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Sönmez MI, Goldack S, Nurkkala E, Schulz C, Klampe B, Schulze T, Hansen A, Eschenhagen T, Koivumäki J, Christ T. Human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium. Europace 2024; 26:euae140. [PMID: 38788213 PMCID: PMC11167676 DOI: 10.1093/europace/euae140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/23/2024] [Indexed: 05/26/2024] Open
Abstract
AIMS Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfil this expectation, the electrophysiology of hiPSC-aCM should closely resemble the situation in the human atrium. Data on the contribution of the slowly activating delayed rectifier currents (IKs) to repolarization are lacking for both human atrium and hiPSC-aCM. METHODS AND RESULTS Human atrial tissues were obtained from patients with sinus rhythm (SR) or atrial fibrillation (AF). Currents were measured in human atrial cardiomyocytes (aCM) and compared with hiPSC-aCM and used to model IKs contribution to action potential (AP) shape. Action potential was recorded by sharp microelectrodes. HMR-1556 (1 µM) was used to identify IKs and to estimate IKs contribution to repolarization. Less than 50% of hiPSC-aCM and aCM possessed IKs. Frequency of occurrence, current densities, activation/deactivation kinetics, and voltage dependency of IKs did not differ significantly between hiPSC-aCM and aCM, neither in SR nor AF. β-Adrenoceptor stimulation with isoprenaline did not increase IKs neither in aCM nor in hiPSC-aCM. In tissue from SR, block of IKs with HMR-1556 did not lengthen the action potential duration, even when repolarization reserve was reduced by block of the ultra-rapid repolarizing current with 4-aminopyridine or the rapidly activating delayed rectifier potassium outward current with E-4031. CONCLUSION I Ks exists in hiPSC-aCM with biophysics not different from aCM. As in adult human atrium (SR and AF), IKs does not appear to relevantly contribute to repolarization in hiPSC-aCM.
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Affiliation(s)
- Muhammed Ikbal Sönmez
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
| | - Silvana Goldack
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
- Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Elina Nurkkala
- Tech Unit and Centre of Excellence in Body-on-Chip Research (CoEBoC), Faculty of Medicine and Health Technology, Tampere University, Tampere, Finnland
| | - Carl Schulz
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
| | - Birgit Klampe
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
| | - Thomas Schulze
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
| | - Arne Hansen
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
| | - Thomas Eschenhagen
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
| | - Jussi Koivumäki
- Tech Unit and Centre of Excellence in Body-on-Chip Research (CoEBoC), Faculty of Medicine and Health Technology, Tampere University, Tampere, Finnland
| | - Torsten Christ
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Martinistrasse 52, 20246 Hamburg, Germany
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Kaur G, Verma SK, Singh D, Singh NK. Role of G-Proteins and GPCRs in Cardiovascular Pathologies. Bioengineering (Basel) 2023; 10:bioengineering10010076. [PMID: 36671648 PMCID: PMC9854459 DOI: 10.3390/bioengineering10010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/19/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Cell signaling is a fundamental process that enables cells to survive under various ecological and environmental contexts and imparts tolerance towards stressful conditions. The basic machinery for cell signaling includes a receptor molecule that senses and receives the signal. The primary form of the signal might be a hormone, light, an antigen, an odorant, a neurotransmitter, etc. Similarly, heterotrimeric G-proteins principally provide communication from the plasma membrane G-protein-coupled receptors (GPCRs) to the inner compartments of the cells to control various biochemical activities. G-protein-coupled signaling regulates different physiological functions in the targeted cell types. This review article discusses G-proteins' signaling and regulation functions and their physiological relevance. In addition, we also elaborate on the role of G-proteins in several cardiovascular diseases, such as myocardial ischemia, hypertension, atherosclerosis, restenosis, stroke, and peripheral artery disease.
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Affiliation(s)
- Geetika Kaur
- Integrative Biosciences Center, Wayne State University, Detroit, MI 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48202, USA
| | - Shailendra Kumar Verma
- Integrative Biosciences Center, Wayne State University, Detroit, MI 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48202, USA
| | - Deepak Singh
- Lloyd Institute of Engineering and Technology, Greater Noida 201306, India
| | - Nikhlesh K. Singh
- Integrative Biosciences Center, Wayne State University, Detroit, MI 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48202, USA
- Correspondence:
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Petersen J, Kloth B, Iqbal S, Reichenspurner H, Geelhoed B, Schnabel R, Eschenhagen T, Christ T, Girdauskas E. Blunted beta-adrenoceptor-mediated inotropy in valvular cardiomyopathy: another piece of the puzzle in human aortic valve disease. Eur J Cardiothorac Surg 2021; 60:56-63. [PMID: 33619556 DOI: 10.1093/ejcts/ezab004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/29/2020] [Accepted: 12/15/2020] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Heart failure induced by valvular cardiomyopathy occurs in a substantial proportion of patients undergoing heart valve surgery. We aimed (i) to quantify beta-adrenoceptor (beta-AR) function by measuring the inotropic effect of isoprenaline in left ventricular (LV) tissue and (ii) to correlate beta-AR-mediated inotropy with clinical markers of heart failure. METHODS A total of 179 LV myocardial samples were obtained from 104 consecutive patients who underwent aortic valve (AV) surgery between 2017 and 2019. Beta-ARs were stimulated by increasing the concentrations of isoprenaline, followed by a single high concentration of forskolin and calcium. Beta-AR sensitivity was estimated as the concentration to achieve half maximum effects (EC50). Maximum effect size was calculated as the relative beta-AR-mediated inotropic response compared to the force in the presence of high calcium [FISO/Ca (%)]. In vitro data were correlated with the clinical indicators of LV disease. RESULTS FISO/Ca was independent of age and sex and amounted to 79.6 ± 20.5%. In a multivariate regression model, we found a significant inverse association between FISO/Ca and preoperative left ventricular end-diastolic diameter increase per 10 mm (OR -9.24, 95% CI -16.66 to -1.82; P = 0.015). Furthermore, patients with end-stage heart failure showed a strong tendency towards more severe reduction of max beta-AR response, as indicated by reduced FISO/Ca in a multivariate model (OR -29.60, 95% CI -61.92 to 2.72; P = 0.055). CONCLUSIONS Our study indicates that in vitro myocardial contractility testing can quantify beta-AR dysfunction in patients with AV disease. We found a significant association between reduced beta-AR sensitivity and increased LV diameter, which may indicate a role of beta-AR dysfunction in the development of heart failure in patients with AV disease.
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Affiliation(s)
- Johannes Petersen
- Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Benjamin Kloth
- Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Shahria Iqbal
- Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Hermann Reichenspurner
- Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Bastian Geelhoed
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Renate Schnabel
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Department of Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Thomas Eschenhagen
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Torsten Christ
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.,Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Evaldas Girdauskas
- Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
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Pecha S, Geelhoed B, Kempe R, Berk E, Engel A, Girdauskas E, Reichenspurner H, Ravens U, Kaumann A, Eschenhagen T, Schnabel RB, Christ T. No impact of sex and age on beta-adrenoceptor-mediated inotropy in human right atrial trabeculae. Acta Physiol (Oxf) 2021; 231:e13564. [PMID: 33002334 DOI: 10.1111/apha.13564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/30/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022]
Abstract
AIM There is an increasing awareness of the impact of age and sex on cardiovascular diseases (CVDs). Differences in physiology are suspected. Beta-adrenoceptors (beta-ARs) are an important drug target in CVD and potential differences might have significant impact on the treatment of many patients. To investigate whether age and sex affects beta-AR function, we analysed a large data set on beta-AR-induced inotropy in human atrial trabeculae. METHODS We performed multivariable analysis of individual atrial contractility data from trabeculae obtained during heart surgery of patients in sinus rhythm (535 trabeculae from 165 patients). Noradrenaline or adrenaline were used in the presence of the beta2 -selective antagonist (ICI 118 551, 50 nmol/L) or the beta1 -selective antagonist (CGP 20712A, 300 nmol/L) to stimulate beta1 -AR or beta2 -AR respectively. Agonist concentration required to achieve half-maximum inotropic effects (EC50 ) was taken as a measure of beta-AR sensitivity. RESULTS Impact of clinical variables was modelled using multivariable mixed model regression. As previously reported, chronic treatment with beta-blockers sensitized beta-AR. However, there was no significant interaction between basal force, maximum force and beta-AR sensitivity when age and sex were modelled continuously. In addition, there was no statistically significant effect of body mass index or diabetes on atrial contractility. CONCLUSION Our large, multivariable analysis shows that neither age nor sex affects beta-AR-mediated inotropy or catecholamine sensitivity in human atrial trabeculae. These findings may have important clinical implications because beta-ARs, as a common drug target in CVD and heart failure, do not behave differently in women and men across age decades.
