Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice.

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval.

Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individuals, followed by replication in independent samples (∼42,000 for resting Tpe and ∼22,000 for Tpe response to exercise and recovery), all from UK Biobank. Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise, respectively, were formally replicated. In a full dataset GWAS, 13 further loci for resting Tpe, 1 for Tpe response to exercise and 1 for Tpe response to exercise were genome-wide significant (p ≤ 5 × 10-8). Sex-specific analyses indicated seven additional loci. In total, we identify 32 loci for resting Tpe, 3 for Tpe response to exercise and 3 for Tpe response to recovery modulating ventricular repolarization, as well as cardiac conduction and contraction. Our findings shed light on the genetic basis of resting Tpe and Tpe response to exercise and recovery, unveiling plausible candidate genes and biological mechanisms underlying ventricular excitability.

Computational prediction of the effect of D172N KCNJ2 mutation on ventricular pumping during sinus rhythm and reentry.

The understanding of cardiac arrhythmia under genetic mutations has grown in interest among researchers. Previous studies focused on the effect of the D172N mutation on electrophysiological behavior. In this study, we analyzed not only the electrophysiological activity but also the mechanical responses during normal sinus rhythm and reentry conditions by using computational modeling. We simulated four different ventricular conditions including normal case of ten Tusscher model 2006 (TTM), wild-type (WT), heterozygous (WT/D172N), and homozygous D172N mutation. The 2D simulation result (in wire-shaped mesh) showed the WT/D172N and D172N mutation shortened the action potential duration by 14%, and by 23%, respectively. The 3D electrophysiological simulation results showed that the electrical wavelength between TTM and WT conditions were identical. Under sinus rhythm condition, the WT/D172N and D172N reduced the pumping efficacy with a lower left ventricle (LV) and aortic pressures, stroke volume, ejection fraction, and cardiac output. Under the reentry conditions, the WT condition has a small probability of reentry. However, in the event of reentry, WT has shown the most severe condition. Furthermore, we found that the position of the rotor or the scroll wave substantially influenced the ventricular pumping efficacy during arrhythmia. If the rotor stays in the LV, it will cause very poor pumping performance. Graphical Abstract A model of a ventricular electromechanical system. This whole model was established to observe the effect of D172N KCNJ2 mutation on ventricular pumping behavior during sinus rhythm and reentry conditions. The model consists of two components; electrical component and mechanical component. The electrophysiological model based on ten Tusscher et al. with the IK1 D172N KCNJ2 mutation, and the myofilament dynamic (cross-bridge) model based on Rice et al. study. The 3D electrical component is a ventricular geometry based on MRI which composed of nodes representing single-cell with electrophysiological activation. The 3D ventricular mechanic is a finite element mesh composed of single-cells myofilament dynamic model. Both components were coupled with Ca2+ concentration. We used Gaussian points for the calcium interpolation from the electrical mesh to the mechanical mesh.

Síndrome Cornelia de Lange: tamaño y función ventricular en seis casos sin cardiopatía congénita / Cornelia de Lange syndrome: Ventricular size and function in six children without congenital heart defects

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HDAC1-mediated repression of the retinoic acid-responsive gene ripply3 promotes second heart field development.

Coordinated transcriptional and epigenetic mechanisms that direct development of the later differentiating second heart field (SHF) progenitors remain largely unknown. Here, we show that a novel zebrafish histone deacetylase 1 (hdac1) mutant allele cardiac really gone (crg) has a deficit of ventricular cardiomyocytes (VCs) and smooth muscle within the outflow tract (OFT) due to both cell and non-cell autonomous loss in SHF progenitor proliferation. Cyp26-deficient embryos, which have increased retinoic acid (RA) levels, have similar defects in SHF-derived OFT development. We found that nkx2.5+ progenitors from Hdac1 and Cyp26-deficient embryos have ectopic expression of ripply3, a transcriptional co-repressor of T-box transcription factors that is normally restricted to the posterior pharyngeal endoderm. Furthermore, the ripply3 expression domain is expanded anteriorly into the posterior nkx2.5+ progenitor domain in crg mutants. Importantly, excess ripply3 is sufficient to repress VC development, while genetic depletion of Ripply3 and Tbx1 in crg mutants can partially restore VC number. We find that the epigenetic signature at RA response elements (RAREs) that can associate with Hdac1 and RA receptors (RARs) becomes indicative of transcriptional activation in crg mutants. Our study highlights that transcriptional repression via the epigenetic regulator Hdac1 facilitates OFT development through directly preventing expression of the RA-responsive gene ripply3 within SHF progenitors.

