a resistor for sham impedance in physiologic range. An RFID detection system and wand (RF Assure, model 200) or mat was tested over wires. Induced current and voltages were recorded via an oscilloscope attached to lead terminals. Inhibition of pacing was determined for the following variables: distance from wires, sham impedance, and programmed sensitivity. RESULTS In bench testing, the RFID system induced a stereotyped EMI signal in temporary pacing wires with peak root-mean-square voltage demonstrating an exponential decay relationship with increasing distance from pacing wires. Induced voltages overlapped with normal sensing range of temporary pacemakers, resulting in pacemaker inhibition at nominal settings (ventricular sensitivity 2.0 mV, distance from wand

Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines post-natally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.

This study sought to determine the long-term effect of dual-site ventricular pacing (i.e., cardiac resynchronization therapy [CRT]) versus single-site pacing in patients with Fontan physiology and high-grade atrioventricular block (AVB).Chronic single-site ventricular pacing in Fontan patients is associated with significant morbidity and mortality.The study conducted a retrospective review of all Fontan patients with high-grade AVB who received pacemakers at a single institution between 1990 and 2016 with follow-up of 12 months or greater. The primary study outcome was a composite of death or heart transplantation.Nineteen patients received CRT devices and 43 patients received single-site ventricular pacemakers (SVPMs), with a median follow-up of 4.9 years (range 1.1 to 11.3 years) and 10.4 years (range 1.1 to 26.8 years), respectively. One (5.3%) CRT patient and 11 (25.6%) SVPM patients reached the composite endpoint of death or transplant (odds ratio: 0.16; 95% confidence interval: 0.02 to 1.36; p = 0.09). Kaplan-Meier analysis showed similar rates of freedom from death or transplant between the 2 study groups over a 5-year follow-up period (p = 0.08). The proportion of SVPM patients with abnormal ventricular systolic function before device implantation (9.5%) and at follow-up (33.3%) significantly increased (p=0.009). The CRT cohort had less change in their ventricular function (42.1% before device implant, 36.8% at follow-up; p = 1.00); however, a Kaplan-Meier analysis over a 5-year follow-up period found no difference in the presence of abnormal ventricular systolic function between groups (p = 0.27).There was no significant difference in long-term outcomes between Fontan patients who were single- or dual-site paced for high-grade AVB.

Rationale: Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. Objective: To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Methods and Results: Tfam inactivation by Nkx2.5 Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Conclusions: Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.

Background The 2005 Bethesda Conference Guidelines advise patients with long QT syndrome against competitive sports. We assessed cardiac event rates during competitive and recreational sports, and daily activities among treated long QT syndrome patients. Methods and Results Long QT syndrome patients aged ≥4 years treated with anti‐adrenergic therapy were included. Demographics included mechanism of presentation, corrected QT interval pretreatment, symptom history, medication compliance, and administration of QT‐prolonging medications. Corrected QT interval ≥550 ms or prior cardiac arrest defined high risk. Sports were categorized by cardiovascular demand per the 2005 Bethesda Conference Guidelines. Each was classified as recreational or competitive. One hundred seventy‐two patients (90; 52% female) with median age 15.2 years (interquartile range 11.4, 19.4) were included. Evaluation was performed for family history (102; 59%), incidental finding (34; 20%), and symptoms (36; 21%). Median corrected QT interval was 474 ms (interquartile range 446, 496) and 14 patients (8%) were deemed high risk. Treatment included β‐blockers (171; 99%), implantable cardioverter‐defibrillator (27; 16%), left cardiac sympathetic denervation (7; 4%), and pacemaker (3; 2%). Sports participation was recreational (66; 38%) or competitive (106; 62%), with 92 (53%) exercising against the Bethesda Conference Guidelines. There were no cardiac events in competitive athletes and no deaths. There were 13 cardiac events in 9 previously symptomatic patients during either recreational exercise or activities of daily life. Conclusions In this cohort of appropriately managed children with long QT syndrome, cardiac event rates were low and occurred during recreational but not competitive activities. This study further supports the need for increased assessment of arrhythmia risk during exercise in this patient population.

