167 results on '"Dudley SC"'
Search Results
2. Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.
- Author
-
Silberman GA, Fan TH, Liu H, Jiao Z, Xiao HD, Lovelock JD, Boulden BM, Widder J, Fredd S, Bernstein KE, Wolska BM, Dikalov S, Harrison DG, Dudley SC Jr, Silberman, Gad A, Fan, Tai-Hwang M, Liu, Hong, Jiao, Zhe, Xiao, Hong D, and Lovelock, Joshua D
- Published
- 2010
- Full Text
- View/download PDF
3. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias.
- Author
-
London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, Viswanathan PC, Pfahnl AE, Shang LL, Madhusudanan M, Baty CJ, Lagana S, Aleong R, Gutmann R, Ackerman MJ, McNamara DM, Weiss R, Dudley SC Jr., London, Barry, and Michalec, Michael
- Published
- 2007
- Full Text
- View/download PDF
4. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases.
- Author
-
Dudley SC Jr., Hoch NE, McCann LA, Honeycutt C, Diamandopoulos L, Fukai T, Harrison DG, Dikalov SI, and Langberg J
- Published
- 2005
5. Awakening – Transformation, agency and virtue from three contemporary philosophical inspirations: Bhaskar, Segal and Slote
- Author
-
Dudley Schreiber
- Subjects
agency, alienation, awakening, consciousness, dualism, emergence, empathy, intention, ontology, receptivity, reflexivity, self, society, transformation, virtue ,The Bible ,BS1-2970 ,Practical Theology ,BV1-5099 - Abstract
For some, ‘transformation’ is the new non-reductive and non-normative ‘development’, attracting attention from interdisciplinary array, but of particular theoretical and practical interest to Spirituality scholars. In philosophical context, transformation theory has suffered greatly from ’agency-structure’ dualism and suspension of ontology in body-mind dualism and rationalist virtue controversy. Drawing on the work of Bhaskar, Segal and Slote, a renegotiated and more meaningful sense of transformation emerges from their cumulative analytical and conceptual enrichment. In the complexity of possible relations between self, self-concept and society, lies the traditionally neglected transformative middle of sui-generis human depth. In redress, arguably, Bhaskar’s meta-philosophy accommodates Segal’s experiential depth analysis and Slote’s understanding of empathy and receptivity as valuable insights for ’awakening’ to transformative process.
- Published
- 2015
- Full Text
- View/download PDF
6. An imperfect syllogism: granulocyte colony-stimulating factor mobilization and cardiac regeneration.
- Author
-
Dudley SC Jr, Simpson D, Dudley, Samuel C Jr, and Simpson, David
- Published
- 2008
- Full Text
- View/download PDF
7. Inhibition of c-Src tyrosine kinase prevents angiotensin II-mediated connexin-43 remodeling and sudden cardiac death.
- Author
-
Sovari AA, Iravanian S, Dolmatova E, Jiao Z, Liu H, Zandieh S, Kumar V, Wang K, Bernstein KE, Bonini MG, Duffy HS, Dudley SC, Sovari, Ali A, Iravanian, Shahriar, Dolmatova, Elena, Jiao, Zhe, Liu, Hong, Zandieh, Shadi, Kumar, Vibhash, and Wang, Kun
- Abstract
Objectives: The aim of this study was to test whether c-Src tyrosine kinase mediates connexin-43 (Cx43) reduction and sudden cardiac death in a transgenic mouse model of cardiac-restricted overexpression of angiotensin-converting enzyme (ACE8/8 mice).Background: Renin-angiotensin system activation is associated with an increased risk for arrhythmia and sudden cardiac death, but the mechanism is not well understood. The up-regulation of c-Src by angiotensin II may result in the reduction of Cx43, which impairs gap junction function and provides a substrate for arrhythmia.Methods: Wild-type and ACE8/8 mice with and without treatment with the c-Src inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) were studied. Telemetry monitoring, in vivo electrophysiologic studies, Western blot analyses for total and phosphorylated c-Src and Cx43, immunohistochemistry staining for Cx43, and functional assessment of Cx43 with fluorescent dye diffusion were performed.Results: The majority of the arrhythmic deaths resulted from ventricular tachycardia degenerating to ventricular fibrillation (83%). Levels of total and phosphorylated c-Src were increased and Cx43 reduced in ACE8/8 mice. PP1 reduced total and phosphorylated c-Src levels, increased Cx43 level by 2.1-fold (p < 0.005), increased Cx43 at the gap junctions (immunostaining), improved gap junctional communication (dye spread), and reduced ventricular tachycardia inducibility and sudden cardiac death. The survival rate increased from 11% to 86% with 4 weeks of PP1 treatment (p < 0.005). Treatment with an inactive analog did not change survival or Cx43 levels.Conclusions: Renin-angiotensin system activation is associated with c-Src up-regulation, Cx43 loss, reduced myocyte coupling, and arrhythmic sudden death, which can be prevented by c-Src inhibition. This suggests that an increase in c-Src activity may help mediate renin-angiotensin system-induced arrhythmias and that c-Src inhibitors might exert antiarrhythmic activity. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
8. Sudden death in myotonic dystrophy.
- Author
-
Dello Russo A, Pace M, Bellocci F, Hermans MCE, Faber CG, Pinto YM, Vrotovec B, Haddad F, Sovari AA, Dudley SC Jr., Groh WJ, Bhakta D, and Pascuzzi RM
- Published
- 2008
9. c-Src Is Responsible for Mitochondria-Mediated Arrhythmic Risk in Ischemic Cardiomyopathy.
- Author
-
Xie A, Kang GJ, Kim EJ, Liu H, Feng F, and Dudley SC Jr
- Subjects
- Animals, Humans, Mice, Phosphorylation, Male, Cardiomyopathies metabolism, Cardiomyopathies genetics, Cardiomyopathies physiopathology, Cardiomyopathies etiology, Cardiomyopathies enzymology, CSK Tyrosine-Protein Kinase metabolism, Myocytes, Cardiac metabolism, Myocytes, Cardiac enzymology, Calcium Channels metabolism, Calcium Channels genetics, Calcium Signaling, Myocardial Infarction metabolism, Myocardial Infarction complications, Myocardial Infarction physiopathology, Myocardial Infarction genetics, Risk Factors, src-Family Kinases metabolism, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac enzymology, Mitochondria, Heart metabolism, Mitochondria, Heart enzymology, Disease Models, Animal, Action Potentials
- Abstract
Background: Increased mitochondrial Ca
2+ uptake has been implicated in the QT prolongation and lethal arrhythmias associated with nonischemic cardiomyopathy. We attempted to define the role of mitochondria in ischemic arrhythmic risk and to identify upstream regulators., Methods: Myocardial infarction (MI) was induced in wild-type FVB/NJ mice by ligation of the left anterior descending coronary artery. Western blot, immunoprecipitation, ECG telemetry, and patch-clamp techniques were used., Results: After MI, c-Src (proto-oncogene tyrosine-protein kinase Src) and its active form (phosphorylated Src, p-Src) were increased. The activation of c-Src was associated with increased diastolic Ca2+ sparks, action potential duration prolongation, and arrhythmia in MI mice. c-Src upregulation and arrhythmia could be reversed by treatment of mice with the Src inhibitor PP1 but not with the inactive analogue PP3. Tyrosine phosphorylated mitochondrial Ca2+ uniporter (MCU) was upregulated in the heart tissues of MI mice and patients with ischemic cardiomyopathy. In a heterologous expression system, c-Src could bind MCU and phosphorylate MCU tyrosines. Overexpression of wild-type c-Src significantly increased the mitochondrial Ca2+ transient while overexpression of dominant-negative c-Src significantly decreased the mitochondrial Ca2+ transient. c-Src inhibition by PP1, MCU inhibition by Ru360, or MCU knockdown could reduce the action potential duration, Ca2+ sparks, and arrhythmia after MI. The human heart tissue showed that patients with ischemic cardiomyopathy had significantly increased c-Src active form associated with increased MCU tyrosine phosphorylation and ventricular arrhythmia., Conclusions: MI leads to increased c-Src active form that results in MCU tyrosine phosphorylation, increased mitochondrial Ca2+ uptake, QT prolongation, and arrhythmia, suggesting c-Src or MCU may represent novel antiarrhythmic targets., Competing Interests: None.- Published
- 2024
- Full Text
- View/download PDF
10. Macrophage IL-1β mediates atrial fibrillation risk in diabetic mice.
- Author
-
Zhou X, Liu H, Feng F, Kang GJ, Liu M, Guo Y, and Dudley SC Jr
- Subjects
- Animals, Mice, Male, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 immunology, Chemokine CCL2 metabolism, Heart Atria metabolism, Heart Atria pathology, Ryanodine Receptor Calcium Release Channel metabolism, Reactive Oxygen Species metabolism, Mice, Inbred C57BL, Diet, High-Fat adverse effects, Inflammation metabolism, Atrial Fibrillation metabolism, Atrial Fibrillation etiology, Atrial Fibrillation immunology, Interleukin-1beta metabolism, Macrophages metabolism, Macrophages immunology, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental immunology
- Abstract
Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). The mechanisms underlying DM-associated AF are unclear. AF and DM are both related to inflammation. We investigated whether DM-associated inflammation contributed to AF risk. Mice were fed with high-fat diet to induce type II DM and were subjected to IL-1β antibodies, macrophage depletion by clodronate liposomes, a mitochondrial antioxidant (mitoTEMPO), or a cardiac ryanodine receptor 2 (RyR2) stabilizer (S107). All tests were performed at 36-38 weeks of age. DM mice presented with increased AF inducibility, enhanced mitochondrial reactive oxygen species (mitoROS) generation, and activated innate immunity in the atria, as evidenced by enhanced monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, and IL-1β levels. Signs of aberrant RyR2 Ca2+ leak were observed in the atria of DM mice. IL-1β neutralization, macrophage depletion, and exposure to mitoTEMPO and S107 significantly ameliorated the AF vulnerability in DM mice. Atrial overexpression of MCP-1 increased AF occurrence in normal mice through the same mechanistic signaling cascade as observed in DM mice. In conclusion, macrophage-mediated IL-1β contributed to DM-associated AF risk through mitoROS modulation of RyR2 Ca2+ leak.