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Affiliation(s)
- Simon Pecha
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Department of Cardiovascular Surgery University Heart and Vascular Center Hamburg Germany
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
| | - Bastiaan Geelhoed
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
- Department of General and Interventional Cardiology University Heart and Vascular Center Hamburg Germany
| | - Romy Kempe
- Department of Pharmacology Dresden University of Technology Dresden Germany
| | - Emanuel Berk
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Department of Pharmacology Dresden University of Technology Dresden Germany
- Department of Internal Medicine St. Joseph‐Stift Hospital Dresden Germany
| | - Andreas Engel
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Department of Pharmacology Dresden University of Technology Dresden Germany
| | - Evaldas Girdauskas
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Department of Cardiovascular Surgery University Heart and Vascular Center Hamburg Germany
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
| | - Hermann Reichenspurner
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Department of Cardiovascular Surgery University Heart and Vascular Center Hamburg Germany
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
| | - Ursula Ravens
- Institute of Experimental Cardiovascular Medicine University Heart Center Freiburg‐Bad KrozingenUniversity of Freiburg Freiburg Germany
| | - Alberto Kaumann
- Department of Pharmacology University of Murcia Murcia Spain
| | - Thomas Eschenhagen
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
| | - Renate B. Schnabel
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
- Department of General and Interventional Cardiology University Heart and Vascular Center Hamburg Germany
| | - Torsten Christ
- Institute of Experimental Pharmacology and Toxicology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- DZHK (German Centre for Cardiovascular Research) Hamburg Germany
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Velmurugan BK, Baskaran R, Huang CY. Detailed insight on β-adrenoceptors as therapeutic targets. Biomed Pharmacother 2019; 117:109039. [PMID: 31176173 DOI: 10.1016/j.biopha.2019.109039] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/15/2019] [Accepted: 05/29/2019] [Indexed: 01/08/2023] Open
Abstract
Human G protein-coupled receptors (GPCRs), especially adrenoceptors, play a crucial role in maintaining important physiological activities including cardiovascular and pulmonary functions. Among all adrenoceptors, β-adrenoceptors are the best characterized GPCRs and possess distinctive features as drug targets. Similarly, ligands that activate/deactivate β-adrenoceptors also hold a significant position in the field of biomarker identification and drug discovery. Several studies regarding molecular characterization of the β-adrenoceptor ligands have revealed that ligands with abilities to inhibit basal or intrinsic receptor activity or prevent receptor desensitization are particularly important to efficiently manage detrimental health conditions, including chronic heart failure, asthma, chronic obstructive pulmonary disease, obesity, and diabetes. Given the importance of β-adrenoceptors as molecular targets for many pathological conditions, this review aims to provide a detailed insight on the structural and functional aspects of β-adrenoceptors, with a particular emphasis on their importance as biomarkers and therapeutic targets.
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Affiliation(s)
- Bharath Kumar Velmurugan
- Toxicology and Biomedicine Research group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Rathinasamy Baskaran
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
| | - Chih-Yang Huang
- Cardiovascular research center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan.
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Yu SMW, Jean-Charles PY, Abraham DM, Kaur S, Gareri C, Mao L, Rockman HA, Shenoy SK. The deubiquitinase ubiquitin-specific protease 20 is a positive modulator of myocardial β 1-adrenergic receptor expression and signaling. J Biol Chem 2018; 294:2500-2518. [PMID: 30538132 DOI: 10.1074/jbc.ra118.004926] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 11/23/2018] [Indexed: 12/27/2022] Open
Abstract
Reversible ubiquitination of G protein-coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial β1-adrenergic receptors (β1ARs) is unknown. We report that ubiquitin-specific protease 20 (USP20) deubiquitinates and attenuates lysosomal trafficking of the β1AR. β1AR-induced phosphorylation of USP20 Ser-333 by protein kinase A-α (PKAα) was required for optimal USP20-mediated regulation of β1AR lysosomal trafficking. Both phosphomimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity. However, unlike USP20 WT and S333D, the S333A mutant associated poorly with the β1AR and failed to deubiquitinate the β1AR. USP20-KO mice showed normal baseline systolic function but impaired β1AR-induced contractility and relaxation. Dobutamine stimulation did not increase cAMP in USP20-KO left ventricles (LVs), whereas NKH477-induced adenylyl cyclase activity was equivalent to WT. The USP20 homolog USP33, which shares redundant roles with USP20, had no effect on β1AR ubiquitination, but USP33 was up-regulated in USP20-KO hearts suggesting compensatory regulation. Myocardial β1AR expression in USP20-KO was drastically reduced, whereas β2AR expression was maintained as determined by radioligand binding in LV sarcolemmal membranes. Phospho-USP20 was significantly increased in LVs of wildtype (WT) mice after a 1-week catecholamine infusion and a 2-week chronic pressure overload induced by transverse aortic constriction (TAC). Phospho-USP20 was undetectable in β1AR KO mice subjected to TAC, suggesting a role for USP20 phosphorylation in cardiac response to pressure overload. We conclude that USP20 regulates β1AR signaling in vitro and in vivo Additionally, β1AR-induced USP20 phosphorylation may serve as a feed-forward mechanism to stabilize β1AR expression and signaling during pathological insults to the myocardium.
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Affiliation(s)
- Samuel Mon-Wei Yu
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Pierre-Yves Jean-Charles
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Dennis M Abraham
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Suneet Kaur
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Clarice Gareri
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Lan Mao
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Howard A Rockman
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
| | - Sudha K Shenoy
- From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
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Abstract
BACKGROUND Cirrhotic cardiomyopathy is characterized by an attenuated contractile response to stress. Long-term exposure of β-adrenergic receptors to persistently high levels of catecholamines has been implicated in its pathogenesis. We hypothesized that β-blockade with metoprolol could reverse the changes in heart function and morphology in cirrhotic cardiomyopathy. PATIENTS AND METHODS In this prospective randomized trial, we included 78 patients aged between 18 and 60 years with abnormal cardiac output response under dobutamine stress echocardiography, without primary cardiac disease or a history of alcohol intake. Patients were assigned randomly to receive metoprolol or placebo for 6 months. The primary endpoint was the improvement in cardiac output response to stress, measured by an increase in the left ventricle stroke volume more than 30%. RESULTS Three (7.3%) patients in the metoprolol group and nine (24.3%) patients in the placebo group showed improved stroke volume (P=0.057). Diastolic dysfunction was found in two (4.8%) patients before and in five (15.6%) patients after therapy in the metoprolol group, and in 10 (27%) patients before and nine (31%) patients after therapy in the placebo group (P=0.67). After treatment, no echocardiography parameter of morphology was significantly different between metoprolol or placebo groups. No significant differences were observed in noradrenaline, plasma renin activity, and troponin levels between groups. Cirrhosis-related clinical events, including hospitalizations and mortality, were not significantly different between the two groups. Six months of therapy with β-blocker did not ameliorate heart function and morphology in patients with cirrhotic cardiomyopathy.