Left ventricular remodeling after the first myocardial infarction in association with LGALS-3 neighbouring variants rs2274273 and rs17128183 and its relative mRNA expression: a prospective study.

Post-infarct left ventricular remodeling (LVR) process increases the risk of heart failure (HF). Circulating galectin-3 has been associated with fibrosis, inflammation and cardiac dysfunction during the remodeling process after myocardial infarction (MI). The aims of this prospective case study were to investigate the association of potentially functional variants in the vicinity of LGALS-3 locus, rs2274273 and rs17128183 with maladaptive LVR and whether these variants could affect LGALS-3 mRNA expression in peripheral blood mononuclear cells of patients 6 months after the first MI. This study encompassed 167 patients with acute MI that were followed up for 6 months. Evidence of LVR was obtained by repeated 2D Doppler echocardiography. Rs2274273, rs17128183 and LGALS-3 mRNA expression were detected by TaqMan® technology. Rs2274273 and rs17128183 rare allele bearing genotypes, according to the dominant model (CT+TT vs. CC and AG+GG vs. AA, respectively), were significantly and independently associated with maladaptive LVR (adjusted OR = 3.02, P = 0.016; adjusted OR = 3.14, P = 0.019, respectively) and higher LGALS-3 mRNA expression (fold induction 1.203, P = 0.03 and 1.214, P = 0.03, respectively). Our exploratory results suggest that rs2274273 and rs17128183 variants affect LGALS-3 mRNA and bear the risk for maladaptive LVR post-MI remodeling. Further replication and validation in a larger group of patients is inevitable.

Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology.

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Knockout of Toll-like receptor 4 improves survival and cardiac function in a murine model of severe sepsis.

Toll-like receptor 4 (TLR4) is a transmembrane pattern­recognition receptor expressed in immune cells and the heart. Activation of TLR4 signaling during sepsis results in the release of cardiac depression mediators that may impair heart function. The present study aimed to determine whether TLR4 contributes to development of severe sepsis­induced myocardial dysfunction. A cecum ligation and puncture (CLP) procedure was employed to establish severe sepsis models. Wild type (WT) and TLR4 knock­out (TLR4­KO) mice were divided into four groups: WT­sham, TLR4­KO­sham, WT­CLP, and TLR4­KO­CLP. Cardiac function of these animals was evaluated at various time points following the surgical procedure. The expression levels of proinflammatory cytokines in the heart tissues were detected by reverse transcription­semi quantitative polymerase chain reaction (RT­PCR). Myocardial neutrophil and macrophage infiltration were investigated by histopathological examination, as well as a myeloperoxidase activity assay in heart tissue by RT­PCR. Myocardium Fas cell surface death receptor/Fas ligand and caspase­3 were also analyzed by RT­PCR. Additionally, myeloid differentiation primary response 88 M, toll or interleukin­1 receptor­domain­containing adapter­inducing interferon­ß and nuclear factor­κB expression levels were observed in the myocardium of all four groups. WT­CLP mice exhibited increased mortality rates, more severe cardiac dysfunction and had increased levels of interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α in heart tissues and increased neutrophil infiltration compared with TRL4­KO­CLP mice. The present study reported that TLR4 aggravates severe sepsis­induced cardiac impairment by promoting the release of proinflammatory cytokines and neutrophil infiltration in hearts.