- Published
- 2024
- Full Text
- View/download PDF
11. Cardiac Development Long Non-Coding RNA ( CARDEL ) Is Activated during Human Heart Development and Contributes to Cardiac Specification and Homeostasis.
- Author
-
Pereira IT, Gomes-Júnior R, Hansel-Frose A, França RSV, Liu M, Soliman HAN, Chan SSK, Dudley SC Jr, Kyba M, and Dallagiovanna B
- Subjects
- Humans, Cell Lineage genetics, Gene Expression Regulation, Developmental, Organogenesis genetics, Pluripotent Stem Cells metabolism, Pluripotent Stem Cells cytology, Cell Differentiation genetics, Heart embryology, Homeostasis, Myocytes, Cardiac metabolism, Myocytes, Cardiac cytology, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene-network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac-development genes by combining a temporal evaluation of human cardiac specification in vitro with an analysis of gene expression in fetal and adult heart tissue. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly into cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after controlled overexpression of CARDEL during differentiation. Altogether, we provide physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.
- Published
- 2024
- Full Text
- View/download PDF
12. Atrial Myopathy Quantified by Speckle-tracking Echocardiography in Mice.
- Author
-
Zhang MJ, Gyberg DJ, Healy CL, Zhang N, Liu H, Dudley SC Jr, and O'Connell TD
- Subjects
- Male, Female, Animals, Mice, Stroke Volume physiology, Ventricular Function, Left, Echocardiography, Heart Atria diagnostic imaging, Heart Failure diagnostic imaging, Heart Failure etiology, Atrial Fibrillation, Muscular Diseases
- Abstract
Background: Emerging evidence suggests that atrial myopathy may be the underlying pathophysiology that explains adverse cardiovascular outcomes in heart failure (HF) and atrial fibrillation. Lower left atrial (LA) function (strain) is a key biomarker of atrial myopathy, but murine LA strain has not been described, thus limiting translational investigation. Therefore, the objective of this study was to characterize LA function by speckle-tracking echocardiography in mouse models of atrial myopathy., Methods: We used 3 models of atrial myopathy in wild-type male and female C57Bl6/J mice: (1) aged 16 to 17 months, (2) Ang II (angiotensin II) infusion, and (3) high-fat diet+Nω-nitro-
L -arginine methyl ester (HF with preserved ejection fraction, HFpEF). LA reservoir, conduit, and contractile strain were measured using speckle-tracking echocardiography from a modified parasternal long-axis window. Left ventricular systolic and diastolic function, and global longitudinal strain were also measured. Transesophageal rapid atrial pacing was used to induce atrial fibrillation., Results: LA reservoir, conduit, and contractile strain were significantly reduced in aged, Ang II and HFpEF mice compared with young controls. There were no sex-based interactions. Left ventricular diastolic function and global longitudinal strain were lower in aged, Ang II and HFpEF, but left ventricular ejection fraction was unchanged. Atrial fibrillation inducibility was low in young mice (5%), moderately higher in aged mice (20%), and high in Ang II (75%) and HFpEF (83%) mice., Conclusions: Using speckle-tracking echocardiography, we observed reduced LA function in established mouse models of atrial myopathy with concurrent atrial fibrillation inducibility, thus providing the field with a timely and clinically relevant platform for understanding the pathophysiology and discovery of novel treatment targets for atrial myopathy., Competing Interests: Disclosures None.- Published
- 2023
- Full Text
- View/download PDF
13. Beyond Ion Homeostasis: Hypomagnesemia, Transient Receptor Potential Melastatin Channel 7, Mitochondrial Function, and Inflammation.
- Author
-
Liu M and Dudley SC Jr
- Subjects
- Humans, Magnesium, Inflammation, Homeostasis, Adenosine Triphosphate, Protein Serine-Threonine Kinases, TRPM Cation Channels, Cardiovascular Diseases
- Abstract
As the second most abundant intracellular divalent cation, magnesium (Mg
2+ ) is essential for cell functions, such as ATP production, protein/DNA synthesis, protein activity, and mitochondrial function. Mg2+ plays a critical role in heart rhythm, muscle contraction, and blood pressure. A significant decline in Mg2+ intake has been reported in developed countries because of the increased consumption of processed food and filtered/deionized water, which can lead to hypomagnesemia (HypoMg). HypoMg is commonly observed in cardiovascular diseases, such as heart failure, hypertension, arrhythmias, and diabetic cardiomyopathy, and HypoMg is a predictor for cardiovascular and all-cause mortality. On the other hand, Mg2+ supplementation has shown significant therapeutic effects in cardiovascular diseases. Some of the effects of HypoMg have been ascribed to changes in Mg2+ participation in enzyme activity, ATP stabilization, enzyme kinetics, and alterations in Ca2+ , Na+ , and other cations. In this manuscript, we discuss new insights into the pathogenic mechanisms of HypoMg that surpass previously described effects. HypoMg causes mitochondrial dysfunction, oxidative stress, and inflammation. Many of these effects can be attributed to the HypoMg-induced upregulation of a Mg2+ transporter transient receptor potential melastatin 7 channel (TRMP7) that is also a kinase. An increase in kinase signaling mediated by HypoMg-induced TRPM7 transcriptional upregulation, independently of any change in Mg2+ transport function, likely seems responsible for many of the effects of HypoMg. Therefore, Mg2+ supplementation and TRPM7 kinase inhibition may work to treat the sequelae of HypoMg by preventing increased TRPM7 kinase activity rather than just altering ion homeostasis. Since many diseases are characterized by oxidative stress or inflammation, Mg2+ supplementation and TRPM7 kinase inhibition may have wider implications for other diseases by acting to reduce oxidative stress and inflammation.- Published
- 2023
- Full Text
- View/download PDF
14. Targeting PERK to treat arrhythmias.
- Author
-
Liu M, Kang GJ, and Dudley SC Jr
- Subjects
- Humans, Arrhythmias, Cardiac drug therapy, Anti-Arrhythmia Agents therapeutic use
- Published
- 2023
- Full Text
- View/download PDF
15. Lysosomal Ca 2+ flux modulates automaticity in ventricular cardiomyocytes and correlates with arrhythmic risk.
- Author
-
Xie A, Kang GJ, Kim EJ, Feng F, Givens SE, Ogle BM, and Dudley SC Jr
- Abstract
Automaticity involves Ca
2+ handling at the cell membrane and sarcoplasmic reticulum (SR). Abnormal or acquired automaticity is thought to initiate ventricular arrhythmias associated with myocardial ischemia. Ca2+ flux from mitochondria can influence automaticity, and lysosomes also release Ca2+ . Therefore, we tested whether lysosomal Ca2+ flux could influence automaticity. We studied ventricular human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), hiPSC 3D engineered heart tissues (EHTs), and ventricular cardiomyocytes isolated from infarcted mice. Preventing lysosomal Ca2+ cycling reduced automaticity in hiPSC-CMs. Consistent with a lysosomal role in automaticity, activating the transient receptor potential mucolipin channel (TRPML1) enhanced automaticity, and two channel antagonists reduced spontaneous activity. Activation or inhibition of lysosomal transcription factor EB (TFEB) increased or decreased total lysosomes and automaticity, respectively. In adult ischemic cardiomyocytes and hiPSC 3D EHTs, reducing lysosomal Ca2+ release also inhibited automaticity. Finally, TRPML1 was up-regulated in cardiomyopathic patients with ventricular tachycardia (VT) compared with those without VT. In summary, lysosomal Ca2+ handling modulates abnormal automaticity, and reducing lysosomal Ca2+ release may be a clinical strategy for preventing ventricular arrhythmias., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)- Published
- 2023
- Full Text
- View/download PDF
16. TRPM7 kinase mediates hypomagnesemia-induced seizure-related death.
- Author
-
Liu M, Liu H, Feng F, Krook-Magnuson E, and Dudley SC
- Subjects
- Mice, Male, Female, Animals, Mice, Inbred C57BL, Magnesium metabolism, Mice, Transgenic, Seizures, TRPM Cation Channels genetics
- Abstract
Hypomagnesemia (HypoMg) can cause seizures and death, but the mechanism is unknown. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function. In this study, we focused on the kinase role of TRPM7 in HypoMg-induced seizures and death. Wild type C57BL/6J mice and transgenic mice with a global homozygous mutation in the TRPM7 kinase domain (TRPM7
K1646R , with no kinase function) were fed with control diet or a HypoMg diet. After 6 weeks of HypoMg diet, mice had significantly decreased serum Mg, elevated brain TRPM7, and a significant rate of death, with females being most susceptible. Deaths were immediately preceded by seizure events. TRPM7K1646R mice showed resistance to seizure-induced death. HypoMg-induced brain inflammation and oxidative stress were suppressed by TRPM7K1646R . Compared to their male counterparts, HypoMg female mice had higher levels of inflammation and oxidative stress in the hippocampus. We concluded that TRPM7 kinase function contributes seizure-induced deaths in HypoMg mice and that inhibiting the kinase reduced inflammation and oxidative stress., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
17. miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure.
- Author
-
Kang GJ, Xie A, Kim E, and Dudley SC Jr
- Subjects
- Humans, Down-Regulation, Myocardial Infarction metabolism, Potassium metabolism, Ischemia metabolism, Heart Failure genetics, MicroRNAs genetics, Kv1.4 Potassium Channel metabolism
- Abstract
Background: MicroRNA miR-448 mediates some of the effects of ischemia on arrhythmic risk. Potassium voltage-gated channel subfamily A member 4 (KCNA4) encodes a K
v 1.4 current that opens in response to membrane depolarization and is essential for regulating the action potential duration in heart. KCNA4 has a miR-448 binding site., Objective: We investigated whether miR-448 was involved in the regulation of KCNA4 messenger RNA expression in ischemia., Methods: Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of KCNA4 and miR-448. Pull-down assays were used to examine the interaction between miR-448 and KCNA4. miR-448 decoy and binding site mutation were used to examine the specificity of the effect for KCNA4., Results: The expression of KCNA4 is diminished in ischemia and human heart failure tissues with ventricular tachycardia. Previously, we have shown that miR-448 is upregulated in ischemia and inhibition can prevent arrhythmic risk after myocardial infarction. The 3'-untranslated region of KCNA4 has a conserved miR-448 binding site. miR-448 bound to this site directly and reduced KCNA4 expression and the transient outward potassium current. Inhibition of miR-448 restored KCNA4., Conclusion: These findings showed a link between Kv 1.4 downregulation and miR-448-mediated upregulation in ischemia, suggesting a new mechanism for the antiarrhythmic effect of miR-448 inhibition., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
18. Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes.