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Muscle Atrophy: Present and Future. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1088:605-624. [DOI: 10.1007/978-981-13-1435-3_29] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Jaiswal A, Nguyen VQ, Le Jemtel TH, Ferdinand KC. Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure. World J Cardiol 2016; 8:401-412. [PMID: 27468333 PMCID: PMC4958691 DOI: 10.4330/wjc.v8.i7.401] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 04/28/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
In advanced heart failure (HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase III inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guideline-directed HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker (BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF.
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Molenaar P, Christ T, Hussain RI, Engel A, Berk E, Gillette KT, Chen L, Galindo-Tovar A, Krobert KA, Ravens U, Levy FO, Kaumann AJ. PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. Br J Pharmacol 2014; 169:528-38. [PMID: 23489141 DOI: 10.1111/bph.12167] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 12/30/2012] [Accepted: 01/02/2013] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND AND PURPOSE PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. EXPERIMENTAL APPROACH Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁ adrenoceptors (β₂ adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂ adrenoceptors (β₁ adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC₅₀s. KEY RESULTS Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. CONCLUSIONS AND IMPLICATIONS Metoprolol induces a control by PDE3 of ventricular effects mediated through both β₁ and β₂ adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β₂ adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.
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Affiliation(s)
- Peter Molenaar
- Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
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Molenaar P, Christ T, Berk E, Engel A, Gillette KT, Galindo-Tovar A, Ravens U, Kaumann AJ. Carvedilol induces greater control of β2- than β 1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium. Naunyn Schmiedebergs Arch Pharmacol 2014; 387:629-40. [PMID: 24668024 DOI: 10.1007/s00210-014-0974-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 03/09/2014] [Indexed: 12/30/2022]
Abstract
The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 μM) or PDE4-selective inhibitor rolipram (1 μM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1-adrenoceptors (β2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2-adrenoceptors (β1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from -logEC50s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β2-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β2-adrenoceptors compared to β1-adrenoceptors. The β2-adrenoceptor-selectivity of carvedilol may provide protection against β2-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.
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Affiliation(s)
- Peter Molenaar
- Faculty of Health, QUT, Brisbane; School of Medicine, University of Queensland and Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, 4032, Australia,
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12
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13
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Li-Sha G, Yi-He C, Na-Dan Z, Teng Z, Yue-Chun L. Effects of carvedilol treatment on cardiac cAMP response element binding protein expression and phosphorylation in acute coxsackievirus B3-induced myocarditis. BMC Cardiovasc Disord 2013; 13:100. [PMID: 24225056 PMCID: PMC3840656 DOI: 10.1186/1471-2261-13-100] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 11/12/2013] [Indexed: 11/21/2022] Open
Abstract
Background The role of β-adrenergic stimulation on viral myocarditis has been investigated in animal models of viral myocarditis. Excess stimulation of β-adrenergic receptors by catecholamines causes phosphorylation/activation of cAMP response element binding protein (CREB) by the cAMP signaling pathway. CREB as an important regulator of gene expression mediates the cardiovascular remodeling process and promotes anti-inflammatory immune responses. However, the CREB expression and phosphorylation have not been studied, and the effects of carvedilol (a nonselective β-adrenoceptor antagonist) on the CREB has not been investigated in the setting of acute viral myocarditis. Methods This study was therefore designed to examine the effects of carvedilol on the transcriptional factor CREB in a murine model of acute viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), effects of carvedilol on plasma noradrenaline, heart rate and blood pressure, myocardial histopathological changes and fibrosis, cardiomyocyte apoptosis, cardiac CREB and phosphorylated CREB, cytokine levels, and viral RNA were studied. Results The expression and phosphorylation of CREB were decreased with concomitant increase of IL-6 and TNF-α in murine coxsackievirus-induced acute viral myocarditis. The levels of IL-6 and TNF-α were correlated with the expression of CREB or phosphorylated CREB. Carvedilol increased the cardiac CREB expression and phosphorylation and decreased the plasma catecholamine levels and the production of IL-6 and TNF-α with amelioration of acute viral myocarditis. Conclusion These results show that CREB may be involved in the pathophysiology of viral myocarditis and carvedilol exerts some of its beneficial effects by increasing the CREB expression and phosphorylation.
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Affiliation(s)
| | | | | | | | - Li Yue-Chun
- Department of Cardiology, Second Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, China.
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Kashihara T, Nakada T, Shimojo H, Horiuchi-Hirose M, Gomi S, Shibazaki T, Sheng X, Hirose M, Hongo M, Yamada M. Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca2+ channel activity through phosphatases in heart failure. Am J Physiol Heart Circ Physiol 2012; 302:H1645-54. [DOI: 10.1152/ajpheart.00589.2011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
L-type Ca2+ channels (LTCCs) play an essential role in the excitation-contraction coupling of ventricular myocytes. We previously found that t-tubular (TT) LTCC current density was halved by the activation of protein phosphatase (PP)1 and/or PP2A, whereas surface sarcolemmal (SS) LTCC current density was increased by the inhibition of PP1 and/or PP2A activity in failing ventricular myocytes of mice chronically treated with isoproterenol (ISO mice). In the present study, we examined the possible involvement of inhibitory heterotrimeric G proteins (Gi/o) in these abnormalities by chronically administrating pertussis toxin (PTX) to ISO mice (ISO + PTX mice). Compared with ISO mice, ISO + PTX mice exhibited significantly higher fractional shortening of the left ventricle. The expression level of Gαi2 proteins was not altered by the treatment of mice with ISO and/or PTX. ISO + PTX myocytes had normal TT and SS LTCC current densities because they had higher and lower availability and/or open probability of TT and SS LTCCs than ISO myocytes, respectively. A selective PKA inhibitor, H-89, did not affect LTCC current densities in ISO + PTX myocytes. A selective PP2A inhibitor, fostriecin, did not affect SS or TT current density in control or ISO + PTX myocytes but significantly increased TT but not SS LTCC current density in ISO myocytes. These results indicate that chronic receptor-mediated activation of Gi/o in vivo decreases basal TT LTCC activity by activating PP2A and increases basal SS LTCC activity by inhibiting PP1 without modulating PKA in heart failure.
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Affiliation(s)
| | | | | | | | - Simmon Gomi
- Departments of Molecular Pharmacology,
- Cardiovascular Medicine, Shinshu University School of Medicine, Nagano
| | - Toshihide Shibazaki
- Departments of Molecular Pharmacology,
- Discovery Research Laboratory II, Research and Development, Kissei Pharmaceutical Company, Limited, Azumino, Nagano
| | - Xiaona Sheng
- Departments of Molecular Pharmacology,
- Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Nagano
| | - Masamichi Hirose
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Iwate Medical University, Iwate; and
| | - Minoru Hongo
- Department of Cardiovascular Medicine, Shinshu University School of Health Science, Nagano, Japan
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Abstract
β-adrenergic receptor (βAR) stimulation by the sympathetic nervous system or circulating catecholamines is broadly involved in peripheral blood circulation, metabolic regulation, muscle contraction, and central neural activities. In the heart, acute βAR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation, whereas chronic βAR stimulation plays an important role in physiological and pathological cardiac remodeling.There are three βAR subtypes, β(1)AR, β(2)AR and β(3)AR, in cardiac myocytes. Over the past two decades, we systematically investigated the molecular and cellular mechanisms underlying the different even opposite functional roles of β(1)AR and β(2)AR subtypes in regulating cardiac structure and function, with keen interest in the development of novel therapies based on our discoveries. We have made three major discoveries, including (1) dual coupling of β(2)AR to G(s) and G(i) proteins in cardiomyocytes, (2) cardioprotection by β(2)AR signaling in improving cardiac function and myocyte viability, and (3) PKA-independent, CaMKII-mediated β(1)AR apoptotic and maladaptive remodeling signaling in the heart. Based on these discoveries and salutary effects of β(1)AR blockade on patients with heart failure, we envision that activation of β(2)AR in combination with clinically used β(1)AR blockade should provide a safer and more effective therapy for the treatment of heart failure.