Suppression of miR-34a Expression in the Myocardium Protects Against Ischemia-Reperfusion Injury Through SIRT1 Protective Pathway.

MicroRNA-34a (miR-34a) is expressed in the myocardium and expression is altered after myocardial injury. We investigated the effects of miR-34a on heart function after ischemia-reperfusion (IR) injury. Cardiomyocytes were isolated from neonatal rat hearts and simulated IR injury was induced in vitro. Following IR injury in rats, infarct size was measured and left ventricular (LV) function was evaluated using echocardiography. Protein expression of silent information regulator 1 (SIRT1), acetylated p53 (ac-p53), Bcl-2 and Bax, and miR-34a and SIRT1 gene levels were analyzed. miR-34a overexpression exacerbated myocardial injury by increasing apoptosis and infarct size and decreasing LV function. Suppression of miR-34a attenuated myocardial IR injury. SIRT1 was negatively regulated by miR-34a and the expression of downstream genes, such as ac-p53, Bcl-2, and Bax were altered correspondingly. Increased expression of miR-34a aggravates injury after IR; miR-34a suppression therapy may represent a new line of treatment for myocardial IR injury.

Cardiomyocyte Circadian Oscillations Are Cell-Autonomous, Amplified by ß-Adrenergic Signaling, and Synchronized in Cardiac Ventricle Tissue.

Circadian clocks impact vital cardiac parameters such as blood pressure and heart rate, and adverse cardiac events such as myocardial infarction and sudden cardiac death. In mammals, the central circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, synchronizes cellular circadian clocks in the heart and many other tissues throughout the body. Cardiac ventricle explants maintain autonomous contractions and robust circadian oscillations of clock gene expression in culture. In the present study, we examined the relationship between intrinsic myocardial function and circadian rhythms in cultures from mouse heart. We cultured ventricular explants or dispersed cardiomyocytes from neonatal mice expressing a PER2::LUC bioluminescent reporter of circadian clock gene expression. We found that isoproterenol, a ß-adrenoceptor agonist known to increase heart rate and contractility, also amplifies PER2 circadian rhythms in ventricular explants. We found robust, cell-autonomous PER2 circadian rhythms in dispersed cardiomyocytes. Single-cell rhythms were initially synchronized in ventricular explants but desynchronized in dispersed cells. In addition, we developed a method for long-term, simultaneous monitoring of clock gene expression, contraction rate, and basal intracellular Ca2+ level in cardiomyocytes using PER2::LUC in combination with GCaMP3, a genetically encoded fluorescent Ca2+ reporter. In contrast to robust PER2 circadian rhythms in cardiomyocytes, we detected no rhythms in contraction rate and only weak rhythms in basal Ca2+ level. In summary, we found that PER2 circadian rhythms of cardiomyocytes are cell-autonomous, amplified by adrenergic signaling, and synchronized by intercellular communication in ventricle explants, but we detected no robust circadian rhythms in contraction rate or basal Ca2+.

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat-Fed Diabetic Mice.

Dipeptidyl peptidase-4 (DPP4) inhibitors used for the treatment of type 2 diabetes are cardioprotective in preclinical studies; however, some cardiovascular outcome studies revealed increased hospitalization rates for heart failure (HF) among a subset of DPP4 inhibitor-treated subjects with diabetes. We evaluated cardiovascular function in young euglycemic Dpp4(-/-) mice and in older, high fat-fed, diabetic C57BL/6J mice treated with either the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide or the highly selective DPP4 inhibitor MK-0626. We assessed glucose metabolism, ventricular function and remodeling, and cardiac gene expression profiles linked to inflammation and fibrosis after transverse aortic constriction (TAC) surgery, a pressure-volume overload model of HF. Young euglycemic Dpp4(-/-) mice exhibited a cardioprotective response after TAC surgery or doxorubicin administration, with reduced fibrosis; however, cardiac mRNA analysis revealed increased expression of inflammation-related transcripts. Older, diabetic, high fat-fed mice treated with the GLP-1R agonist liraglutide exhibited preservation of cardiac function. In contrast, diabetic mice treated with MK-0626 exhibited modest cardiac hypertrophy, impairment of cardiac function, and dysregulated expression of genes and proteins controlling inflammation and cardiac fibrosis. These findings provide a model for the analysis of mechanisms linking fibrosis, inflammation, and impaired ventricular function to DPP4 inhibition in preclinical studies.

