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  • 1
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    Spontaneously beating cardiomyocytes derived from white mature adipocytes
    Oxford University Press (OUP) ; 2010
    In:  Cardiovascular Research Vol. 85, No. 1 ( 2010-1-1), p. 17-27
    Details
    In: Cardiovascular Research, Oxford University Press (OUP), Vol. 85, No. 1 ( 2010-1-1), p. 17-27
    Type of Medium: Online Resource
    ISSN: 1755-3245 , 0008-6363
    URL: Article
    DOI: 10.1093/cvr/cvp267
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2010
    detail.hit.zdb_id: 1499917-1
    detail.hit.zdb_id: 80340-6
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  • 2
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    Return of calcium: Manipulating intracellular calcium to prevent cardiac pathologies
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 16 ( 2004-04-20), p. 5697-5698
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 16 ( 2004-04-20), p. 5697-5698
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0401518101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
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    Abstract 16705: Abnormal Atrial Substrate Underlies Atrial Fibrillation in Rats With Heart Failure With Preserved Ejection Fraction
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 138, No. Suppl_1 ( 2018-11-06)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. Suppl_1 ( 2018-11-06)
    Abstract: Introduction: Atrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF), and heralds a poor prognosis, but the underlying mechanisms are not well studied. Hypothesis: We tested the hypothesis that prolonged atrial effective refractory period (AERP) and slow conduction predispose to AF in HFpEF rats. Methods: Dahl salt-sensitive rats were fed a high-salt diet from 7 weeks of age to induce HFpEF (n=32). Normal-salt fed rats were used as controls (n=26). Echocardiograms at 14-15 weeks of age were used to verify diastolic dysfunction and to assess left atrial size. Electrical phenotype was probed by electrocardiography (P wave duration, PR interval) and in vivo provocative electrophysiological testing (using a 1.5 French catheter) in echo-verified HFpEF and control rats. Optical mapping was performed to measure action potential duration (APD) and conduction velocity (CV) in ex vivo HFpEF and control hearts. Results: High-salt fed rats showed decreased E/E’ ratio with preserved ejection fraction (60-70%), hence were diagnosed with HFpEF. Left atrial size was increased in rats with HFpEF compared to controls (29.1±0.8 vs. 19.5±1.1 mm 2 , p 〈 0.001). P waves were prolonged in HFpEF rats compared to controls (17.8±0.5 vs. 13.5±0.6 ms, p 〈 0.001), as was the PR interval (57.8±1.1 vs. 48.8±1.3 ms, p 〈 0.001). AF induction after burst pacing was much easier in HFpEF rats (27/32 HFpEF rats compared to 5/26 controls, 84.4 vs. 19.2%, p 〈 0.001). Atrial effective refractory period (AERP) was prolonged in HFpEF rats compared to controls (37.8±1.7 vs. 30.6±1.8 ms, p 〈 0.01). During optical mapping, APD was prolonged in left atrium of HFpEF rats compared to controls (APD90 42.3±3.6 vs. 30.9±2.2 ms, p 〈 0.05), atrial CV was slower in HFpEF rats compared to controls (0.31±0.03 vs. 0.46±0.02 mm/ms, p 〈 0.01). Conclusions: Rats with HFpEF were at increased risk of inducible AF after burst pacing. Decreased atrial conduction velocity and prolonged AERP contribute to the pathogenesis of AF in HFpEF.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.138.suppl_1.16705
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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  • 4
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    Role of Inotropic Agents in the Treatment of Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Circulation Vol. 121, No. 14 ( 2010-04-13), p. 1655-1660
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 121, No. 14 ( 2010-04-13), p. 1655-1660
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.109.899294
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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  • 5
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    Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Research Vol. 129, No. 12 ( 2021-12-03), p. 1125-1140
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 129, No. 12 ( 2021-12-03), p. 1125-1140
    Abstract: Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca 2+ -sensitivity, and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Objective: Phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome were analyzed. Methods and Results: Dahl salt–sensitive rats fed a high-salt diet, with echocardiographically verified diastolic dysfunction, were randomly assigned to either intracoronary CDCs or placebo. Dahl salt–sensitive rats receiving low salt diet served as controls. Protein and phosphorylated Ser, Thr, and Tyr residues from left ventricular tissue were quantified by mass spectrometry. HFpEF hearts exhibited extensive hyperphosphorylation with 98% of the 529 significantly changed phospho-sites increased compared with control. Of those, 39% were located within the sarcomeric subproteome, with a large group of proteins located or associated with the Z-disk. CDC treatment partially reverted the hyperphosphorylation, with 85% of the significantly altered 76 residues hypophosphorylated. Bioinformatic upstream analysis of the differentially phosphorylated protein residues revealed PKC as the dominant putative regulatory kinase. PKC isoform analysis indicated increases in PKC α, β, and δ concentration, whereas CDC treatment led to a reversion of PKCβ. Use of PKC isoform specific inhibition and overexpression of various PKC isoforms strongly suggests that PKCβ is the dominant kinase involved in hyperphosphorylation in HFpEF and is altered with CDC treatment. Conclusions: Increased protein phosphorylation at the Z-disk is associated with diastolic dysfunction, with PKC isoforms driving most quantified phosphorylation changes. Because CDCs reverse the key abnormalities in HFpEF and selectively reverse PKCβ upregulation, PKCβ merits being classified as a potential therapeutic target in HFpEF, a disease notoriously refractory to medical intervention.