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Reinkober J, Tscheschner H, Pleger ST, Most P, Katus HA, Koch WJ, Raake PWJ. Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade. Gene Ther 2012; 19:686-93. [PMID: 22336718 DOI: 10.1038/gt.2012.9] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of β-adrenergic receptor antagonism.
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Affiliation(s)
- J Reinkober
- Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany
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17
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Abstract
Increasing numbers of compounds, previously classified as antagonists, were shown to inhibit this spontaneous or constitutive receptor activity, instead of leave it unaffected as expected for a formal antagonist. In addition, some other antagonists did not have any effect by themselves, but prevented the inhibition of constitutive activity induced by thought-to-be antagonists. These thought-to-be antagonists with negative efficacy are now known as "inverse agonists." Inverse agonism at βAR has been evidenced for both subtypes in wild-type GPCRs systems and in engineered systems with high constitutive activity. It is important to mention that native systems are of particular importance for analyzing the in vivo relevance of constitutive activity because these systems have physiological expression levels of target receptors. Studies of inverse agonism of β blockers in physiological setting have also evidenced that pathophysiological conditions can affect pharmacodynamic properties of these ligands. To date, hundreds of clinically well-known drugs have been tested and classified for this property. Prominent examples include the beta-blockers propranolol, alprenolol, pindolol, and timolol used for treating hypertension, angina pectoris, and arrhythmia that act on the β₂ARs, metoprolol, and bisoprolol used for treating hypertension, coronary heart disease, and arrhythmias by acting on β₁ARs. Inverse agonists seem to be useful in the treatment of chronic disease characterized by harmful effects resulting from β₁AR and β₂AR overactivation, such as heart failure and asthma, respectively.
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Affiliation(s)
- Carlos A Taira
- Cátedra de Farmacología, Instituto de Fisiopatología y Bioquímica Clínica, Universidad de Buenos Aires, CONICET, Junín 956, Buenos Aires, Argentina
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de Montmollin E, Annane D. Nouvelles pistes dans le traitement du sepsis — Modulation β-adrénergique au cours du sepsis. MEDECINE INTENSIVE REANIMATION 2011. [DOI: 10.1007/s13546-010-0133-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Chakir K, Daya SK, Aiba T, Tunin RS, Dimaano VL, Abraham TP, Jaques-Robinson KM, Jacques K, Lai EW, Pacak K, Zhu WZ, Xiao RP, Tomaselli GF, Kass DA. Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy. Circulation 2009; 119:1231-40. [PMID: 19237665 PMCID: PMC2850078 DOI: 10.1161/circulationaha.108.774752] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown. METHODS AND RESULTS We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, beta(1) and beta(2) stimulation was enhanced, coupled to increased beta(1) receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha(i)) suppression of beta-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha(i) expression itself was unaltered; however, expression of negative regulators of Galpha(i) signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control. CONCLUSIONS CRT improves rest and beta-adrenergic-stimulated myocyte function and calcium handling, upregulating beta(1) receptors and adenylate cyclase activity and suppressing G(i)-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.
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Affiliation(s)
- Khalid Chakir
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
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Van Tassell BW, Rondina MT, Huggins F, Gilbert EM, Munger MA. Carvedilol increases blood pressure response to phenylephrine infusion in heart failure subjects with systolic dysfunction: evidence of improved vascular alpha1-adrenoreceptor signal transduction. Am Heart J 2008; 156:315-21. [PMID: 18657662 PMCID: PMC2577898 DOI: 10.1016/j.ahj.2008.04.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2008] [Accepted: 04/01/2008] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Alpha(1)-adrenergic receptor (alpha(1)-AR) stimulation produces smooth muscle contraction, vasoconstriction, and myocyte hypertrophy, suggesting a potential therapeutic role for alpha(1)-AR antagonists to reduce cardiac workload and myocardial hypertrophy. Preliminary reports suggest that vascular alpha(1)-ARs are desensitized in heart failure (HF) in a manner similar to myocardial beta(1)-ARs. We examined alpha(1)-AR signal transduction by repeat phenylephrine (PE) infusions in patients with HF receiving chronic carvedilol therapy. METHODS Twelve subjects with HF not currently receiving beta-blockers were up-titrated to maximum tolerable doses of carvedilol. Subjects underwent alpha(1)-AR stimulation testing at study baseline, 2 weeks after each dose titration, and 6 months after maintenance of maximum carvedilol dose. Phenylephrine infusions began at 0.5 microg kg(-1) min(-1), with dose titrations every 10 minutes, to a maximum of 5 microg kg(-1) min(-1). Phenylephrine dose response was evaluated by the PE rate required to elicit a 20 mm Hg increase in systolic blood pressure (BP), designated PS(20). RESULTS All doses of carvedilol significantly reduced preinfusion measures of heart rate, systolic BP, diastolic BP, and mean arterial pressure. However, carvedilol also produced a paradoxical trend toward PS(20) reduction (indicating increased PE response) that reached significance at the completion of carvedilol dose titration (PS(20) ratio vs baseline = 0.78; P < .001). All effects were maintained over a 6-month treatment period with no evidence of tolerance. CONCLUSIONS Increasing BP response to PE infusion suggests improvement in vascular alpha(1)-AR signal transduction with chronic carvedilol therapy. This effect is evident despite no detectable tolerance to preinfusion BP reductions. The varying affinities of alpha(1)-AR subtypes for carvedilol and PE may have contributed to this finding.
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Leosco D, Rengo G, Iaccarino G, Filippelli A, Lymperopoulos A, Zincarelli C, Fortunato F, Golino L, Marchese M, Esposito G, Rapacciuolo A, Rinaldi B, Ferrara N, Koch WJ, Rengo F. Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation. Am J Physiol Heart Circ Physiol 2007; 293:H1596-H1603. [PMID: 17557919 DOI: 10.1152/ajpheart.00308.2007] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cardiac beta-adrenergic receptor (beta-AR) signaling and left ventricular (LV) responses to beta-AR stimulation are impaired with aging. It is shown that exercise and beta-AR blockade have a favorable effect on cardiac and vascular beta-AR signaling in several cardiovascular diseases. In the present study, we examined the effects of these two different strategies on beta-AR dysregulation and LV inotropic reserve in the aging heart. Forty male Wistar-Kyoto aged rats were randomized to sedentary, exercise (12 wk treadmill training), metoprolol (250 mg.kg(-1).day(-1) for 4 wk), and exercise plus metoprolol treatment protocols. Ten male Wistar-Kyoto sedentary young rats were also used as a control group. Old trained, old metoprolol-treated, and old trained plus metoprolol-treated rats showed significantly improved LV maximal and minimal first derivative of the pressure rise responses to beta-AR stimulation (isoproterenol) compared with old untrained animals. We found a significant reduction in cardiac sarcolemmal membrane beta-AR density and adenylyl cyclase activity in old untrained animals compared with young controls. Exercise training and metoprolol, alone or combined, restored cardiac beta-AR density and G-protein-dependent adenylyl cyclase activation in old rats. Although cardiac membrane G-protein-receptor kinase 2 levels were not upregulated in untrained old compared with young control rats, both exercise and metoprolol treatment resulted in a dramatic reduction of G-protein-receptor kinase 2 protein levels, which is a further indication of beta-AR signaling amelioration in the aged heart induced by these treatment modalities. In conclusion, we demonstrate for the first time that exercise and beta-AR blockade can similarly ameliorate beta-AR signaling in the aged heart, leading to improved beta-AR responsiveness and corresponding LV inotropic reserve.