- Author
-
Garay BI, Givens S, Abreu P, Liu M, Yücel D, Baik J, Stanis N, Rothermel TM, Magli A, Abrahante JE, Goloviznina NA, Soliman HAN, Dhoke NR, Kyba M, Alford PW, Dudley SC Jr, van Berlo JH, Ogle B, and Perlingeiro RRC
- Published
- 2023
- Full Text
- View/download PDF
19. Reduced sarcoplasmic reticulum Ca 2+ pump activity is antiarrhythmic in ischemic cardiomyopathy.
- Author
-
Xie A, Liu H, Kang GJ, Feng F, and Dudley SC Jr
- Subjects
- Mice, Animals, Sarcoplasmic Reticulum metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Calcium metabolism, Myocytes, Cardiac metabolism, Anti-Arrhythmia Agents, Myocardial Ischemia complications, Myocardial Ischemia metabolism, Myocardial Infarction metabolism, Cardiomyopathies etiology, Cardiomyopathies metabolism
- Abstract
Background: We have described an arrhythmic mechanism seen only in cardiomyopathy that involves increased mitochondrial Ca
2+ handling and selective transfer of Ca2+ to the sarcoplasmic reticulum (SR). Modeling suggested that mitochondrial Ca2+ transfer to the SR via type 2a sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA2a) is a crucial element of this arrhythmic mechanism., Objective: We tested the role of SERCA2a in arrhythmias during ischemic cardiomyopathy., Methods: Myocardial infarction (MI) was induced in wild-type (Wt) and SERCA2a heterozygous knockdown (SERCA+/- ) mice., Results: Compared with Wt MI mice, SERCA2a heterozygous knockdown (SERCA+/- ) MI mice had a substantially lower mortality after 3 weeks of MI without a significant change in MI area. Aside from a significant delay of the cytoplasmic Ca2+ transient decay existed in SERCA+/- compared with Wt, SERCA+/- did not affect cardiac systolic and diastolic function at the whole organ or single cell levels either before or after MI. After MI, SERCA+/- mice had reduced SERCA2a expression in the MI border zone compared with Wt MI mice. SERCA+/- mice had significantly decreased corrected QT intervals and less ventricular tachycardia compared with Wt MI mice. SERCA+/- cardiomyocytes from MI mice showed a reduced action potential duration and reduced triggered activity compared with Wt MI cardiomyocytes. Reduction in arrhythmic risk was accompanied by reduced diastolic SR Ca2+ sparks, reduced SR Ca2+ content, reduced oxidized ryanodine receptor, and increased calsequestrin 2 in SERCA+/- MI mice., Conclusion: SERCA2a knockdown was antiarrhythmic after MI without affecting overall systolic performance. Possible antiarrhythmic mechanisms included reduced SR free Ca2+ and reduced diastolic SR Ca2+ release., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
20. Inflammatory Macrophage Interleukin-1β Mediates High-Fat Diet-Induced Heart Failure With Preserved Ejection Fraction.
- Author
-
Liu H, Huang Y, Zhao Y, Kang GJ, Feng F, Wang X, Liu M, Shi G, Revelo X, Bernlohr D, and Dudley SC Jr
- Abstract
Diabetes mellitus (DM) is a main risk factor for diastolic dysfunction (DD) and heart failure with preserved ejection fraction. High-fat diet (HFD) mice presented with diabetes mellitus, DD, higher cardiac interleukin (IL)-1β levels, and proinflammatory cardiac macrophage accumulation. DD was significantly ameliorated by suppressing IL-1β signaling or depleting macrophages. Mice with macrophages unable to adopt a proinflammatory phenotype were low in cardiac IL-1β levels and were resistant to HFD-induced DD. IL-1β enhanced mitochondrial reactive oxygen species (mitoROS) in cardiomyocytes, and scavenging mitoROS improved HFD-induced DD. In conclusion, macrophage-mediated inflammation contributed to HFD-associated DD through IL-1β and mitoROS production., Competing Interests: This project was supported by National Institutes of Health grants R01 HL104025 (Dr Dudley) and R01 HL106592 (Dr Dudley). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)
- Published
- 2022
- Full Text
- View/download PDF
21. Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes.
- Author
-
Garay BI, Givens S, Abreu P, Liu M, Yücel D, Baik J, Stanis N, Rothermel TM, Magli A, Abrahante JE, Goloviznina NA, Soliman HAN, Dhoke NR, Kyba M, Alford PW, Dudley SC Jr, van Berlo JH, Ogle B, and Perlingeiro RRC
- Subjects
- Cell Differentiation physiology, Cells, Cultured, Humans, Infant, Newborn, Myocytes, Cardiac metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs and prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day 30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, T-tubule density, calcium handling, and electrophysiology, many equivalent to day 60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof of concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery., Competing Interests: Conflicts of interest The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
22. Circulating S-Glutathionylated cMyBP-C as a Biomarker for Cardiac Diastolic Dysfunction.
- Author
-
Zhou X, Jeong EM, Liu H, Kaseer B, Liu M, Shrestha S, Imran H, Kavanagh K, Jiang N, Desimone LA, Feng F, Shi G, Jeong GE, Zhou A, Stockwell P, and Dudley SC Jr
- Subjects
- Animals, Biomarkers, Carrier Proteins metabolism, Chlorocebus aethiops, Diastole physiology, Humans, Mice, Myocardial Contraction, Myocardium metabolism, Phosphorylation, Carrier Proteins analysis, Heart Diseases metabolism
- Abstract
Background cMyBP-C (Cardiac myosin binding protein-C) regulates cardiac contraction and relaxation. Previously, we demonstrated that elevated myocardial S-glutathionylation of cMyBP-C correlates with diastolic dysfunction (DD) in animal models. In this study, we tested whether circulating S-glutathionylated cMyBP-C would be a biomarker for DD. Methods and Results Humans, African Green monkeys, and mice had DD determined by echocardiography. Blood samples were acquired and analyzed for S-glutathionylated cMyBP-C by immunoprecipitation. Circulating S-glutathionylated cMyBP-C in human participants with DD (n=24) was elevated (1.46±0.13-fold, P =0.014) when compared with the non-DD controls (n=13). Similarly, circulating S-glutathionylated cMyBP-C was upregulated by 2.13±0.47-fold ( P =0.047) in DD monkeys (n=6), and by 1.49 (1.22-2.06)-fold ( P =0.031) in DD mice (n=5) compared with the respective non-DD controls. Circulating S-glutathionylated cMyBP-C was positively correlated with DD in humans. Conclusions Circulating S-glutathionylated cMyBP-C was elevated in humans, monkeys, and mice with DD. S-glutathionylated cMyBP-C may represent a novel biomarker for the presence of DD.
- Published
- 2022
- Full Text
- View/download PDF
23. Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias.
- Author
-
Liu M, Kang GJ, and Dudley SC Jr
- Subjects
- Anti-Arrhythmia Agents pharmacology, Anti-Arrhythmia Agents therapeutic use, Humans, Ion Channels metabolism, Ion Channels therapeutic use, Unfolded Protein Response, Arrhythmias, Cardiac drug therapy, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac metabolism, Myocardial Infarction
- Abstract
Cardiomyopathies are associated with arrhythmias and cardiac ion channel downregulation. This downregulation is arrhythmogenic. Paradoxically, antiarrhythmic therapies are based on ion channel-blocking drugs that further downregulate these channels and exhibit proarrhythmic risk. Recent studies have shown that inhibition of the protein kinase RNA-like ER kinase (PERK) arm of the unfolded protein response (UPR) prevents select cardiac ion channel downregulation and plays a protective role against arrhythmias. Prevention of ion channel downregulation represents as a novel therapeutic strategy to treat arrhythmias in myocardial infarction and heart failure., Competing Interests: Declaration of interests The authors declare that no conflict of interest exists., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
24. The genomics of heart failure: design and rationale of the HERMES consortium.
- Author
-
Lumbers RT, Shah S, Lin H, Czuba T, Henry A, Swerdlow DI, Mälarstig A, Andersson C, Verweij N, Holmes MV, Ärnlöv J, Svensson P, Hemingway H, Sallah N, Almgren P, Aragam KG, Asselin G, Backman JD, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunner-La Rocca HP, Carey DJ, Chaffin MD, Chasman DI, Chazara O, Chen X, Chen X, Chung JH, Chutkow W, Cleland JGF, Cook JP, de Denus S, Dehghan A, Delgado GE, Denaxas S, Doney AS, Dörr M, Dudley SC, Engström G, Esko T, Fatemifar G, Felix SB, Finan C, Ford I, Fougerousse F, Fouodjio R, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Haggerty CM, van der Harst P, Hedman ÅK, Helgadottir A, Hillege H, Hyde CL, Jacob J, Jukema JW, Kamanu F, Kardys I, Kavousi M, Khaw KT, Kleber ME, Køber L, Koekemoer A, Kraus B, Kuchenbaecker K, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Mann D, Margulies KB, Marston NA, März W, McMurray JJV, Melander O, Melloni G, Mordi IR, Morley MP, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Newton-Cheh C, Niessner A, Niiranen T, Nowak C, O'Donoghue ML, Owens AT, Palmer CNA, Paré G, Perola M, Perreault LL, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Roselli C, Rotter JI, Ruff CT, Sabatine MS, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stefansson K, Stender S, Stott DJ, Sveinbjörnsson G, Tammesoo ML, Tardif JC, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tuckwell D, Tyl B, Uitterlinden AG, Vaura F, Veluchamy A, Visscher PM, Völker U, Voors AA, Wang X, Wareham NJ, Weeke PE, Weiss R, White HD, Wiggins KL, Xing H, Yang J, Yang Y, Yerges-Armstrong LM, Yu B, Zannad F, Zhao F, Wilk JB, Holm H, Sattar N, Lubitz SA, Lanfear DE, Shah S, Dunn ME, Wells QS, Asselbergs FW, Hingorani AD, Dubé MP, Samani NJ, Lang CC, Cappola TP, Ellinor PT, Vasan RS, and Smith JG
- Subjects
- Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Prognosis, Genome-Wide Association Study, Heart Failure genetics
- Abstract
Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10
-8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)- Published
- 2021
- Full Text
- View/download PDF
25. Oxidative stress: a bystander or a causal contributor to atrial remodelling and fibrillation?
- Author
-
Dobrev D and Dudley SC
- Subjects
- Arrhythmias, Cardiac, Heart Atria, Humans, Oxidative Stress, Atrial Remodeling
- Published
- 2021
- Full Text
- View/download PDF
26. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction.
