Euy-Myoung Jeong

Alpert Medical School - Brown University, Providence, Rhode Island, United States

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Publications (13)66.52 Total impact

  • Euy-Myoung Jeong, Samuel C Dudley
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    ABSTRACT: Despite the fact that up to half of all heart failure occurs in patients without evidence of systolic cardiac dysfunction, there are no universally accepted diagnostic markers and no approved therapies for heart failure with preserved ejection fraction (HFpEF). HFpEF, otherwise known as diastolic heart failure, has nearly the same grim prognosis as systolic heart failure, and diastolic heart failure is increasing in incidence and prevalence. Major trials have shown that many of the treatments that are salutary in systolic heart failure have no beneficial effects in diastolic heart failure, suggesting different underlying mechanisms for these two disorders. Even criteria for diagnosis of HFpEF are still debated, and there is still no gold standard marker to detect diastolic dysfunction. Here, we will review some promising new insights into the pathogenesis of diastolic dysfunction that may lead to new diagnostic and therapeutic tools. [Abbreviations: tetrahydrobiopterin, BH4 ;cardiac magnetic resonance, CMR; diabetes mellitus, DM; heart failure with preserved ejection fraction, HFpEF; cardiac myosin binding protein C, MyBP-C; nitric oxide synthase, NOS] [Full text available at http://rimed.org/rimedicaljournal-2014-02.asp, free with no login].
    Rhode Island medical journal 01/2014; 97(2):35-7.
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    ABSTRACT: -Human heart failure (HF) increases alternative mRNA splicing of the SCN5A cardiac Na(+) channel, generating variants encoding truncated, nonfunctional channels that are trapped in the endoplasmic reticulum. In this work, we tested whether truncated Na(+) channels activate the unfolded protein response (UPR), contributing to SCN5A electrical remodeling in HF. -UPR and SCN5A were analyzed in human ventricular systolic HF tissue samples and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Cells were exposed to angiotensin II (AngII) and hypoxia, known activators of abnormal SCN5A mRNA splicing, or were induced to overexpress SCN5A variants. UPR effectors, PERK, calreticulin, and CHOP, were increased in human HF tissues. Induction of SCN5A variants with AngII or hypoxia or the expression of exogenous variants induced the UPR with concomitant downregulation of Na(+) current. PERK activation destabilized SCN5A and, surprisingly, Kv4.3 channel mRNAs but not TRPM7 channel mRNA. PERK inhibition prevented the loss of full-length SCN5A and Kv4.3 mRNA levels resulting from expressing Na(+) channel mRNA splice variants. -UPR can be initiated by Na(+) channel mRNA splice variants and is involved in the reduction of cardiac Na(+) current during human HF. Since the effect is not entirely specific to the SCN5A transcript, the UPR may play an important role in downregulation of multiple cardiac genes in HF.
    Circulation Arrhythmia and Electrophysiology 09/2013; · 5.95 Impact Factor
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    ABSTRACT: BACKGROUND: -Previously, we showed a mouse model (ACE8/8) of cardiac renin-angiotensin system (RAS) activation has a high rate of spontaneous ventricular tachycardia (VT) and sudden cardiac death (SCD) secondary to a reduction in connexin43 (Cx43) level. Angiotensin-II activation increases reactive oxygen species (ROS) production, and ACE8/8 mice show increased cardiac ROS. We sought to determine the source of ROS and if ROS played a role in the arrhythmogenesis. METHODS AND RESULTS: -Wild-type and ACE8/8 mice with and without two weeks of treatment with L-NIO (nitric oxide synthase inhibitor), sepiapterin (precursor of tetrahydrobiopterin), MitoTEMPO (mitochondria-targeted antioxidant), TEMPOL (a general antioxidant), apocynin (NADPH oxidase inhibitor), allopurinol (xanthine oxidase inhibitor), and ACE8/8 crossed with P67 dominant negative mice to inhibit the NADPH oxidase were studied. Western blotting, detection of mitochondrial ROS by MitoSOX Red, electron microscopy, immunohistochemistry, fluorescent dye diffusion technique for functional assessment of Cx43, telemetry monitoring, and in-vivo electrophysiology studies were performed. Treatment with MitoTEMPO reduced SCD in ACE8/8 mice (from 74% to 18%, P<0.005), decreased spontaneous ventricular premature beats, decreased VT inducibility (from 90% to 17%, P<0.05), diminished elevated mitochondrial ROS to the control level, prevented structural damage to mitochondria, resulted in 2.6 fold increase in Cx43 level at the gap junctions, and corrected gap junction conduction. None of the other antioxidant therapies prevented VT and SCD in ACE8/8 mice. CONCLUSIONS: -Mitochondrial oxidative stress plays a central role in angiotensin II-induced gap junction remodeling and arrhythmia. Mitochondria-targeted antioxidants may be effective antiarrhythmic drugs in cases of RAS activation.