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Affiliation(s)
- Dario Leosco
- Department of Internal Medicine, Cardiovascular Sciences and Immunology, University Federico II, Via Pansini 5, Edificio 2, 80131 Naples, Italy.
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Molenaar P, Savarimuthu SM, Sarsero D, Chen L, Semmler ABT, Carle A, Yang I, Bartel S, Vetter D, Beyerdörfer I, Krause EG, Kaumann AJ. (-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through beta2 -adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:11-28. [PMID: 17295024 DOI: 10.1007/s00210-007-0138-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Accepted: 01/18/2007] [Indexed: 01/08/2023]
Abstract
Activation of either coexisting beta1- or beta2 -adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium. Previous biochemical work with the beta2 -selective agonist zinterol is consistent with activation of the cascade beta2 -adrenoceptors-->Gsalpha-protein-->adenylyl cyclase-->cAMP-->protein kinase (PKA)-->phosphorylation of phospholamban, troponin I, and C-protein-->hastened relaxation of human atria from nonfailing hearts. However, in feline and rodent myocardium, catecholamines and zinterol usually do not hasten relaxation through activation of beta2 -adrenoceptors, presumably because of coupling of the receptors to Gi protein. It is unknown whether the endogenously occurring beta2 -adrenoceptor agonist adrenaline acts through the above cascade in human atrium and whether its mode of action could be changed in heart failure. We assessed the effects of (-)-adrenaline, mediated through beta2 -adrenoceptors (in the presence of CGP 20712A 300 nM to block beta1 -adrenoceptors), on contractility and relaxation of right atrial trabecula obtained from nonfailing and failing human hearts. Cyclic AMP levels were measured as well as phosphorylation of phospholamban, troponin I, and protein C with Western blots and the back-phosphorylation procedure. For comparison, beta1 -adrenoceptor-mediated effects of (-)-noradrenaline were investigated in the presence of ICI 118,551 (50 nM to block beta2 -adrenoceptors). The positive inotropic effects of both (-)-noradrenaline and (-)-adrenaline were accompanied by reductions in time to peak force and time to reach 50% relaxation. (-)-Adrenaline caused similar positive inotropic and lusitropic effects in atrial trabeculae from failing hearts. However, the inotropic potency, but not the lusitropic potency, of (-)-noradrenaline was reduced fourfold in atrial trabeculae from heart failure patients. Both (-)-adrenaline and (-)-noradrenaline enhanced cyclic AMP levels and produced phosphorylation of phospholamban, troponin I, and C-protein to a similar extent in atrial trabeculae from nonfailing hearts. The hastening of relaxation caused by (-)-adrenaline together with the PKA-catalyzed phosphorylation of the three proteins involved in relaxation, indicate coupling of beta2 -adrenoceptors to Gs protein. The phosphorylation of phospholamban at serine16 and threonine17 evoked by (-)-adrenaline through beta2 -adrenoceptors and by (-)-noradrenaline through beta1 -adrenoceptors was not different in atria from nonfailing and failing hearts. Activation of beta2 -adrenoceptors caused an increase in phosphorylase a activity in atrium from failing hearts further emphasizing the presence of the beta2 -adrenoceptor-Gsalpha-protein pathway in human heart. The positive inotropic and lusitropic potencies of (-)-adrenaline were conserved across Arg16Gly- and Gln27Glu-beta2 -adrenoceptor polymorphisms in the right atrium from patients undergoing coronary artery bypass surgery, chronically treated with beta1 -selective blockers. The persistent relaxant and biochemical effects of (-)-adrenaline through beta2 -adrenoceptors and of (-)-noradrenaline through beta1 -adrenoceptors in heart failure are inconsistent with an important role of coupling of beta2 -adrenoceptors with Gialpha-protein in human atrial myocardium.
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Affiliation(s)
- Peter Molenaar
- Department of Medicine, The University of Queensland, The Prince Charles Hospital, Chermside, Queensland, 4032, Australia.
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Brodde OE. β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2007; 374:361-72. [PMID: 17216434 DOI: 10.1007/s00210-006-0125-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2006] [Accepted: 11/17/2006] [Indexed: 11/29/2022]
Abstract
Recent studies showed that chronic beta-adrenoceptor (AR) blocker treatment exerts beneficial effects in patients with chronic heart failure (CHF). In CHF, sympathetic drive to the heart is increased, and this causes pathological changes in cardiac beta-AR-G-protein(s)-adenylyl cyclase system: Cardiac beta-1 AR are decreased, and amount and activity of cardiac G(i)-protein and G-protein-coupled receptor kinase (GRK) are increased resulting in diminished cardiac beta-AR functional responsiveness. One possible mechanism of beneficial effects of beta-AR blockers could be that they prevent adverse effects of increased sympathetic activity and up-regulate cardiac (and vascular) beta-AR density, and by this, enhance beta-AR-mediated effects. Another possibility could be that chronic beta-AR blocker treatment normalizes activity of G(i)-protein and may thereby restore beta-AR functional responsiveness. Moreover, failing human heart exhibits an inverse force-frequency relationship. beta-AR blockers reduce heart rate; this may, therefore, improve force of contraction. One of the strongest stimuli to activate GRK is increased sympathetic activity (as in CHF) via beta-AR stimulation. beta-AR blockers, by blocking beta-AR, can prevent GRK activation and/or can reduce the (previously enhanced) GRK activity, and this might-at least partly-contribute to beneficial effects of beta-AR blockers in CHF treatment. Finally, the "loss-of-function" Arg389Gly beta-1 AR polymorphism seems to determine heart rate and blood pressure responses to beta-1 AR blocker administration: Arg389Arg beta-1 AR subjects exhibit stronger effects than subjects with one or two Gly389 alleles. Thus, it might be predicted that patients homozygous Arg389 beta-1 AR should be good responders, whereas patients homozygous Gly389 beta-1 AR polymorphism should be poor or non-responders.
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Affiliation(s)
- Otto-Erich Brodde
- Department of Nephrology and Pathophysiology, University of Essen School of Medicine, IG I., 9.OG, Hufelandstr. 55, 45147 Essen, Germany.
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Birkeland JAK, Sjaastad I, Brattelid T, Qvigstad E, Moberg ER, Krobert KA, Bjørnerheim R, Skomedal T, Sejersted OM, Osnes JB, Levy FO. Effects of treatment with a 5-HT4 receptor antagonist in heart failure. Br J Pharmacol 2006; 150:143-52. [PMID: 17160012 PMCID: PMC2042907 DOI: 10.1038/sj.bjp.0706966] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT(4) receptor. We investigated whether chronic 5-HT(4) receptor blockade improved cardiac function in CHF rats. EXPERIMENTAL APPROACH Rats were given either the 5-HT(4) antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MI(int)) or placebo (MI(pl)) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR. KEY RESULTS LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MI(int) compared to MI(pl). SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl). CONCLUSIONS AND IMPLICATIONS Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT(4) receptor antagonist in CHF.