- Author
-
Liu M, Liu H, Parthiban P, Kang GJ, Shi G, Feng F, Zhou A, Gu L, Karnopp C, Tolkacheva EG, and Dudley SC Jr
- Subjects
- Adenine analogs & derivatives, Adenine pharmacology, Animals, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac metabolism, Down-Regulation, Female, Heart Disease Risk Factors, Humans, Indoles pharmacology, Ion Channels metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Cardiovascular, Protein Kinase Inhibitors pharmacology, Unfolded Protein Response drug effects, eIF-2 Kinase deficiency, eIF-2 Kinase genetics, Arrhythmias, Cardiac prevention & control, Myocardial Infarction complications, Myocardial Infarction metabolism, Unfolded Protein Response physiology, eIF-2 Kinase antagonists & inhibitors
- Abstract
Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels. When activated, the protein kinase-like ER kinase (PERK) branch of the UPR reduces protein translation and abundance. We hypothesized that PERK inhibition could prevent ion channel downregulation and reduce arrhythmia risk after myocardial infarct (MI). MI induced in mice by coronary artery ligation resulted in reduced ion channel levels, ventricular tachycardia (VT), and prolonged corrected intervals between the Q and T waves on the ECGs (QTc). Protein levels of major cardiac ion channels were decreased. MI cardiomyocytes showed significantly prolonged action potential duration and decreased maximum upstroke velocity. Cardiac-specific PERK KO reduced electrical remodeling in response to MI, with shortened QTc intervals, fewer VT episodes, and higher survival rates. Pharmacological PERK inhibition had similar effects. In conclusion, we found that activated PERK during MI contributed to arrhythmia risk by the downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmia risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmia mechanism and that maintenance of ion channel levels is antiarrhythmic.
- Published
- 2021
- Full Text
- View/download PDF
27. Cardiac Resynchronization and Circulating Markers of Sarcoplasmic Reticulum Calcium Handling and Sudden Death Risk.
- Author
-
Jiang N, Zhou A, Imran H, Shi G, Kaseer B, Siu V, Chu AF, Donaldson DM, Kirk MM, Philips BB, and Dudley SC Jr
- Subjects
- Biomarkers, Calcium, Death, Sudden, Humans, Sarcoplasmic Reticulum, Cardiac Resynchronization Therapy
- Abstract
Cardiac resynchronization therapy (CRT) can improve heart function and decrease arrhythmic events. We tested whether CRT altered circulating markers of calcium handling and sudden death risk. Circulating cardiac sodium channel messenger RNA (mRNA) splicing variants indicate arrhythmic risk, and a reduction in sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) is thought to diminish contractility in heart failure. CRT was associated with a decreased proportion of circulating, nonfunctional sodium channels and improved SERCA2a mRNA expression. Patients without CRT did not have improvement in the biomarkers. These changes might explain the lower arrhythmic risk and improved contractility associated with CRT., Competing Interests: Funding Support and Author Disclosures Dr Dudley is the inventor on the following patent applications: SCN5A Splice Variants for Use in Methods Relating to Sudden Cardiac Death and Need for Implanted Cardiac Defibrillators, PCT/US2012/20564; and SCN5A Splicing Factors and Splice Variants for Use in Diagnostic and Prognostic Methods, 13/291,826. Supported by National Institutes of Health grants R01 HL104025 and HL106592. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
28. Magnesium Deficiency Causes a Reversible, Metabolic, Diastolic Cardiomyopathy.
- Author
-
Liu M, Liu H, Feng F, Xie A, Kang GJ, Zhao Y, Hou CR, Zhou X, and Dudley SC Jr
- Subjects
- Adenosine Triphosphate metabolism, Animals, Antioxidants pharmacology, Calcium Signaling, Cardiomyopathies drug therapy, Cardiomyopathies metabolism, Cardiomyopathies physiopathology, Carrier Proteins metabolism, Diastole, Disease Models, Animal, Mice, Inbred C57BL, Mitochondria, Heart drug effects, Myocytes, Cardiac drug effects, Organophosphorus Compounds pharmacology, Piperidines pharmacology, Reactive Oxygen Species metabolism, Mice, Cardiomyopathies etiology, Magnesium Deficiency complications, Mitochondria, Heart metabolism, Myocardial Contraction drug effects, Myocytes, Cardiac metabolism, Ventricular Function, Left drug effects
- Abstract
Background Dietary Mg intake is associated with a decreased risk of developing heart failure, whereas low circulating Mg level is associated with increased cardiovascular mortality. We investigated whether Mg deficiency alone could cause cardiomyopathy. Methods and Results C57BL/6J mice were fed with a low Mg (low-Mg, 15-30 mg/kg Mg) or a normal Mg (nl-Mg, 600 mg/kg Mg) diet for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with nl-Mg diet for another 6 weeks. Low-Mg diet significantly decreased mouse serum Mg (0.38±0.03 versus 1.14±0.03 mmol/L for nl-Mg; P <0.0001) with a reciprocal increase in serum Ca, K, and Na. Low-Mg mice exhibited impaired cardiac relaxation (ratio between mitral peak early filling velocity E and longitudinal tissue velocity of the mitral anterior annulus e, 21.1±1.1 versus 15.4±0.4 for nl-Mg; P =0.011). Cellular ATP was decreased significantly in low-Mg hearts. The changes were accompanied by mitochondrial dysfunction with mitochondrial reactive oxygen species overproduction and membrane depolarization. cMyBPC (cardiac myosin-binding protein C) was S -glutathionylated in low-Mg mouse hearts. All these changes were normalized with Mg repletion. In vivo (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride treatment during low-Mg diet improved cardiac relaxation, increased ATP levels, and reduced S -glutathionylated cMyBPC. Conclusions Mg deficiency caused a reversible diastolic cardiomyopathy associated with mitochondrial dysfunction and oxidative modification of cMyBPC. In deficiency states, Mg supplementation may represent a novel treatment for diastolic heart failure.
- Published
- 2021
- Full Text
- View/download PDF
29. Life's Simple 7 cardiovascular health score and premature atrial contractions: The atherosclerosis risk in communities (ARIC) study.
- Author
-
Krishnappa D, Wang W, Rooney MR, Norby FL, Oldenburg NC, Soliman EZ, Alonso A, O-Uchi J, Dudley SC Jr, Lutsey PL, and Chen LY
- Subjects
- Aged, Exercise, Humans, Prospective Studies, Risk Assessment, Risk Factors, Atherosclerosis diagnosis, Atherosclerosis epidemiology, Atrial Premature Complexes diagnosis, Atrial Premature Complexes epidemiology
- Abstract
Background: Premature atrial contractions (PACs) are associated with increased risk of atrial fibrillation (AF) and ischemic stroke. Although lifestyle and risk factor modification reduces AF incidence, their relationship to PACs frequency is unclear. We assessed the association of Life's Simple 7 (LS7) and individual LS7 factors in midlife with PACs frequency in late life in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: We followed 1924 participants from ARIC clinic Visit 3 (1993--95) to Visit 6 (2016-17) when a 2-week continuous heart rhythm monitor (Zio®XT Patch) was applied. LS7 factors were assessed at Visit 3 and a composite score was calculated. PACs frequency was categorized as minimal (<0.1%), occasional (≥0.1%-5%) and frequent (>5%). Logistic regression was used to evaluate the association of LS7 score and individual factors with PACs frequency., Results: Each 1-point LS7 score increase was associated with lower odds of frequent PACs vs. no PACs (OR [95% CI]: 0.87 [0.78, 0.98]) and frequent PACs vs. occasional PACs (OR [95% CI]: 0.88 [0.79, 0.98]). Of the individual LS7 factors, compared with ideal physical activity, poor physical activity was associated with 81% higher odds of frequent PACs vs. no PACs. Compared with ideal BMI, poor BMI was associated with 41% higher odds of occasional PACs vs. no PACs., Conclusion: Lifestyle risk factors, particularly physical activity and BMI, are associated with higher odds of PACs frequency. More research is needed to determine whether modifying these risk factors in midlife would prevent frequent PACs, and thereby prevent AF and stroke in older age., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
30. Frequent Premature Atrial Contractions Are Associated With Poorer Cognitive Function in the Atherosclerosis Risk in Communities (ARIC) Study.