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.119.316311
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 80100-8
    detail.hit.zdb_id: 1467838-X
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  • 6
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    Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 145, No. 1 ( 2022-01-04), p. 45-60
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 145, No. 1 ( 2022-01-04), p. 45-60
    Abstract: The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. Methods: Dahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. Results: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired β-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the “membrane clock” (ion channels) and the “Ca 2+ clock” (spontaneous Ca 2+ release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. Conclusions: Chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.121.054976
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
    detail.hit.zdb_id: 80099-5
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  • 7
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    Activation of reverse Na + -Ca 2+ exchange by the Na + current augments the cardiac Ca 2+ transient: evidence from NCX knockout mice : I Na -induced NCX and excitation-contraction coupling
    Wiley ; 2010
    In:  The Journal of Physiology Vol. 588, No. 17 ( 2010-09-01), p. 3267-3276
    Details
    In: The Journal of Physiology, Wiley, Vol. 588, No. 17 ( 2010-09-01), p. 3267-3276
    Type of Medium: Online Resource
    ISSN: 0022-3751
    URL: Article
    DOI: 10.1113/jphysiol.2010.187708
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 3115-X
    SSG: 12
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  • 8
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    Regulation of calcium clock‐mediated pacemaking by inositol‐1,4,5‐trisphosphate receptors in mouse sinoatrial nodal cells
    Wiley ; 2015
    In:  The Journal of Physiology Vol. 593, No. 12 ( 2015-06-15), p. 2649-2663
    Details
    In: The Journal of Physiology, Wiley, Vol. 593, No. 12 ( 2015-06-15), p. 2649-2663
    Abstract: Inositol‐1,4,5‐trisphosphate receptors (IP 3 Rs) modulate pacemaking in embryonic heart, but their role in adult sinoatrial node (SAN) pacemaking is uncertain. We found that stimulation of IP 3 Rs accelerates spontaneous pacing rate in isolated mouse SAN cells, whereas inhibition of IP 3 Rs slows pacing. In atrial‐specific sodium‐calcium exchanger (NCX) knockout (KO) SAN cells, where the Ca 2+ clock is uncoupled from the membrane clock, IP 3 R agonists and antagonists modulate the rate of spontaneous Ca 2+ waves, suggesting that IP 3 R‐mediated Ca 2+ release modulates the Ca 2+ clock. IP 3 R modulation also regulates Ca 2+ spark parameters, a reflection of ryanodine receptor open probability, consistent with the effect of IP 3 signalling on Ca 2+ clock frequency. Modulation of Ca 2+ clock frequency by IP 3 signalling in NCX KO SAN cells demonstrates that the effect is independent of NCX. These findings support development of IP 3 signalling modulators for regulation of heart rate, particularly in heart failure where IP 3 Rs are upregulated. Abstract Cardiac pacemaking initiated by the sinus node is attributable to the interplay of several membrane currents. These include the depolarizing ‘funny current’ ( I f ) and the sodium‐calcium exchanger current ( I NCX ). The latter is activated by ryanodine receptor (RyR)‐mediated calcium (Ca 2+ ) release from the sarcoplasmic reticulum (SR). Another SR Ca 2+ release channel, the inositol‐1,4,5‐triphosphate receptor (IP 3 R), has been implicated in the generation of spontaneous Ca 2+ release in atrial and ventricular cardiomyocytes. Whether IP 3 R‐mediated Ca 2+ release also influences SAN automaticity is controversial, in part due to the confounding influence of periodic Ca 2+ flux through the sarcolemma accompanying each beat. We took advantage of atrial‐specific sodium–calcium exchanger (NCX) knockout (KO) SAN cells to study the influence of IP 3 signalling on cardiac pacemaking in a system where periodic intracellular Ca 2+ cycling persists despite the absence of depolarization or Ca 2+ flux across the sarcolemma. We recorded confocal line scans of spontaneous Ca 2+ release in WT and NCX KO SAN cells in the presence or absence of an IP 3 R blocker (2‐aminoethoxydiphenyl borate, 2‐APB), or during block of IP 3 production by the phospholipase C inhibitor U73122. 2‐APB and U73122 decreased the frequency of spontaneous Ca 2+ transients and waves in WT and NCX KO cells, respectively. Alternatively, increased IP 3 production induced by phenylephrine increased Ca 2+ transient and wave frequency. We conclude that IP 3 R‐mediated SR Ca 2+ flux is crucial for initiating and modulating the RyR‐mediated Ca 2+ cycling that regulates SAN pacemaking. Our results in NCX KO SAN cells also demonstrate that RyRs, but not NCX, are required for IP 3 to modulate Ca 2+ clock frequency.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    URL: Article