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Affiliation(s)
- J A K Birkeland
- Institute for Experimental Medical Research, University of Oslo, Oslo, Norway
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Brixius K, Frank KF, Bölck B, Hoyer F, Schwinger RHG. [Reverse remodeling of the intracellular Ca(2+)-homeostasis: new concepts of pathophysiology and therapy of heart failure]. Wien Med Wochenschr 2006; 156:209-15. [PMID: 16823538 DOI: 10.1007/s10354-005-0239-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2005] [Accepted: 10/21/2005] [Indexed: 01/08/2023]
Abstract
Cardiac contraction is dependent on a rapid alteration of the intracellular Ca(2+) concentration, especially the Ca(2+) released during systole. In end-stage heart failure, cardiac contractility is depressed due to alterations in the structure and function of proteins or protein complexes. Over recent years, new insights have been obtained regarding the regulation of the intracellular Ca(2+) homeostasis and its pathophysiological alteration in end-stage heart failure. This review focuses on the mechanisms involved in the release of Ca(2+) from the sarcoplasmic reticulum (SR) during systole via the ryanodine receptors and the Ca(2+)-uptake into the SR by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a). In addition, new therapeutic options will be introduced which may be of importance for the treatment of heart failure patients.
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Affiliation(s)
- Klara Brixius
- Labor für Herzmuskelphysiologie und Molekulare Kardiologie, Klinik III für Innere Medizin, Köln
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Abstract
The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT can produce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflex bradycardia), increased atrial contractility and production of atrial arrhythmias. Acute inotropic, lusitropic and arrhythmic effects of 5-HT on human ventricle become conspicuous after inhibition of phosphodiesterase (PDE) activity. Human cardiostimulation is mediated through 5-HT4 receptors. Atrial and ventricular PDE3 activity exerts a protective role against potentially harmful cardiostimulation. Chronic exposure to high levels of 5-HT (from metastatic carcinoid tumours), the anorectic drug fenfluramine and its metabolites, as well as the ecstasy drug 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) are associated with proliferative disease and thickening of cardiac valves, mediated through 5-HT2B receptors. 5-HT2B receptors have an obligatory physiological role in murine cardiac embryology but whether this happens in humans requires research. Congenital heart block (CHB) is, on occasion, associated with autoantibodies against 5-HT4 receptors. Acute vascular constriction by 5-HT is usually shared by 5-HT1B and 5-HT2A receptors, except in intracranial arteries which constrict only through 5-HT1B receptors. Both 5-HT1B and 5-HT2A receptors can mediate coronary artery spasm but only 5-HT1B receptors appear involved in coronary spasm of patients treated with triptans or with Prinzmetal angina. 5-HT2A receptors constrict the portal venous system including oesophageal collaterals in cirrhosis. Chronic exposure to 5-HT can contribute to pulmonary hypertension through activation of constrictor 5-HT1B receptors and proliferative 5-HT2B receptors, and possibly through direct intracellular effects.
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Sato N, Yamamoto T, Akutsu K, Fujita N, Asai K, Takayama M, Takano T, Tanaka K. Arterial baroreflex sensitivity is a good predictor of inotropic responses to a phosphodiesterase inhibitor in human heart failure. Clin Cardiol 2006; 29:263-7. [PMID: 16796077 PMCID: PMC6653923 DOI: 10.1002/clc.4960290608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Experimental study has shown that blunted arterial baroreflex function markedly attenuated inotropic responses to a phosphodiesterase inhibitor (PDEI) even in normal hearts. However, whether arterial baroreflex function is related to the inotropic responsiveness to a PDEI has not been clarified in human heart failure (HF). HYPOTHESIS The goal of this study was to examine the relationship between inotropic responses to a PDEI and arterial baroreflex sensitivity in human HF. METHODS Twelve patients with HF were examined, and hemodynamic responses to milrinone (12.5, 25, and 50 microg/kg, intravenous injection) and arterial baroreflex sensitivity were assessed by pulse interval-left ventricular (LV) systolic pressure slope using nitroglycerin and phenylephrine. RESULTS Milrinone (25 microg/kg) significantly increased LV dP/dt. Arterial baroreflex sensitivity was only one predictor of inotropic responses to milrinone by multivariate analysis; a strong positive correlation was also found between LV dP/dt and baroreflex sensitivity (y = 6.656X - 3.326, r = 0.93, p = 0.000). CONCLUSION Inotropic effects of milrinone, a PDEI, correlated significantly with arterial baroreflex sensitivity, suggesting that the more baroreflex function was impaired, the more the inotropic effect of a PDEI was depressed in human HF.
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Affiliation(s)
- Naoki Sato
- Intensive and Cardiac Care Unit, Nippon Medical School, Tokyo, Japan.
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Dhein S, Garbade J, Rouabah D, Abraham G, Ungemach FR, Schneider K, Ullmann C, Aupperle H, Gummert JF, Mohr FW. Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure. J Cardiothorac Surg 2006; 1:17. [PMID: 16800896 PMCID: PMC1533828 DOI: 10.1186/1749-8090-1-17] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2006] [Accepted: 06/26/2006] [Indexed: 01/01/2023] Open
Abstract
Background Since only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation. Methods White male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks) to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC) and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β1- and β2-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping. Results In doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity. Conclusion BMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure.
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Affiliation(s)
- Stefan Dhein
- Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
| | - Jens Garbade
- Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
| | - Djazia Rouabah
- Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
| | - Getu Abraham
- Institute for Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Germany
| | - Fritz-Rupert Ungemach
- Institute for Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Germany
| | - Katja Schneider
- Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
| | - Cris Ullmann
- Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
| | - Heike Aupperle
- Institute of Veterinary Pathology, University of Leipzig, Faculty of Veterinary Medicine, Germany
| | - Jan Fritz Gummert
- Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Germany
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Dhalla NS, Dent MR, Tappia PS, Sethi R, Barta J, Goyal RK. Subcellular remodeling as a viable target for the treatment of congestive heart failure. J Cardiovasc Pharmacol Ther 2006; 11:31-45. [PMID: 16703218 DOI: 10.1177/107424840601100103] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.
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Affiliation(s)
- Naranjan S Dhalla
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
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Perrino C, Naga Prasad SV, Patel M, Wolf MJ, Rockman HA. Targeted Inhibition of β-Adrenergic Receptor Kinase-1–Associated Phosphoinositide-3 Kinase Activity Preserves β-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression. J Am Coll Cardiol 2005; 45:1862-70. [PMID: 15936620 DOI: 10.1016/j.jacc.2005.02.062] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2004] [Revised: 01/28/2005] [Accepted: 02/14/2005] [Indexed: 01/08/2023]
Abstract
OBJECTIVES Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1). BACKGROUND beta-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the betaARK1/PI3K complex is recruited to agonist-stimulated betaARs. Here we tested the hypothesis that in vivo selective inhibition of betaARK1-associated PI3K activity would preserve betaAR signaling and, therefore, improve cardiac function and survival in experimental heart failure. METHODS We used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3Kgamma (PI3Kgamma(inact)) to competitively displace endogenous PI3K from betaARK1. RESULTS Catalytically inactive PI3KgammaPI3K overexpression in CSQ mice inhibited betaARK1-associated PI3K activity, normalized betaAR levels, and preserved betaAR responsiveness to isoproterenol (ISO). Restoration of betaAR signaling via PI3Kgamma(inact) overexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kgamma(inact) overexpression were restricted to betaAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3Kgamma(inact) mice. CONCLUSIONS These data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival.