- Author
-
Rooney MR, Norby FL, Maheshwari A, Lutsey PL, Dudley SC Jr, Soliman EZ, Loehr LR, Mosley TH, Coresh J, Alonso A, and Chen LY
- Subjects
- Aged, Aged, 80 and over, Atherosclerosis diagnosis, Atherosclerosis etiology, Atrial Premature Complexes diagnosis, Atrial Premature Complexes physiopathology, Cognitive Dysfunction diagnosis, Cognitive Dysfunction epidemiology, Cross-Sectional Studies, Dementia diagnosis, Dementia epidemiology, Electrocardiography, Ambulatory, Female, Health Surveys, Humans, Logistic Models, Male, Multivariate Analysis, Neuropsychological Tests, Prevalence, Risk Assessment, Risk Factors, Atrial Premature Complexes psychology, Cognitive Dysfunction etiology, Dementia etiology
- Abstract
Objective: To evaluate the association of premature atrial contraction (PAC) frequency with cognitive test scores and prevalence of dementia or mild cognitive impairment (MCI)., Materials and Methods: We conducted a cross-sectional analysis using Atherosclerosis Risk in Communities study visit 6 (January 1, 2016, through December 31, 2017) data. We included 2163 participants without atrial fibrillation (AF) (age mean ± SD, 79±4 years; 1273 (58.9%) female; and 604 (27.97.0% Black) who underwent cognitive testing and wore a leadless, ambulatory electrocardiogram monitor for 14 days. We categorized PAC frequency based on the percent of beats: less than 1%, minimal; 1% to <5%, occasional; greater than or equal to 5%, frequent. We derived cognitive domain-specific factor scores (memory, executive function, language, and global z-score). Dementia and MCI were adjudicated., Results: During a mean analyzable time of 12.6±2.6 days, 339 (15.7%) had occasional PACs and 107 (4.9%) had frequent PACs. Individuals with frequent PACs (vs minimal) had lower executive function factor scores by 0.30 (95% CI, -0.46 to -0.14) and lower global factor scores by 0.20 (95% CI, -0.33 to -0.07) after multivariable adjustment. Individuals with frequent PACs (vs minimal) had higher odds of prevalent dementia or MCI after multivariable adjustment (odds ratio, 1.74; 95% CI, 1.09 to 2.79). These associations were unchanged with additional adjustment for stroke., Conclusion: In community-dwelling older adults without AF, frequent PACs were cross-sectionally associated with lower executive and global cognitive function and greater prevalence of dementia or MCI, independently of stroke. Our findings lend support to the notion that atrial cardiomyopathy may be a driver of AF-related outcomes. Further research to confirm these associations prospectively and to elucidate underlying mechanisms is warranted., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
31. IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.
- Author
-
Gupta A, Fei YD, Kim TY, Xie A, Batai K, Greener I, Tang H, Ciftci-Yilmaz S, Juneman E, Indik JH, Shi G, Christensen J, Gupta G, Hillery C, Kansal MM, Parikh DS, Zhou T, Yuan JX, Kanthi Y, Bronk P, Koren G, Kittles R, Duarte JD, Garcia JGN, Machado RF, Dudley SC, Choi BR, and Desai AA
- Subjects
- Adult, Anemia, Sickle Cell blood, Anemia, Sickle Cell physiopathology, Animals, Arrhythmias, Cardiac blood, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac physiopathology, Cardiomyopathies blood, Cardiomyopathies physiopathology, Humans, Interleukin-18 analysis, Male, Mice, Tachycardia, Ventricular blood, Tachycardia, Ventricular physiopathology, Young Adult, Anemia, Sickle Cell complications, Cardiomyopathies etiology, Interleukin-18 blood, Tachycardia, Ventricular etiology
- Abstract
Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.
- Published
- 2021
- Full Text
- View/download PDF
32. Interleukin-1β, Oxidative Stress, and Abnormal Calcium Handling Mediate Diabetic Arrhythmic Risk.
- Author
-
Liu H, Zhao Y, Xie A, Kim TY, Terentyeva R, Liu M, Shi G, Feng F, Choi BR, Terentyev D, Hamilton S, and Dudley SC Jr
- Abstract
Diabetes mellitus (DM) is associated with increased arrhythmia. Type 2 DM (T2DM) mice showed prolonged QT interval and increased ventricular arrhythmic inducibility, accompanied by elevated cardiac interleukin (IL)-1β, increased mitochondrial reactive oxygen species (mitoROS), and oxidation of the sarcoplasmic reticulum (SR) Ca
2+ release channel (ryanodine receptor 2 [RyR2]). Inhibiting IL-1β and mitoROS reduced RyR2 oxidation and the ventricular arrhythmia in DM. Inhibiting SR Ca2+ leak by stabilizing the oxidized RyR2 channel reversed the diabetic arrhythmic risk. In conclusion, cardiac IL-1β mediated the DM-associated arrhythmia through mitoROS generation that enhances SR Ca2+ leak. The mechanistic link between inflammation and arrhythmias provides new therapeutic options., Competing Interests: This work was supported by National Heart Lung and Blood Institute Grant Nos. R01HL134791 and R01HL104025. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)- Published
- 2021
- Full Text
- View/download PDF
33. The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2.
- Author
-
Turan NN, Moshal KS, Roder K, Baggett BC, Kabakov AY, Dhakal S, Teramoto R, Chiang DY, Zhong M, Xie A, Lu Y, Dudley SC Jr, MacRae CA, Karma A, and Koren G
- Subjects
- Action Potentials, Animals, Genome-Wide Association Study, Humans, Myocytes, Cardiac cytology, NAV1.5 Voltage-Gated Sodium Channel genetics, Nedd4 Ubiquitin Protein Ligases genetics, Nuclear Proteins genetics, Protein Binding, Protein Transport, Rabbits, Transcription Factors genetics, Ubiquitination, Zebrafish, Endosomes metabolism, Myocytes, Cardiac metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism, Nedd4 Ubiquitin Protein Ligases metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism, Ubiquitin metabolism
- Abstract
The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current I
Na and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Turan et al.)- Published
- 2020
- Full Text
- View/download PDF
34. Association of Life's Simple 7 with Atrial Fibrillation Burden (From the Atherosclerosis Risk in Communities Study).
- Author
-
Wang W, Norby FL, Rooney MR, Zhang M, Gutierrez A, Garg P, Soliman EZ, Alonso A, Dudley SC Jr, Lutsey PL, and Chen LY
- Subjects
- Aged, Atherosclerosis complications, Atherosclerosis epidemiology, Atrial Fibrillation etiology, Atrial Fibrillation therapy, Body Mass Index, Female, Humans, Incidence, Male, Middle Aged, Prospective Studies, Risk Factors, United States epidemiology, Atherosclerosis prevention & control, Atrial Fibrillation epidemiology, Exercise physiology, Health Status, Risk Assessment methods, Risk Reduction Behavior
- Abstract
The American Heart Association's Life's Simple 7 (LS7) metric consists of 7 modifiable risk factors. Although a more favorable LS7 risk factor profile is associated with lower AF incidence, this relation is unknown in regard to AF burden. We assessed the prospective association of overall LS7 score and individual LS7 risk factors in midlife with AF burden in late-life in the Atherosclerosis Risk in Communities Study. LS7 components were assessed at Visit 3 (1993 to 1995) and a composite score ranging from 0 to 14 was calculated. A higher score indicates better cardiovascular health. AF burden was measured at Visit 6 (2016 to 2017) with a 2-week Zio XT Patch. AF burden, defined as the percent of time a participant was in AF, was categorized as none, intermittent (>0 to <100%), or continuous (100%). Weighted multinomial logistic regression was used. Of the 2,363 participants, 58% were female and 24% were black. Participants were aged 57 ± 5 years at Visit 3 and 79 ± 5 years at Visit 6. From the Zio XT Patch, 5% had continuous AF, 4% had intermittent AF, and 91% had none. After multivariable adjustment, each 1-point increase in LS7 score had 0.87 (95% CI: 0.79 to 0.95) higher odds of continuous AF than no AF. Individually, poor levels of physical activity, BMI, and fasting blood glucose were associated with greater AF burden. In conclusion, this population-based prospective cohort study reports that unfavorable cardiovascular health profile in midlife is associated with higher AF burden in late-life and future research to evaluate the effectiveness of optimizing physical activity, BMI, and fasting blood glucose in lowering AF burden is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this report., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
35. MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel.
- Author
-
Kang GJ, Xie A, Liu H, and Dudley SC Jr
- Subjects
- Animals, Antagomirs metabolism, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac prevention & control, Gene Expression Regulation genetics, Heart Rate genetics, Humans, Male, Mice, Mice, Inbred C57BL, MicroRNAs metabolism, Myocardial Infarction genetics, Myocardial Infarction metabolism, Myocardial Ischemia metabolism, Myocardium metabolism, Myocytes, Cardiac metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism, Sodium metabolism, MicroRNAs genetics, Myocardial Ischemia genetics, NAV1.5 Voltage-Gated Sodium Channel genetics
- Abstract
Cardiac ischemia is associated with arrhythmias; however, effective therapies are currently limited. The cardiac voltage-gated sodium channel α subunit (SCN5A), encoding the Nav1.5 current, plays a key role in the cardiac electrical conduction and arrhythmic risk. Here, we show that hypoxia reduces Nav1.5 through effects on a miR, miR-448. miR-448 expression is increased in ischemic cardiomyopathy. miR-448 has a conserved binding site in 3'-UTR of SCN5A. miR-448 binding to this site suppressed SCN5A expression and sodium currents. Hypoxia-induced HIF-1α and NF-κB were major transcriptional regulators for MIR448. Moreover, hypoxia relieved MIR448 transcriptional suppression by RE1 silencing transcription factor. Therefore, miR-448 inhibition reduced arrhythmic risk after myocardial infarction. Here, we show that ischemia drove miR-448 expression, reduced Nav1.5 current, and increased arrhythmic risk. Arrhythmic risk was improved by preventing Nav1.5 downregulation, suggesting a new approach to antiarrhythmic therapy.
- Published
- 2020
- Full Text
- View/download PDF
36. Magnesium, Oxidative Stress, Inflammation, and Cardiovascular Disease.
- Author
-
Liu M and Dudley SC Jr
- Abstract
Hypomagnesemia is commonly observed in heart failure, diabetes mellitus, hypertension, and cardiovascular diseases. Low serum magnesium (Mg) is a predictor for cardiovascular and all-cause mortality and treating Mg deficiency may help prevent cardiovascular disease. In this review, we discuss the possible mechanisms by which Mg deficiency plays detrimental roles in cardiovascular diseases and review the results of clinical trials of Mg supplementation for heart failure, arrhythmias and other cardiovascular diseases.
- Published
- 2020
- Full Text
- View/download PDF
37. Serum magnesium and burden of atrial and ventricular arrhythmias: The Atherosclerosis Risk in Communities (ARIC) Study.