Inactivation of INK4a and ARF induces myocardial proliferation and improves cardiac repair following ischemia­reperfusion.

The growth of the heart during mammalian embryonic development is primarily dependent on an increase in the number of cardiomyocytes (CM). However, shortly following birth, CMs cease proliferating and further growth of the myocardium is achieved via hypertrophic expansion of the existing CM population. The cyclin-dependent kinase inhibitor 2A (Cdkn2a) locus encodes overlapping genes for two tumor suppressor proteins, p16INK4a and p19 alternative reading frame (ARF). To determine whether decreased Cdkn2a gene expression results in improved cardiac regeneration in vitro and in vivo following cardiac injury, the proliferation of CMs isolated from Cdkn2a knockout (KO) and wild­type (WT) mice in vitro and in vivo were evaluated following generation of ischemia reperfusion (IR) injury. The KO mice demonstrated enhanced CM proliferation not only in vitro, but also in vivo. Furthermore, heart function was improved and scar size was decreased in the KO mice compared with that of the WT mice. The results also indicated that microRNA (miR)­1 and miR­195 expression levels associated with cell proliferation were reduced following IR injury in KO mice compared with those of WT mice. These results suggested that the inactivation of INK4a and ARF stimulated CM proliferation and promoted cardiac repair.

Value of human brain natriuretic peptide in treatment of acute anterior myocardial infarction evaluated via three-dimensional speckle tracking imaging.

Three-dimensional ultrasound speckle tracking imaging was used to evaluate the effects of recombinant human brain natriuretic peptide (rhBNP) in acute anterior and extensive anterior myocardial infarction. Ninety patients with acute anterior or extensive myocardial infarction were randomly divided into 3 groups: Group A [emergency percutaneous coronary intervention (PCI)], Group B (emergency PCI + rhBNP early treatment), and Group C (emergency PCI + late rhBNP treatment). Within 6 h of admission and at 1 week and 3 and 6 months after PCI, patients underwent routine transthoracic echocardiography and real-time three-dimensional echocardiography. At 1 week, 1 month, 3 months, 6 months, and 12 months, ejection fraction values in groups B and C were significantly greater than those in group A (P < 0.05), and left ventricular end-diastolic volume and left ventricular end-systolic volume values in groups B and C were less than those in group A (P < 0.05). Within 6 h of admission in each group, long-axis, radial, circumferential, and area variables corresponding to anterior descending artery segments showed no significant difference (all P > 0.05). However, at 1 week, 1 month, 3 months, 6 months, and 12 months, long-axis, radial, circumferential and area variables in groups B and C were significantly less than those in group A (P < 0.05). Intervention with rhBNP can im-prove resilience of the local myocardium, left ventricular mechanical function, and cardiac remodeling. Within 6 h of admission or after PCI, rhBNP application showed no significant difference in heart function improvement or myocardial remodeling inhibition.

Reduction of prohibitin expression contributes to left ventricular hypertrophy via enhancement of mitochondrial reactive oxygen species formation in spontaneous hypertensive rats.