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Affiliation(s)
- Cinzia Perrino
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
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Müller FU, Loser K, Kleideiter U, Neumann J, von Wallbrunn C, Dobner T, Scheld HH, Bantel H, Engels IH, Schulze-Osthoff K, Schmitz W. Transcription factor AP-2alpha triggers apoptosis in cardiac myocytes. Cell Death Differ 2005; 11:485-93. [PMID: 14752511 DOI: 10.1038/sj.cdd.4401383] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Idiopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology associated with apoptosis, cardiac dilatation, progressive heart failure and increased mortality. An elevation of the transcription factor activator protein 2alpha (AP-2alpha) is involved in vertebrate embryonic development and oncogenesis. Here, we show that AP-2alpha protein is expressed in the human heart and increased in human failing myocardium with IDC. Adenovirus-mediated overexpression of human AP-2alpha triggered apoptosis and increased mRNA levels of Bcl-2 family members Bax and Bcl-x in rat cardiomyocytes. Immunohistological analysis of human myocardium revealed an increased percentage of AP-2alpha-positive nuclei in IDC and, interestingly, a colocalization of AP-2alpha-positive but not -negative cells with a caspase-cleaved fragment of poly(ADP-ribose)polymerase. We suggest AP-2alpha as a novel cardiac regulator implicated in the activation of apoptosis in IDC.
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Affiliation(s)
- F U Müller
- Institute of Pharmacology and Toxicology, University of Münster, Domagkstr. 12, Münster D-48129, Germany.
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Movsesian MA, Bristow MR. Alterations in cAMP-mediated signaling and their role in the pathophysiology of dilated cardiomyopathy. Curr Top Dev Biol 2005; 68:25-48. [PMID: 16124995 DOI: 10.1016/s0070-2153(05)68002-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Dilated cardiomyopathy is a disease characterized by enlargement of the chambers of the heart and a decrease in contractility of the heart muscle. The process involves several alterations in proteins involved in cyclic adenosine monophosphate (cAMP) generation that result in a decrease in intracellular cAMP content per unit of adrenergic stimulation in cardiac myocytes. A fundamental question is whether these changes constitute a pathologic mechanism that contributes to chamber enlargement and hypocontractility or a compensatory adaptation that protects the heart from the adverse effects of increased catecholamine stimulation. Clinical studies in humans suggest that the latter effect may be more important. Studies in animal models, however, make the picture more complex: changes in cAMP-mediated signaling can have different effects depending on the specific protein whose expression or function is altered and the setting in which the alteration occurs. It may be that dilated cardiomyopathy represents a collection of different diseases in which alterations in cAMP-mediated signaling have different roles in the pathophysiology of the disease, and, furthermore, that changes in the phosphorylation of individual substrates of cAMP-dependent protein kinase may be either beneficial or harmful. Identifying differences among patients with dilated cardiomyopathy with respect to the role of altered cAMP-mediated signaling in their pathology, and identifying the "good" and "bad" substrates of cAMP-dependent protein kinase, are important areas for further research.
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Affiliation(s)
- Matthew A Movsesian
- Cardiology Section, VA Salt Lake City Health Care System, Department of Internal Medicine (Cardiology), University of Utah, Salt Lake City, Utah 84148, USA
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Abstract
The concept that heart failure is simply the consequence of impaired pump function is now outmoded. Congestive heart failure is a neuroendocrine syndrome in with activation of the adrenergic nervous system and specific endocrine pathways is integral to its pathogenesis. It is now clear that chronic increases in adrenergic drive associated with heart failure have detrimental effects on myocardial function. The use of BAAs is now standard therapy for people who develop heart failure caused by systolic dysfunction. Beta-blockade may have a role in the management of dogs with heart failure.
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Affiliation(s)
- Jonathan A Abbott
- Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Technical Institute, Phase II Duckpond Drive, Blacksburg, VA 24061, USA.
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Abstract
This review addresses open questions about the role of beta-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three beta-adrenergic receptor subtypes-beta1, beta2, and, at least in some species, beta3. The beta1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The beta2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the beta1 subtype. In heart failure, the sympathetic system is activated, cardiac beta-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, beta-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the beta-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.
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Affiliation(s)
- Martin J Lohse
- Institute of Pharmacology, Versbacher Strasse 9, 97078 Wuerzburg, Germany.
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35
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Waagstein F, Strömblad O, Andersson B, Böhm M, Darius M, Delius W, Goss F, Osterziel KJ, Sigmund M, Trenkwalder SP, Wahlqvist I. Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiop. Eur J Heart Fail 2003; 5:679-91. [PMID: 14607208 DOI: 10.1016/s1388-9842(03)00105-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND the effects of long-term administration of beta-blockers on left ventricular (LV) function during exercise in patients with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM) are controversial. PATIENTS AND METHODS patients with stable congestive heart failure (CHF) (New York heart association [NYHA] class II and III) and ejection fraction (EF) < or =0.40 were randomized to metoprolol, 50 mg t.i.d. or placebo for 6 months. Patients were divided into two groups: ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM). The mean EF was 0.29 in both groups and 92% were taking angiotensin-converting enzyme (ACE) inhibitors. In the IHD group, 84% had suffered a myocardial infarction (MI) and 64% had undergone revascularization at least 6 months before the study. LV volumes were measured by equilibrium radionuclide angiography. Mitral regurgitation was assessed by Doppler echocardiography. All values are changes for metoprolol subtracted by changes for placebo. RESULTS metoprolol improved LV function markedly both at rest and during sub-maximal exercise in both groups. The mean increase in EF was 0.069 at rest (P<0.001) and 0.078 during submaximal exercise (P<0.001). LV end-diastolic volume decreased by 22 ml at rest (P=0.006) and by 15 ml during exercise (P=0.006). LV end-systolic volume decreased by 23 ml both at rest (P=0.001) and during exercise (P=0.004). Exercise time increased by 39 s (P=0.08). In the metoprolol group, mitral regurgitation decreased (P=0.0026) and only one patient developed atrial fibrillation vs. eight in the placebo group (P=0.01). CONCLUSION metoprolol improves EF both at rest and during submaximal exercise and prevents LV dilatation in mild to moderate CHF due to IHD or DCM.
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Affiliation(s)
- F Waagstein
- Wallenberg Laboratory and Department of Cardiology, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
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Lutz S, Mura RA, Hippe HJ, Tiefenbacher C, Niroomand F. Plasma membrane-associated nucleoside diphosphate kinase (nm23) in the heart is regulated by beta-adrenergic signaling. Br J Pharmacol 2003; 140:1019-26. [PMID: 14559858 PMCID: PMC1574115 DOI: 10.1038/sj.bjp.0705527] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
1. Receptor-independent activation of heterotrimeric G proteins by plasma membrane-associated nucleoside diphosphate kinase (NDPK) has been demonstrated in vivo, and elevated levels of NDPK were found in purified sarcolemmal membranes of patients with end-stage heart failure. 2. Among 22 consecutive patients with chronic heart failure who underwent cardiac transplantation, those treated with a beta-blocker (n=8) had a 65% lower NDPK content and activity in the cardiac sarcolemma, compared to patients with similar base line characteristics who had no beta-blocker therapy (n=14). 3. The lower NDPK was associated with a reduced NDPK-dependent, Gi-mediated inhibition of adenylyl cyclase activity, as assessed by in vitro measurement of adenylyl cyclase activity in the presence of GDP or its kinase-resistant analog guanosine 5'-O-(2-thio)diphosphate (GDPbetaS). 4. We further tested whether treatment with a beta-adrenergic agonist would induce an increase in sarcolemmal NDPK. Rats treated with isoproterenol developed myocardial hypertrophy, and NDPK in the sarcolemma rose by 60% during 14 days of treatment. The beta-blocker propranolol prevented both effects. When hypertrophy was induced with thyroid hormone, NDPK did not increase. 5. In conclusion, chronic activation of beta-adrenergic receptors increases the binding of NDPK to cardiac sarcolemma, where it may activate heterotrimeric G proteins.