- Author
-
Rooney MR, Lutsey PL, Alonso A, Selvin E, Pankow JS, Rudser KD, Dudley SC Jr, and Chen LY
- Subjects
- Aged, Aged, 80 and over, Cross-Sectional Studies, Electrocardiography, Electrocardiography, Ambulatory, Female, Humans, Magnesium, Male, Atherosclerosis, Atrial Fibrillation epidemiology
- Abstract
Introduction: Low serum magnesium (Mg) is associated with an increased incidence of atrial and ventricular arrhythmias. A richer phenotyping of arrhythmia indices, such as burden or frequency, may provide etiologic insights., Objectives: To evaluate cross-sectional associations of serum Mg with burden of atrial arrhythmias [atrial fibrillation (AF), premature atrial contractions (PAC), supraventricular tachycardia (SVT)], and ventricular arrhythmias [premature ventricular contractions (PVC), non-sustained ventricular tachycardia (NSVT)] over 2-weeks of ECG monitoring., Methods: We included 2513 ARIC Study visit 6 (2016-2017) participants who wore the Zio XT Patch-a leadless, ambulatory ECG-monitor-for up to 2-weeks. Serum Mg was modeled categorically and continuously. AF burden was categorized as intermittent or continuous based on the percent of analyzable time spent in AF. Other arrhythmia burdens were defined by the average number of abnormal beats per day. Linear regression was used for continuous outcomes; logistic and multinomial regression were used for categorical outcomes., Results: Participants were mean ± SD age 79 ± 5 years, 58% were women and 25% black. Mean serum Mg was 0.82 ± 0.08 mmol/L and 19% had hypomagnesemia (<0.75 mmol/L). Serum Mg was inversely associated with PVC burden and continuous AF. The AF association was no longer statistically significant with further adjustment for traditional lifestyle risk factors, only the association with PVC burden remained significant. There were no associations between serum Mg and other arrhythmias examined., Conclusions: In this community-based cohort of older adults, we found little evidence of independent cross-sectional associations between serum Mg and arrhythmia burden., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
38. Metabolic regulation of endothelial SK channels and human coronary microvascular function.
- Author
-
Liu Y, Kabakov AY, Xie A, Shi G, Singh AK, Sodha NR, Ehsan A, Usheva A, Agbortoko V, Koren G, Dudley SC Jr, Sellke FW, and Feng J
- Subjects
- Arterioles, Coronary Vessels diagnostic imaging, Heart, Humans, Diabetes Mellitus, Endothelial Cells
- Abstract
Background: Diabetic (DM) inactivation of small conductance calcium-activated potassium (SK) channels contributes to coronary endothelial dysfunction. However, the mechanisms responsible for this down-regulation of endothelial SK channels are poorly understood. Thus, we hypothesized that the altered metabolic signaling in diabetes regulates endothelial SK channels and human coronary microvascular function., Methods: Human atrial tissue, coronary arterioles and coronary artery endothelial cells (HCAECs) obtained from DM and non-diabetic (ND) patients (n = 12/group) undergoing cardiac surgery were used to analyze metabolic alterations, endothelial SK channel function, coronary microvascular reactivity and SK gene/protein expression/localization., Results: The relaxation response of DM coronary arterioles to the selective SK channel activator SKA-31 and calcium ionophore A23187 was significantly decreased compared to that of ND arterioles (p < 0.05). Diabetes increases the level of NADH and the NADH/NAD
+ ratio in human myocardium and HCAECs (p < 0.05). Increase in intracellular NADH (100 μM) in the HCAECs caused a significant decrease in endothelial SK channel currents (p < 0.05), whereas, intracellular application of NAD+ (500 μM) increased the endothelial SK channel currents (p < 0.05). Mitochondrial reactive oxygen species (mROS) of HCAECs and NADPH oxidase (NOX) and PKC protein expression in the human myocardium and coronary microvasculature were increased respectively (p < 0.05)., Conclusions: Diabetes is associated with metabolic changes in the human myocardium, coronary microvasculature and HCAECs. Endothelial SK channel function is regulated by the metabolite pyridine nucleotides, NADH and NAD+ , suggesting that metabolic regulation of endothelial SK channels may contribute to coronary endothelial dysfunction in the DM patients with diabetes., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
39. Evidence for Inflammation as a Driver of Atrial Fibrillation.
- Author
-
Zhou X and Dudley SC Jr
- Abstract
Atrial fibrillation (AF) is one of the most common types of arrhythmias and increases cardiovascular morbidity and mortality. Current therapeutic approaches to AF that focus on rhythm control have high recurrence rates and no life prolongation value. While possible explanations include toxicity of current therapies, another likely explanation may be that current therapies do not address fundamental mechanisms of AF initiation and maintenance. Inflammation has been shown to affect signaling pathways that lead to the development of AF. This paper reviews the roles of inflammation in the occurrence, development, and mechanisms of AF and reviews the therapeutic implications of the correlation of inflammation and AF., (Copyright © 2020 Zhou and Dudley.)
- Published
- 2020
- Full Text
- View/download PDF
40. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.
- Author
-
Shah S, Henry A, Roselli C, Lin H, Sveinbjörnsson G, Fatemifar G, Hedman ÅK, Wilk JB, Morley MP, Chaffin MD, Helgadottir A, Verweij N, Dehghan A, Almgren P, Andersson C, Aragam KG, Ärnlöv J, Backman JD, Biggs ML, Bloom HL, Brandimarto J, Brown MR, Buckbinder L, Carey DJ, Chasman DI, Chen X, Chen X, Chung J, Chutkow W, Cook JP, Delgado GE, Denaxas S, Doney AS, Dörr M, Dudley SC, Dunn ME, Engström G, Esko T, Felix SB, Finan C, Ford I, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gutmann R, Haggerty CM, van der Harst P, Hyde CL, Ingelsson E, Jukema JW, Kavousi M, Khaw KT, Kleber ME, Køber L, Koekemoer A, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Margulies KB, März W, Melander O, Mordi IR, Morgan T, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Niessner A, Niiranen T, O'Donoghue ML, Owens AT, Palmer CNA, Parry HM, Perola M, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Rotter JI, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stender S, Stott DJ, Svensson P, Tammesoo ML, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tyl B, Uitterlinden AG, Veluchamy A, Völker U, Voors AA, Wang X, Wareham NJ, Waterworth D, Weeke PE, Weiss R, Wiggins KL, Xing H, Yerges-Armstrong LM, Yu B, Zannad F, Zhao JH, Hemingway H, Samani NJ, McMurray JJV, Yang J, Visscher PM, Newton-Cheh C, Malarstig A, Holm H, Lubitz SA, Sattar N, Holmes MV, Cappola TP, Asselbergs FW, Hingorani AD, Kuchenbaecker K, Ellinor PT, Lang CC, Stefansson K, Smith JG, Vasan RS, Swerdlow DI, and Lumbers RT
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Cardiomyopathies pathology, Carrier Proteins genetics, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p21 genetics, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Microfilament Proteins genetics, Muscle Proteins genetics, Risk Factors, Atrial Fibrillation genetics, Cardiomyopathies genetics, Coronary Artery Disease genetics, Heart Failure genetics, Heart Failure pathology, Ventricular Function, Left genetics
- Abstract
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
- Published
- 2020
- Full Text
- View/download PDF
41. Isolevuglandin scavenger attenuates pressure overload-induced cardiac oxidative stress, cardiac hypertrophy, heart failure and lung remodeling.
- Author
-
Shang L, Weng X, Wang D, Yue W, Mernaugh R, Amarnath V, Weir EK, Dudley SC, Xu Y, Hou M, and Chen Y
- Subjects
- Animals, Benzylamines pharmacology, Cardiomegaly genetics, Cardiomegaly metabolism, Cardiomegaly pathology, Disease Models, Animal, Heart Failure genetics, Heart Failure metabolism, Heart Failure pathology, Humans, Hypertrophy, Left Ventricular drug therapy, Hypertrophy, Left Ventricular metabolism, Hypertrophy, Left Ventricular pathology, Lung drug effects, Lung metabolism, Lung pathology, Mice, Myocytes, Cardiac drug effects, Oxidative Stress drug effects, Pneumonia genetics, Pneumonia metabolism, Pneumonia pathology, Ventricular Dysfunction, Left genetics, Ventricular Dysfunction, Left metabolism, Ventricular Dysfunction, Left pathology, Ventricular Remodeling drug effects, Cardiomegaly drug therapy, Heart Failure drug therapy, Lipids genetics, Pneumonia drug therapy, Ventricular Dysfunction, Left drug therapy
- Abstract
Increased levels of reactive isolevuglandins (IsoLGs) are associated with vascular inflammation and hypertension, two important factors affect heart failure (HF) development. The role of IsoLGs in HF development is unknown. Here we studied the role of IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) in transverse aortic constriction (TAC) induced heart failure. We observed that TAC caused a significant increase of IsoLG protein adducts in cardiac and lung tissues in mice. Both IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) and its less reactive isomer 4-hydroxybenzylamine (4-HOBA) significantly attenuated the left ventricular (LV) and lung IsoLGs in mice after TAC. 2-HOBA and 4-HOBA attenuated TAC-induced LV hypertrophy, heart failure, and the increase of lung weight in mice, and also improved TAC-induced LV dysfunction. Moreover, both 2-HOBA and 4-HOBA effectively attenuated LV cardiomyocyte hypertrophy, lung inflammation, lung fibrosis. These findings suggest that methods to reduce IsoLGs may be useful for HF therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
42. Short term Pm2.5 exposure caused a robust lung inflammation, vascular remodeling, and exacerbated transition from left ventricular failure to right ventricular hypertrophy.