    DOI: 10.1113/jphysiol.2015.593.issue-12
    DOI: 10.1113/JP270082
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1475290-6
    detail.hit.zdb_id: 3115-X
    SSG: 12
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  • 9
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    Mice overexpressing the cardiac sodium‐calcium exchanger: defects in excitation–contraction coupling
    Wiley ; 2004
    In:  The Journal of Physiology Vol. 554, No. 3 ( 2004-02), p. 779-789
    Details
    In: The Journal of Physiology, Wiley, Vol. 554, No. 3 ( 2004-02), p. 779-789
    Abstract: Homozygous overexpression of the cardiac Na + –Ca 2+ exchanger causes cardiac hypertrophy and increases susceptibility to heart failure in response to stress. We studied the functional effects of homozygous overexpression of the exchanger at the cellular level in isolated mouse ventricular myocytes. Compared with patch‐clamped myocytes from wild‐type animals, non‐failing myocytes from homozygous transgenic mice exhibited increased cell capacitance (from 208 ± 16 pF to 260 ± 15 pF, P 〈 0.05 ). Intracellular Ca 2+ oscillations were readily elicited in homozygous transgenic animals during depolarizations to +80 mV, consistent with rapid Ca 2+ overload caused by reverse Na + –Ca 2+ exchange. After normalization to cell capacitance, transgenic myocytes had significant increases in Na + –Ca 2+ exchange activity (318%) and peak L ‐type Ca 2+ current (8.2 ± 0.7 pA pF −1 at 0 mV test potential) compared to wild‐type (5.8 ± 0.9 pA pF −1 at 0 mV, P 〈 0.02 ). The peak Ca 2+ current amplitude and its rate of inactivation could be modulated by rapid reversible block of the exchanger. Thus, we describe an unexpected direct influence of Na + –Ca 2+ exchange activity on the L ‐type Ca 2+ channel. Despite intact sarcoplasmic reticular Ca 2+ content and larger peak L ‐type Ca 2+ currents, homozygous transgenic animals exhibited smaller Ca 2+ transients (Δ[Ca 2+ ] i = 466 ± 48 n m in transgenics versus 892 ± 104 n m in wild‐type, P 〈 0.0005) and substantially reduced gain of excitation–contraction coupling. These alterations in excitation–contraction coupling may underlie the tendency for these animals to develop heart failure following haemodynamic stress.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Article
    DOI: 10.1113/jphysiol.2003.055046
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2004
    detail.hit.zdb_id: 1475290-6
    detail.hit.zdb_id: 3115-X
    SSG: 12
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  • 10
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    Induction of Monocyte Binding to Endothelial Cells by MM-LDL : Role of Lipoxygenase Metabolites
    Ovid Technologies (Wolters Kluwer Health) ; 1999
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 19, No. 3 ( 1999-03), p. 680-686
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 19, No. 3 ( 1999-03), p. 680-686
    Abstract: Abstract —Treatment of human aortic endothelial cells (EC) with minimally oxidized LDL (or minimally modified LDL, MM-LDL) produces a specific pattern of endothelial cell activation distinct from that produced by LPS, tumor necrosis factor-α, and interleukin-1, but similar to other agents that elevate cAMP. The current studies focus on the signal transduction pathways by which MM-LDL activates EC to bind monocytes. We now demonstrate that, in addition to an elevation of cAMP, lipoxygenase products are necessary for the MM-LDL response. Treatment of EC with inhibitors of the lipoxygenase pathway, 5,8,11,14-eicosatetraynoic acid (ETYA) or cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), blocked monocyte binding in MM-LDL-treated EC (MM-LDL=118±13%; MM-LDL+ETYA=33±4%; MM-LDL+CDC=23±4% increase in monocyte binding) without reducing cAMP levels. To further investigate the role of the lipoxygenase pathway, cellular phospholipids were labeled with arachidonic acid. Treatment of cells for 4 hours with 50 to 100 μg/mL MM-LDL, but not native LDL, caused a 60% increase in arachidonate release into the medium and increased the intracellular formation of 12(S)-HETE (≈100% increase). There was little 15(S)-HETE present, and no increase in its levels was observed. We demonstrated that 12(S)-HETE reversed the inhibitory effect of CDC. We also observed a 70% increase in the formation of 11,12-epoxyeicosatrienoic acid (11,12-EET) in cells treated with MM-LDL. To determine the mechanism of arachidonate release induced by MM-LDL, we examined the effects of MM-LDL on intracellular calcium levels. Treatment of EC with both native LDL and MM-LDL caused a rapid release of intracellular calcium from internal stores. However, several pieces of evidence suggest that calcium release alone does not explain the increased arachidonate release in MM-LDL-treated cells. The present studies suggest that products of 12-lipoxygenase play an important role in MM-LDL action on the induction of monocyte binding to EC.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.19.3.680
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1999
    detail.hit.zdb_id: 1221433-4
    detail.hit.zdb_id: 1494427-3
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