Introduction: Cardiac hypertrophy is an adaptive response to increased physiologic or pathologic hemodynamic stress. Previous work from our laboratory suggested that the CEBPβ/ CITED4 pathway plays an important role in exercise-induced cardiac hypertrophy. Consistent with this model, our laboratory recently found that inducible cardiac expression of CITED4 in adult mice increases in heart weight and cardiomyocyte size with normal systolic function and a gene expression profile consistent with physiologic growth. After ischemia-reperfusion injury (IRI), induced CITED4 mice show significant functional recovery and evidence for decreased adverse remodeling. Hypothesis: Here, we assessed the hypothesis that CITED4 gene therapy delivered in a clinically relevant time frame after IRI in a mouse model, will also lead to improved systolic function and favorable cardiac remodeling. Methods and Results: Cardiomyocyte-specific CITED4 gene delivery via intravenous AAV9 (CITED4 and GFP control) injections in young wild type (WT) mice led to a steady 4-fold increase in cardiac CITED4 expression. After four weeks, CITED4 treated animals developed physiologic cardiac hypertrophy with increased heart weights (heart weight to tibia length controls 6.54±0.17g/mm vs. CITED4 7.31±0.12g/mm), as well as increased left ventricular mass index and wall thickness with unchanged systolic function evaluated by echocardiography. CITED4 gene therapy in the setting of IRI, delivered 20min. after reperfusion, promoted decreased maladaptive remodeling with improved systolic function (%FS controls 37.5±3.6 vs. C4KO 47.9±1.6), a smaller scar size (% fibrotic area controls 9.1±1.9 vs. C4KO 2.4±0.5) and a favorable gene expression profile eight weeks after IRI. After injury, CITED4 gene therapy led to a 6-fold overexpression already after one week post-IRI, responsible for less apoptosis, fibrosis and inflammation when compared to control mice. Conclusion: Taken together, our data identify CITED4 as a regulator of physiologic cardiac growth that protects against adverse remodeling after ischemic injury in a clinically relevant therapeutic intervention after IRI. CITED4 may represent a novel therapeutic target to mitigate adverse ventricular remodeling.

Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.

Inherited arrhythmia disorders are a group of potentially lethal diseases that remain diagnostic and management challenges. While the genetic basis for many of these disorders is well known, the pathogenicity of individual mutations and the resulting clinical outcomes are difficult to predict. Treatment options remain imperfect, and optimizing therapy for individual patients can be difficult. Recent advances in the derivation of induced pluripotent stem cells (iPSCs) from patients and creation of genetically engineered human models using CRISPR/Cas9 has the potential to dramatically advance translational arrhythmia research. In this review, we discuss the current state of modeling inherited arrhythmia disorders using human iPSC-derived cardiomyocytes. We also discuss current limitations and areas for further study.

The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.

Heart failure (HF) is a leading cause of morbidity and mortality in the elderly. However, despite the strong independent association between aging and HF, the intrinsic mechanisms by which the aging process contributes to HF pathophysiology in older adults remain unclear. Targeted proteomic

Background: Exercise induces physiological cardiac growth and protects against adverse cardiac remodeling. microRNAs (miRNA) are important regulators in cardiovascular pathology and disease. Less is known about miRNA roles in the cardiac effects of exercise, and we investigated their roles in exercise-induced cardiac growth. Methods and Results: Based on cardiac miRNA profiling in two exercise models (swimming, running) and functional screening in neonatal rat cardiomyocytes (NRCMs), miR-222 was selected for further study. miR-222 was upregulated ~2-fold in both exercise models, pathological hypertrophic and failing hearts (pp27 , Hipk1 , Hipk2 , and Hmbox-1 ) were identified and confirmed as direct targets. siRNA knockdown (KD) of p27 or Hipk2 inhibited NRCM apoptosis. To investigate miR-222’s cardiac role in vivo , we made transgenic mice with cardiac-specific, inducible (TgI-miR-222) or constitutive (TgC-miR-222) expression of miR-222. RT-PCR showed that miR-222 is increased ~6-fold in TgI-miR-222 hearts after induction and ~10-fold in TgC-miR-222 hearts. Surprisingly, both transgenic lines have normal heart size and function, and the 4 miR-222 targets are unaffected at baseline. After ischemia-reperfusion injury (IRI), TgI-miR-222 had no difference in initial infarct size or dysfunction but were protected against adverse remodeling over the next six weeks with better function (pCol1a1 , Col3a1 , Mmp2, p) and apoptosis ( Caspase 1, 3, 8, p Conclusion: Cardiac miR-222 is upregulated by exercise and protects against adverse remodeling and cardiac dysfunction after IRI or TAC.