- Author
-
Yue W, Tong L, Liu X, Weng X, Chen X, Wang D, Dudley SC, Weir EK, Ding W, Lu Z, Xu Y, and Chen Y
- Subjects
- Animals, Disease Models, Animal, Disease Susceptibility, Fibrosis, Heart Failure pathology, Heart Function Tests, Humans, Hypertrophy, Right Ventricular pathology, Male, Mice, Oxidative Stress, Pneumonia pathology, Respiratory Function Tests, Time Factors, Vascular Cell Adhesion Molecule-1 metabolism, Environmental Exposure, Heart Failure etiology, Hypertrophy, Right Ventricular etiology, Particulate Matter, Pneumonia etiology, Vascular Remodeling
- Abstract
Heart failure (HF) is the single largest cause for increased hospitalization after fine particulate matter (PM2.5) exposure. Patients with left HF often progress to right ventricular (RV) failure even with optimal medical care. An increase of PM2.5 of 10 μg per cubic meter was associated with a 76% increase in the risk of death from cardiovascular disease in 4 years' period. However, the role and mechanism of PM2.5 in HF progression are not known. Here we investigated the role of PM2.5 exposure in mice with existing HF mice produced by transverse aortic constriction (TAC). TAC-induced HF caused lung inflammation, vascular remodeling and RV hypertrophy. We found increased PM2.5 profoundly exacerbated lung oxidative stress in mice with existing left HF. To our surprise, PM2.5 exposure had no effect on LV hypertrophy and function, but profoundly exacerbated lung inflammation, vascular remodeling, and RV hypertrophy in mice with existing left HF. These striking findings demonstrate that PM2.5 and/or air pollution is a critical factor for overall HF progression by regulating lung oxidative stress, inflammation and remodeling as well as RV hypertrophy. Improving air quality may save HF patients from a dismal fate., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2019
- Full Text
- View/download PDF
43. Magnesium supplementation improves diabetic mitochondrial and cardiac diastolic function.
- Author
-
Liu M, Jeong EM, Liu H, Xie A, So EY, Shi G, Jeong GE, Zhou A, and Dudley SC Jr
- Abstract
In heart failure and type 2 diabetes mellitus (DM), the majority of patients have hypomagnesemia, and magnesium (Mg) supplementation has improved cardiac function and insulin resistance. Recently, we have shown that DM can cause cardiac diastolic dysfunction (DD). Therefore, we hypothesized that Mg supplementation would improve diastolic function in DM. High-fat diet-induced diabetic mouse hearts showed increased cardiac DD and hypertrophy. Mice with DM showed a significantly increased E/e' ratio (the ratio of transmitral Doppler early filling velocity [E] to tissue Doppler early diastolic mitral annular velocity [e']) in the echocardiogram, left ventricular end diastolic volume (LVEDV), incidence of DD, left ventricular posterior wall thickness in diastole (PWTd), and ratio of heart weight to tibia length (HW/TL) when compared with controls. DM mice also had hypomagnesemia. Ventricular cardiomyocytes isolated from DM mice exhibited decreased mitochondrial ATP production, a 1.7- ± 0.2-fold increase of mitochondrial ROS, depolarization of the mitochondrial membrane potential, and mitochondrial Ca2+ overload. Dietary Mg administration (50 mg/ml in the drinking water) for 6 weeks increased plasma Mg concentration and improved cardiac function. At the cellular level, Mg improved mitochondrial function with increased ATP, decreased mitochondrial ROS and Ca2+ overload, and repolarized mitochondrial membrane potential. In conclusion, Mg supplementation improved mitochondrial function, reduced oxidative stress, and prevented DD in DM.
- Published
- 2019
- Full Text
- View/download PDF
44. Functional cardiac Na + channels are expressed in human melanoma cells.
- Author
-
Xie A, Gallant B, Guo H, Gonzalez A, Clark M, Madigan A, Feng F, Chen HD, Cui Y, Dudley SC Jr, and Wan Y
- Abstract
Resting membrane potential (RMP) and intracellular Ca
2+ concentration [(Ca2+ )i ] are involved in tumorigenesis and metastasis. The present study investigated whether functional cardiac Na+ channels are expressed in human melanoma cells (WM 266-4) and its nonmalignant human melanocytes (HMC), as well as whether they participate in RMP maintenance and Ca2+ homeostasis. Confocal microscopy and western blot analysis were used to detect Na+ channels. The patch-clamp technique was employed to record Na+ currents and action potentials. Cytoplasmic Ca2+ was measured by loading Fluo-4. Cardiac (Nav 1.5) Na+ channels were expressed in HMCs and WM 266-4 cells. Tetrodotoxin (TTX) dose-dependently blocked Na+ currents in WM 266-4 while HMCs had no Na+ currents. Ultraviolet light induced similar action potentials in HMCs and WM 266-4 cells, which were abolished by transient receptor potential A1 channel-specific blocker, HC-030031. Compared with HMCs, RMP was substantially depolarized in WM 266-4. TTX hyperpolarized RMP in WM 266-4 cells at a concentration of 30 µM, which facilitated Ca2+ influx. Compared with HMCs, (Ca2+ )i was significantly higher in WM 266-4 cells and was elevated by 30 µM TTX. Collectively, Cardiac Na+ channels depolarize RMP and inhibit Ca2+ uptake in melanoma cells possibly contributing to tumorigenesis and metastasis. Na+ channel agonists may be developed to treat melanoma such as WM 266-4.- Published
- 2018
- Full Text
- View/download PDF
45. Mitochondrial Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes.
- Author
-
Xie A, Zhou A, Liu H, Shi G, Liu M, Boheler KR, and Dudley SC Jr
- Subjects
- Animals, Cations, Divalent metabolism, Cell Line, Cytoplasm metabolism, Embryonic Stem Cells metabolism, Heart Ventricles cytology, Humans, Induced Pluripotent Stem Cells metabolism, Mice, Myocytes, Cardiac cytology, Ryanodine Receptor Calcium Release Channel deficiency, Ryanodine Receptor Calcium Release Channel genetics, Sarcolemma metabolism, Action Potentials physiology, Calcium metabolism, Heart Ventricles metabolism, Mitochondria metabolism, Myocytes, Cardiac metabolism
- Abstract
Introduction: Ca2+ release from sarcoplasmic reticulum (SR) is known to contribute to automaticity via the cytoplasmic Na+-Ca2+ exchanger (NCX). Mitochondria participate in Ca2+ cycling. We studied the role of mitochondrial Ca2+ flux in ventricular spontaneous electrical activity., Methods: Spontaneously contracting mouse embryonic stem cells (ESC)-derived ventricular cardiomyocytes (CMs) were differentiated from wild type and ryanodine receptor type 2 (RYR2) knockout mouse ESCs and differentiated for 19-21 days. Automaticity was also observed in human induced pluripotent stem cell (hiPSC)-derived ventricular CMs differentiated for 30 days, and acute isolated adult mouse ventricular cells in ischemic simulated buffer. Action potentials (APs) were recorded by perforated whole cell current-clamp. Cytoplasmic and mitochondrial Ca2+ transients were determined by fluorescent imaging., Results: In mouse ESC-derived ventricular CMs, spontaneous beating was dependent on the L-type Ca2+ channel, cytoplasmic NCX and mitochondrial NCX. Spontaneous beating was modulated by SR Ca2+ release from RYR2 or inositol trisphosphate receptors (IP3R), the pacemaker current (If) and mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU). In RYR2 knockout mouse ESC-derived ventricular CMs, mitochondrial Ca2+ flux influenced spontaneous beating independently of the SR Ca2+ release from RYR2, and the mitochondrial effect was dependent on IP3R SR Ca2+ release. Depolarization of mitochondria and preservation of ATP could terminate spontaneous beating. A contribution of mitochondrial Ca2+ flux to automaticity was confirmed in hiPSC-derived ventricular CMs and ischemic adult mouse ventricular CMs, confirming the findings across species and cell maturity levels., Conclusions: Mitochondrial and sarcolemma NCX fluxes are required for ventricular automaticity. Mitochondrial Ca2+ uptake plays a modulatory role. Mitochondrial Ca2+ uptake through MCU is influenced by IP3R-dependent SR Ca2+ release., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
- Full Text
- View/download PDF
46. HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure.
- Author
-
Zhou A, Xie A, Kim TY, Liu H, Shi G, Kang GJ, Jiang N, Liu M, Jeong EM, Choi BR, and Dudley SC Jr
- Subjects
- Animals, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac pathology, Cells, Cultured, ELAV-Like Protein 1 biosynthesis, Heart Failure complications, Heart Failure metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Myocardium metabolism, NAV1.5 Voltage-Gated Sodium Channel biosynthesis, Reverse Transcriptase Polymerase Chain Reaction, Arrhythmias, Cardiac genetics, ELAV-Like Protein 1 genetics, Gene Expression Regulation, Heart Failure genetics, Myocardium pathology, NAV1.5 Voltage-Gated Sodium Channel genetics, RNA, Messenger genetics
- Abstract
Background: Downregulated sodium currents in heart failure (HF) have been linked to increased arrhythmic risk. Reduced expression of the messenger RNA (mRNA)-stabilizing protein HuR (also known as ELAVL1) may be responsible for the downregulation of sodium channel gene SCN5A mRNA., Objective: The purpose of this article was to investigate whether HuR regulates SCN5A mRNA expression and whether manipulation of HuR benefits arrhythmia control in HF., Methods: Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of SCN5A. Optical mapping of the intact heart was adopted to study the effects of HuR on the conduction velocity and action potential upstroke in mice with myocardial infarct and HF after injection of AAV9 viral particles carrying HuR., Results: HuR was associated with SCN5A mRNA in cardiomyocytes, and expression of HuR was downregulated in failing hearts. The association of HuR and SCN5A mRNA protected SCN5A mRNA from decay. Injection of AAV9 viral particles carrying HuR increased SCN5A expression in mouse heart tissues after MI. Optical mapping of the intact heart demonstrated that overexpression of HuR improved action potential upstroke and conduction velocity in the infarct border zone, which reduced the risk of reentrant arrhythmia after MI., Conclusion: Our data indicate that HuR is an important RNA-binding protein in maintaining SCN5A mRNA abundance in cardiomyocytes. Reduced expression of HuR may be at least partially responsible for the downregulation of SCN5A mRNA expression in ischemic HF. Overexpression of HuR may rescue decreased SCN5A expression and reduce arrhythmic risk in HF. Increasing mRNA stability to increase ion channel currents may correct a fundamental defect in HF and represent a new paradigm in antiarrhythmic therapy., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