Left ventricular hypertrophy (LVH) in hypertension is characterized by thickening of myocardium and decrease in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. In this work, we investigate whether mitochondrial prohibitin (PHB) was involved in the progression of LVH in spontaneous hypertensive rats (SHR). First, it was found that mitochondrial dysfunction occurred in left ventricles of SHR. Through analysis using quantitative reverse transcription polymerase chain reaction and Western blotting, it was found that PHB mRNA and mitochondrial PHB levels in left ventricles of SHR were significantly lower than that in Wistar-Kyoto rats. Furthermore, PHB mRNA levels were negatively correlated to left ventricles weight-to-body weight ratio in SHR. Knockdown of PHB led to increased formation of mitochondrial reactive oxygen species (ROS) and reduced activities of complex I, mitochondrial adenosine triphosphate generation and mitochondrial membrane potential in cultured cardiomyocytes. Knockdown of PHB contributed to the cardiomyocyte hypertrophy, which could be attenuated by treatment with the Tempol. Angiotensin II (AngII) was increased in plasma and left ventricles of SHR. Incubation with AngII reduced mitochondrial PHB expression in cardiomyocytes, which was reversed when pretreated with losartan. In conclusion, reduction of PHB expression in left ventricles in SHR contributed to LVH, at least in part, through promoting mitochondrial ROS formation.

Voluntary physical activity protects from susceptibility to skeletal muscle contraction-induced injury but worsens heart function in mdx mice.

It is well known that inactivity/activity influences skeletal muscle physiological characteristics. However, the effects of inactivity/activity on muscle weakness and increased susceptibility to muscle contraction-induced injury have not been extensively studied in mdx mice, a murine model of Duchenne muscular dystrophy with dystrophin deficiency. In the present study, we demonstrate that inactivity (ie, leg immobilization) worsened the muscle weakness and the susceptibility to contraction-induced injury in mdx mice. Inactivity also mimicked these two dystrophic features in wild-type mice. In contrast, we demonstrate that these parameters can be improved by activity (ie, voluntary wheel running) in mdx mice. Biochemical analyses indicate that the changes induced by inactivity/activity were not related to fiber-type transition but were associated with altered expression of different genes involved in fiber growth (GDF8), structure (Actg1), and calcium homeostasis (Stim1 and Jph1). However, activity reduced left ventricular function (ie, ejection and shortening fractions) in mdx, but not C57, mice. Altogether, our study suggests that muscle weakness and susceptibility to contraction-induced injury in dystrophic muscle could be attributable, at least in part, to inactivity. It also suggests that activity exerts a beneficial effect on dystrophic skeletal muscle but not on the heart.

Neonatal transfer of membrane-bound stem cell factor improves survival and heart function in aged mice after myocardial ischemia.

Stem cell mobilization to injured tissue contributes to neovascularization, resulting in regeneration after myocardial infarction (MI). We previously showed that direct cardiac injection of a recombinant lentivirus (LV) that engineers expression of membrane-bound stem cell factor (mSCF) improves outcomes immediately after MI. In this study, we evaluated the effect of neonatal LV/mSCF transduction on MI outcomes in aged mice. We constructed a recombinant LV harboring an α-myosin heavy chain promoter that drives mSCF expression and injected it into the temporal vein of neonatal mice. One year later, sustained expression of mSCF in the adult mouse hearts was detected by genomic and quantitative RT-PCR and immunohistochemistry. To evaluate the contribution of neonatal LV/mSCF delivery to recovery from MI, we induced an MI in adult LV/mSCF-transduced, LV only-transduced, and nontransduced control mice. Strikingly, LV/mSCF transduction reduced infarct scar size, enhanced angiogenesis, improved ventricular function, and significantly increased survival of the mice. Regional overexpression of CD11b, a marker of monocytes and proangiogenic cells, was observed on monocytes isolated from the infarcted hearts of LV/mSCF-transduced mice. Our data suggest a model of neonatal gene delivery that leads to sustained mSCF expression during adulthood to aid recovery from MI and prevent heart failure.

Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes.