    Circulation Arrhythmia and Electrophysiology 04/2013; · 5.95 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). · 4.44 Impact Factor
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    ABSTRACT: Despite the increasing prevalence of heart failure with preserved left ventricular function, there are no specific treatments, partially because the mechanism of impaired relaxation is incompletely understood. Evidence indicates that cardiac relaxation may depend on nitric oxide (NO), generated by NO synthase (NOS) requiring the co-factor tetrahydrobiopterin (BH(4)). Recently, we reported that hypertension-induced diastolic dysfunction was accompanied by cardiac BH(4) depletion, NOS uncoupling, a depression in myofilament cross-bridge kinetics, and S-glutathionylation of myosin binding protein C (MyBP-C). We hypothesized that the mechanism by which BH(4) ameliorates diastolic dysfunction is by preventing glutathionylation of MyBP-C and thus reversing changes of myofilament properties that occur during diastolic dysfunction. We used the deoxycorticosterone acetate (DOCA)-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction. Mice were divided into two groups that received control diet and two groups that received BH(4) supplement for 7days after developing diastolic dysfunction at post-operative day 11. Mice were assessed by echocardiography. Left ventricular papillary detergent-extracted fiber bundles were isolated for simultaneous determination of force and ATPase activity. Sarcomeric protein glutathionylation was assessed by immunoblotting. DOCA-salt mice exhibited diastolic dysfunction that was reversed after BH(4) treatment. Diastolic sarcomere length (DOCA-salt 1.70 ± 0.01 vs. DOCA-salt+BH(4) 1.77 ± 0.01 μm, P<0.001) and relengthening (relaxation constant, τ, DOCA-salt 0.28 ± 0.02 vs. DOCA-salt+BH(4) 0.08 ± 0.01, P<0.001) were also restored to control by BH(4) treatment. pCa(50) for tension increased in DOCA-salt compared to sham but reverted to sham levels after BH(4) treatment. Maximum ATPase rate and tension cost (ΔATPase/ΔTension) decreased in DOCA-salt compared to sham, but increased after BH(4) treatment. Cardiac MyBP-C glutathionylation increased in DOCA-salt compared to sham, but decreased with BH(4) treatment. MyBP-C glutathionylation correlated with the presence of diastolic dysfunction. Our results suggest that by depressing S-glutathionylation of MyBP-C, BH(4) ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. These data provide evidence for modulation of cardiac relaxation by post-translational modification of myofilament proteins.
    Journal of Molecular and Cellular Cardiology 12/2012; · 5.15 Impact Factor
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    ABSTRACT: Cardiomyopathy is associated with cardiac Na(+) channel downregulation that may contribute to arrhythmias. Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na(+) current (I(Na)) signaled by an increase in mitochondrial reactive oxygen species (ROS). In this study, we tested whether the NADH-mitochondria ROS pathway was involved in the reduction of I(Na) in a nonischemic cardiomyopathic model and correlated the findings with myopathic human hearts. Nonischemic cardiomyopathy was induced in C57BL/6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt-water substitution. Sham operated mice were used as controls. After six weeks, heart tissue and ventricular myocytes isolated from mice were utilized for whole-cell patch clamp recording, NADH/NAD(+) level measurements, and mitochondrial ROS monitoring with confocal microscopy. Human explanted hearts were studied using optical mapping. Compared to the sham mice, the arterial blood pressure was higher, the left ventricular volume was significantly enlarged (104.7±3.9 vs. 87.9±6.1 μL, P<0.05), and the ejection fraction was reduced (37.1±1.8% vs. 49.4±3.7%, P<0.05) in DOCA mice. Both the whole cell and cytosolic NADH level were increased (279±70% and 123±2% of sham, respectively, P<0.01), I(Na) was decreased (60±10% of sham, P<0.01), and mitochondrial ROS overproduction was observed (2.9±0.3-fold of sham, P<0.01) in heart tissue and myocytes of myopathic mice vs. sham. Treatment of myocytes with NAD(+) (500μM), mitoTEMPO (10μM), chelerythrine (50μM), or forskolin (5μM) restored I(Na) back to the level of sham. Injection of NAD(+) (100mg/kg) or mitoTEMPO (0.7mg/kg) twice (at 24h and 1h before myocyte isolation) to animals also restored I(Na). All treatments simultaneously reduced mitochondrial ROS levels to that of controls. CD38 was found to transduce the extracellular NAD(+) signal. Correlating with the mouse model, failing human hearts showed a reduction in conduction velocity that improved with NAD(+). Nonischemic cardiomyopathy was associated with elevated NADH level, PKC activation, mitochondrial ROS overproduction, and a concomitant decrease in I(Na). Reducing mitochondrial ROS by application of NAD(+), mitoTEMPO, PKC inhibitors, or PKA activators, restored I(Na). NAD(+) improved conduction velocity in human myopathic hearts.