47. Multi-ethnic genome-wide association study for atrial fibrillation.
- Author
-
Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM, Almgren P, Alonso A, Anderson CD, Aragam KG, Arking DE, Barnard J, Bartz TM, Benjamin EJ, Bihlmeyer NA, Bis JC, Bloom HL, Boerwinkle E, Bottinger EB, Brody JA, Calkins H, Campbell A, Cappola TP, Carlquist J, Chasman DI, Chen LY, Chen YI, Choi EK, Choi SH, Christophersen IE, Chung MK, Cole JW, Conen D, Cook J, Crijns HJ, Cutler MJ, Damrauer SM, Daniels BR, Darbar D, Delgado G, Denny JC, Dichgans M, Dörr M, Dudink EA, Dudley SC, Esa N, Esko T, Eskola M, Fatkin D, Felix SB, Ford I, Franco OH, Geelhoed B, Grewal RP, Gudnason V, Guo X, Gupta N, Gustafsson S, Gutmann R, Hamsten A, Harris TB, Hayward C, Heckbert SR, Hernesniemi J, Hocking LJ, Hofman A, Horimoto ARVR, Huang J, Huang PL, Huffman J, Ingelsson E, Ipek EG, Ito K, Jimenez-Conde J, Johnson R, Jukema JW, Kääb S, Kähönen M, Kamatani Y, Kane JP, Kastrati A, Kathiresan S, Katschnig-Winter P, Kavousi M, Kessler T, Kietselaer BL, Kirchhof P, Kleber ME, Knight S, Krieger JE, Kubo M, Launer LJ, Laurikka J, Lehtimäki T, Leineweber K, Lemaitre RN, Li M, Lim HE, Lin HJ, Lin H, Lind L, Lindgren CM, Lokki ML, London B, Loos RJF, Low SK, Lu Y, Lyytikäinen LP, Macfarlane PW, Magnusson PK, Mahajan A, Malik R, Mansur AJ, Marcus GM, Margolin L, Margulies KB, März W, McManus DD, Melander O, Mohanty S, Montgomery JA, Morley MP, Morris AP, Müller-Nurasyid M, Natale A, Nazarian S, Neumann B, Newton-Cheh C, Niemeijer MN, Nikus K, Nilsson P, Noordam R, Oellers H, Olesen MS, Orho-Melander M, Padmanabhan S, Pak HN, Paré G, Pedersen NL, Pera J, Pereira A, Porteous D, Psaty BM, Pulit SL, Pullinger CR, Rader DJ, Refsgaard L, Ribasés M, Ridker PM, Rienstra M, Risch L, Roden DM, Rosand J, Rosenberg MA, Rost N, Rotter JI, Saba S, Sandhu RK, Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA, Seppälä I, Shaffer C, Shah S, Shalaby AA, Shim J, Shoemaker MB, Siland JE, Sinisalo J, Sinner MF, Slowik A, Smith AV, Smith BH, Smith JG, Smith JD, Smith NL, Soliman EZ, Sotoodehnia N, Stricker BH, Sun A, Sun H, Svendsen JH, Tanaka T, Tanriverdi K, Taylor KD, Teder-Laving M, Teumer A, Thériault S, Trompet S, Tucker NR, Tveit A, Uitterlinden AG, Van Der Harst P, Van Gelder IC, Van Wagoner DR, Verweij N, Vlachopoulou E, Völker U, Wang B, Weeke PE, Weijs B, Weiss R, Weiss S, Wells QS, Wiggins KL, Wong JA, Woo D, Worrall BB, Yang PS, Yao J, Yoneda ZT, Zeller T, Zeng L, Lubitz SA, Lunetta KL, and Ellinor PT
- Subjects
- Atrial Fibrillation ethnology, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Humans, Quantitative Trait Loci, Transcriptome, Atrial Fibrillation genetics, Ethnicity genetics
- Abstract
Atrial fibrillation (AF) affects more than 33 million individuals worldwide
1 and has a complex heritability2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.- Published
- 2018
- Full Text
- View/download PDF
48. RNA Binding Protein, HuR, Regulates SCN5A Expression Through Stabilizing MEF2C transcription factor mRNA.
- Author
-
Zhou A, Shi G, Kang GJ, Xie A, Liu H, Jiang N, Liu M, Jeong EM, and Dudley SC Jr
- Subjects
- Binding Sites, Cell Line, ELAV-Like Protein 1 genetics, Humans, MEF2 Transcription Factors genetics, MEF2 Transcription Factors metabolism, NAV1.5 Voltage-Gated Sodium Channel genetics, Promoter Regions, Genetic, RNA, Messenger genetics, Transcriptional Activation, Up-Regulation, ELAV-Like Protein 1 metabolism, Myocytes, Cardiac metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism, RNA Stability, RNA, Messenger metabolism
- Abstract
Background: Although transcription is the initial process of gene expression, posttranscriptional gene expression regulation has also played a critical role for fine-tuning gene expression in a fast, precise, and cost-effective manner. Although the regulation of sodium channel α-subunit ( SCN5A ) mRNA expression has been studied at both transcriptional and pre-mRNA splicing levels, the molecular mechanisms governing SCN5A mRNA expression are far from clear., Methods and Results: Herein, we show that, as evidenced by ribonucleoprotein immunoprecipitation assay, RNA binding protein Hu antigen R/ELAV like RNA binding protein 1 (HuR/ELAVL1) and myocyte enhancer factor-2C (MEF2C) transcription factor mRNA are associated. HuR positively regulated transcription factor MEF2C mRNA expression by protecting its mRNA from degradation. As demonstrated by both chromatin immunoprecipitation-quantitative polymerase chain reaction assay and an electrophoretic mobility shift assay, MEF2C enhanced SCN5A transcription by binding to a putative MEF2C binding site within SCN5A promoter region. Overexpression of HuR increased the expression of SCN5A mRNA, and this effect was attenuated by the presence of MEF2C small interfering RNA in cardiomyocytes., Conclusions: In conclusion, our results suggested that HuR participates in a combined network at the DNA and RNA levels that regulates SCN5A mRNA expression. HuR upregulates MEF2C mRNA expression by protecting MEF2C mRNA from degradation, and consequently, the elevated MEF2C enhances SCN5A mRNA transcription., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
- Published
- 2018
- Full Text
- View/download PDF
49. Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy.
- Author
-
Xie A, Song Z, Liu H, Zhou A, Shi G, Wang Q, Gu L, Liu M, Xie LH, Qu Z, and Dudley SC Jr
- Subjects
- Action Potentials physiology, Animals, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, Cardiomyopathies complications, Cardiomyopathies pathology, Disease Models, Animal, Heart Ventricles pathology, Heart Ventricles physiopathology, Male, Mice, Mice, Inbred C57BL, Myocytes, Cardiac pathology, Sodium-Calcium Exchanger metabolism, Arrhythmias, Cardiac etiology, Cardiomyopathies metabolism, Heart Ventricles metabolism, Mitochondria, Heart metabolism, Myocytes, Cardiac metabolism
- Abstract
Background: Heart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca
2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis., Methods and Results: A model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol-induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L-type Ca2+ currents, increased Na+ -Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes ( P <0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter-specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+ -Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L-type Ca2+ current, consistent with the experimental observations., Conclusions: Mitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)- Published
- 2018
- Full Text
- View/download PDF
50. Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes.
- Author
-
Liu M, Shi G, Zhou A, Rupert CE, Coulombe KLK, and Dudley SC Jr
- Subjects
- Action Potentials drug effects, Adenine analogs & derivatives, Adenine pharmacology, Endoribonucleases metabolism, Humans, Indoles pharmacology, Ion Channel Gating drug effects, Isoproterenol pharmacology, Myocytes, Cardiac drug effects, Protein Serine-Threonine Kinases metabolism, Tunicamycin pharmacology, Ventricular Remodeling drug effects, eIF-2 Kinase metabolism, Down-Regulation drug effects, Induced Pluripotent Stem Cells cytology, Ion Channels metabolism, Myocytes, Cardiac metabolism, Unfolded Protein Response drug effects
- Abstract
Rationale: Heart failure is characterized by electrical remodeling that contributes to arrhythmic risk. The unfolded protein response (UPR) is active in heart failure and can decrease protein levels by increasing mRNA decay, accelerating protein degradation, and inhibiting protein translation., Objective: Therefore, we investigated whether the UPR downregulated cardiac ion channels that may contribute to arrhythmogenic electrical remodeling., Methods: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study cardiac ion channels. Action potentials (APs) and ion channel currents were measured by patch clamp recording. The mRNA and protein levels of channels and the UPR effectors were determined by quantitative RT-PCR and Western blotting. Tunicamycin (TM, 50 ng/mL and 5 μg/mL), GSK2606414 (GSK, 300 nmol/L), and 4μ8C (5 μmol/L) were utilized to activate the UPR, inhibit protein kinase-like ER kinase (PERK) and inositol-requiring protein-1 (IRE1), respectively., Results: TM-induced activation of the UPR caused significant prolongation of the AP duration (APD) and a reduction of the maximum upstroke velocity (dV/dt
max ) of the AP phase 0 in both acute (20-24 h) and chronic treatment (6 days). These changes were explained by reductions in the sodium, L-type calcium, the transient outward and rapidly/slowly activating delayed rectifier potassium currents. Nav 1.5, Cav 1.2, Kv 4.3, and Kv LQT1 channels showed concomitant reductions in mRNA and protein levels under activated UPR. Inhibition of PERK or IRE1 shortened the APD and reinstated dV/dtmax . The PERK branch regulated Nav 1.5, Kv 4.3, hERG, and Kv LQT1. The IRE1 branch regulated Nav 1.5, hERG, Kv LQT1, and Cav 1.2., Conclusions: Activated UPR downregulates all major cardiac ion currents and results in electrical remodeling in hiPSC-CMs. Both PERK and IRE1 branches downregulate Nav 1.5, hERG, and Kv LQT1. The PERK branch specifically downregulates Kv 4.3, while the IRE1 branch downregulates Cav 1.2. Therefore, the UPR contributed to electrical remodeling, and targeting the UPR might be anti-arrhythmic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.