BACKGROUND: MicroRNAs (miRs) negatively regulate transcription and are important determinants of normal heart development and heart failure pathogenesis. Despite the significant knowledge gained in mouse studies, their functional roles in human (h) heart remain elusive. METHODS AND RESULTS: We hypothesized that miRs that figure prominently in cardiac differentiation are differentially expressed in differentiating, developing, and terminally mature human cardiomyocytes (CMs). As a first step, we mapped the miR profiles of human (h) embryonic stem cells (ESCs), hESC-derived (hE), fetal (hF) and adult (hA) ventricular (V) CMs. 63 miRs were differentially expressed between hESCs and hE-VCMs. Of these, 29, including the miR-302 and -371/372/373 clusters, were associated with pluripotency and uniquely expressed in hESCs. Of the remaining miRs differentially expressed in hE-VCMs, 23 continued to express highly in hF- and hA-VCMs, with miR-1, -133, and -499 displaying the largest fold differences; others such as miR-let-7a, -let-7b, -26b, -125a and -143 were non-cardiac specific. Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p<0.05) and contractile protein expression without affecting their electrophysiological properties (p>0.05). By contrast, LV-miR-1 transduction did not bias the yield (p>0.05) but decreased APD and hyperpolarized RMP/MDP in hE-VCMs due to increased I(to), I(Ks) and I(Kr), and decreased I(f) (p<0.05) as signs of functional maturation. Also, LV-miR-1 but not -499 augmented the immature Ca(2+) transient amplitude and kinetics. Molecular pathway analyses were performed for further insights. CONCLUSION: We conclude that miR-1 and -499 play differential roles in cardiac differentiation of hESCs in a context-dependent fashion. While miR-499 promotes ventricular specification of hESCs, miR-1 serves to facilitate electrophysiological maturation.

Heritability of Tpeak-Tend interval and T-wave amplitude: a twin study.

BACKGROUND: Tpeak-Tend interval (TpTe) and T-wave amplitude (Tamp) carry diagnostic and prognostic information regarding cardiac morbidity and mortality. Heart rate and QT interval are known to be heritable traits. The heritability of T-wave morphology parameters such as TpTe and Tamp is unknown. TpTe and Tamp were evaluated in a large sample of twins. METHODS AND RESULTS: Twins from the GEMINAKAR study (611 pairs, 246 monozygotic, 365 dizygotic; mean age, 38±11 years; 49% men) who had an ECG performed during 1997 to 2000 were included. Tamp was measured in leads V1 and V5. Duration variables (RR interval, QTpeak and QTend interval) were measured and averaged over 3 consecutive beats in lead V5. TpTe was calculated as the QTend- and QTpeak-interval difference. Heritability was assessed using structural equation models adjusting for age, sex, and body mass index. All models were reducible to a model of additive genetics and unique environment. All variables had considerable genetic components. Adjusted heritability estimates were as follows: TpTe, 46%; Tamp lead V1, 34%; Tamp lead V5, 47%; RR interval, 55%; QT interval, 67%; and Bazett-corrected QT interval, 42%. CONCLUSIONS: RR interval, QT interval, Tamp, and TpTe interval are heritable ECG parameters.

Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.

BACKGROUND: We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. METHODS AND RESULTS: Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05). CONCLUSIONS: Renin-angiotensin-aldosterone system-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.

Establishment of the mouse ventricular conduction system.

The ventricular conduction system represents the electrical wiring responsible for the co-ordination of cardiac contraction. Defects in the circuit produce a delay or conduction block and induce cardiac arrhythmias. Understanding how this circuit forms and identification of the factors important for its development thus provide insights into the origin of cardiac arrhythmias. Recent advances, using genetically modified mouse models, have contributed to our understanding of how the ventricular conduction system is established during heart development. Transgenic mice carrying different reporter genes have highlighted the conservation of the anatomy and development of the ventricular conduction system between mice and humans. Lineage tracing and retrospective clonal analysis have established the myogenic origin of the ventricular conduction system and determined properties of conductive progenitor cells. Finally, gene knock-out models reproducing human cardiac defects have led to the identification of transcription factors important for the development of the ventricular conduction system. These transcription factors operate at the levels of both conduction system morphogenesis and differentiation by controlling the expression of genes responsible for the electrical activity of the heart. In summary, defects in the ventricular conduction system are a major cause of arrhythmias, and deciphering the molecular pathways responsible for conduction system morphogenesis and the differentiation of conductive myocytes furthers our understanding of the mechanisms underlying heart disease.