    Journal of Molecular and Cellular Cardiology 10/2012; · 5.15 Impact Factor
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    ABSTRACT: Diastolic dysfunction (DD) with preserved left ventricular (LV) ejection fraction (EF) has been linked to obesity. Adiponectin is a cytokine related to obesity and obesity-linked cardiovascular complications. The authors aimed to determine the independent association of DD with adiponectin. Fifty patients with impaired relaxation DD and a normal EF and age-matched normal controls were recruited. Plasma levels of total and high molecular weight (HMW) adiponectin were measured. Mid and low molecular weight (MMW+LMW) fractions of adiponectin were calculated by subtracting HMW fraction from total adiponectin. The DD group had significantly lower total (median, 4.4 vs 12.7 μg/mL; P=.001), HMW fraction (median, 1.3 vs 3.4 μg/mL; P=.02), and MMW+LMW fraction of adiponectin (median, 3.8 vs 7.2 μg/mL; P=.01). Body mass index (BMI) negatively correlated with total (r:-0.46, P=.003), HMW (r:-0.32, P=.038), and MMW+LMW (r:-0.40, P=.006) fractions of adiponectin. DD had an independent association with both BMI (P<.05) and total adiponectin (P<.001) in linear regression model using sex, BMI, blood pressure, and total adiponectin as covariates. DD was associated with BMI (P=.02), HMW fraction (P=.03), and MMW+LMW fraction (P=.004) in similar linear regression analyses. Adiponectin deficiency may be one explanation for the adiposity-related cardiac oxidation known to be involved in the pathogenesis of DD.
    Congestive Heart Failure 07/2012; 18(4):187-91.
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    ABSTRACT: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux. Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine. Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) nor the Ca(2+) transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics. Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.
    Circulation Research 02/2012; 110(6):841-50. · 11.86 Impact Factor
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    ABSTRACT: Cardiac arrhythmias can cause sudden cardiac death (SCD) and add to the current heart failure (HF) health crisis. Nevertheless, the pathological processes underlying arrhythmias are unclear. Arrhythmic conditions are associated with systemic and cardiac oxidative stress caused by reactive oxygen species (ROS). In excitable cardiac cells, ROS regulate both cellular metabolism and ion homeostasis. Increasing evidence suggests that elevated cellular ROS can cause alterations of the cardiac sodium channel (Na(v)1.5), abnormal Ca(2+) handling, changes of mitochondrial function, and gap junction remodeling, leading to arrhythmogenesis. This review summarizes our knowledge of the mechanisms by which ROS may cause arrhythmias and discusses potential therapeutic strategies to prevent arrhythmias by targeting ROS and its consequences. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
    Journal of Molecular and Cellular Cardiology 02/2012; 52(2):454-63. · 5.15 Impact Factor
  • Biophysical Journal 01/2012; 102(3):341-. · 3.67 Impact Factor
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    ABSTRACT: Human heart failure is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na+ channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.
    Circulation 08/2011; 124(10):1124-31. · 15.20 Impact Factor
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    ABSTRACT: Diastolic heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 ± 0.03 in SAMR1 mice to 1.2 ± 0.03 in SAMP8 mice (P < 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 ± 0.9 mm/s in SAMR1 to 21.1 ± 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 ± 0.02 to 0.8 ± 0.03 in SAMR1 vs. SAMP8 mice, respectively (P < 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 ± 0.05 vs. 0.8 ± 0.14; P < 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 ± 0.04 to 0.8 ± 0.09% and perivascular collagen area increased from 1.0 ± 0.11 to 1.6 ± 0.14%. Transforming growth factor-β and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P < 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies.
    AJP Heart and Circulatory Physiology 07/2011; 301(3):H824-31. · 4.01 Impact Factor
  • Journal of Cardiac Failure. 18(8):S7.

Publication Stats

81 Citations
66.52 Total Impact Points

Institutions

  • 2013
    • Alpert Medical School - Brown University
      Providence, Rhode Island, United States
  • 2011–2013
    • University of Illinois at Chicago
      • Section of Cardiology
      Chicago, Illinois, United States
  • 2012
    • Jesse Brown VA Medical Center
      Chicago, Illinois, United States