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Affiliation(s)
- Susanne Lutz
- Klinikum der Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, Heidelberg D-69115, Germany
| | - Roman A Mura
- Klinikum der Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, Heidelberg D-69115, Germany
| | - Hans Joerg Hippe
- Klinikum der Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, Heidelberg D-69115, Germany
| | - Christiane Tiefenbacher
- Klinikum der Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, Heidelberg D-69115, Germany
| | - Feraydoon Niroomand
- Klinikum der Universität Heidelberg, Innere Medizin III, Bergheimer Str. 58, Heidelberg D-69115, Germany
- Author for correspondence:
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Callaerts-Vegh Z, Evans KLJ, Shipley GL, Davies PJA, Cuba DL, Gurji HA, Giles H, Bond RA. Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery. Br J Pharmacol 2003; 138:1505-16. [PMID: 12721106 PMCID: PMC1573808 DOI: 10.1038/sj.bjp.0705205] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
1. We have studied the effects of three betaAR ligands (carvedilol, alprenolol, and ICI-118551) with different pharmacological profiles and negative efficacy at the beta2AR on cardiac in vivo, in vitro, biochemical and gene expression parameters in mice with permanent occlusion of the left anterior descending coronary artery. 2. Cardiac in vivo parameters were determined using Doppler studies. Mitral-wave E peak velocity (EPV) and aortic peak velocity (AoPV) decreased in the first 2 weeks postocclusion. After 3 weeks of drug treatment, EPV was improved in the carvedilol group to preocclusion values; however, a further reduction in EPV in the alprenolol and control permanent occlusion group was measured and there was no change after ICI-118551 treatment. AoPV was unchanged between weeks 2 and 5 in all groups. 3. The left atria were isolated to record isometric tension responses to isoprenaline. Permanent occlusion significantly reduced the maximum isoprenaline response to 30% of control and carvedilol increased the maximum response to isoprenaline significantly to 60%. 4. The biochemical and gene expression studies revealed different effects of the three betaAR ligands. Most notably, carvedilol reduced gene expression of myosin heavy chain beta. 5. These results indicate that chronic treatment with carvedilol is beneficial in a mouse model of myocardial damage resulting from ischaemia. We hypothesise that these beneficial effects of the drug may be because of the negative efficacy at the beta2AR, combined with beta1AR antagonism.
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Affiliation(s)
- Zsuzsanna Callaerts-Vegh
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, U.S.A
| | - Kenda L J Evans
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, U.S.A
| | - Gregory L Shipley
- Department of Integrative Biology, Pharmacology and Physiology, University of Texas, Houston Health Science Center, Houston, TX, 77030, U.S.A
| | - Peter J A Davies
- Department of Integrative Biology, Pharmacology and Physiology, University of Texas, Houston Health Science Center, Houston, TX, 77030, U.S.A
| | - Donald L Cuba
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, U.S.A
| | - Hunaid A Gurji
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, U.S.A
| | - Heather Giles
- GlaxoSmithKline, Receptor Pharmacology, Stevenage SG1 2NY
| | - Richard A Bond
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, U.S.A
- Author for correspondence:
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Rau T, Nose M, Remmers U, Weil J, Weissmüller A, Davia K, Harding S, Peppel K, Koch WJ, Eschenhagen T. Overexpression of wild-type Galpha(i)-2 suppresses beta-adrenergic signaling in cardiac myocytes. FASEB J 2003; 17:523-5. [PMID: 12631586 DOI: 10.1096/fj.02-0660fje] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The role of Galpha(i)-2 overexpression in desensitization of beta-adrenergic signaling in heart failure is controversial. An adenovirus-based approach was used to investigate whether overexpression of Galpha(i)-2 impairs beta-adrenergic stimulation of adenylyl cyclase (AC) activity and cAMP levels in neonatal rat cardiac myocytes (NRCM) and cell shortening of adult rat ventricular myocytes (ARVM). Infection of NRCM with Ad5Galpha(i)-2 increased Galpha(i)-2 by 50-600% in a virus dose-dependent manner. Overexpression was paralleled by suppression of GTP- and isoprenaline-stimulated AC by 10-72% (P<0.001) in a PTX-sensitive manner. Isoprenaline-stimulated shortening of Ad5Galpha(i)-2-infected ARVM was attenuated by 34% (P<0.01). Ad5Galpha(i)-2/GFP (Galpha(i)-2, green fluorescent protein; bicistronic) was constructed to monitor transfection homogeneity and target Galpha(i)-2 overexpression to levels found in heart failure. At Galpha(i)-2 levels of 93% above control, isoprenaline-stimulated AC activity and cAMP levels were reduced by 17% and 40% (P<0.02), respectively. Beta1- and beta2-adrenergic stimulation was reduced similarly. Our results suggest that (a) the Galpha(i)-2 system exhibits tonic inhibition of stimulated AC in cardiac myocytes, (b) Galpha(i)-2-mediated inhibition is concentration-dependent and occurs at Galpha(i)-2 levels seen in heart failure, and (c) Galpha(i)-2-mediated inhibition affects both beta1- and beta2-adrenergic stimulation of AC. The data argue for an important, independent role of the Galpha(i)-2 increase in heart failure.
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Affiliation(s)
- Thomas Rau
- Institute of Pharmacology and Toxicology, Friedrich Alexander University Erlangen, Germany
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Bristow M. β-Adrenergic Receptors and Phosphodiesterase: Present and Future Perspectives. Semin Cardiothorac Vasc Anesth 2003. [DOI: 10.1177/108925320300700104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Michael Bristow
- Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO, USA
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Müller FU, Lewin G, Matus M, Neumann J, Riemann B, Wistuba J, Schütz G, Schmitz W. Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene. FASEB J 2003; 17:103-5. [PMID: 12475904 DOI: 10.1096/fj.02-0486fje] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Congestive heart failure is the common endpoint of various cardiac diseases representing a leading cause of cardiovascular mortality in Western countries. Characteristic functional alterations of the failing heart are explained by expressional changes of myocardial regulatory proteins; however, little is known about underlying mechanisms regulating cardiac gene expression in the failing heart. Here, we address the specific role of transcription factor CREM for cardiac function in CREM mutant mice with complete inactivation of the CREM gene. We show that CREM mutant mice display distinct alterations of cardiac function resembling characteristic functional defects of the failing heart. Left ventricular hemodynamic assessment of CREM mutant mice revealed impairment of both cardiac contraction and relaxation in basal state, as well as a decreased responsiveness to beta-adrenergic stimulation. The diminished cardiac contractile performance was associated with a selective down-regulation of beta1-adrenergic receptors and a decreased ventricular expression of SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. The cardiac phenotype of CREM mutant mice provides the first evidence that CREM represents an important key regulator of cardiac gene expression, which is essential for normal left ventricular contractile performance and response to beta-adrenoreceptor stimulation.
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Affiliation(s)
- Frank U Müller
- Institute of Pharmacology and Toxicology, University of Münster, Germany.
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Bristow MR, Shakar SF, Linseman JV, Lowes BD. Inotropes and beta-blockers: is there a need for new guidelines? J Card Fail 2001; 7:8-12. [PMID: 11605160 DOI: 10.1054/jcaf.2001.26655] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Beta-adrenergic blocking agents are standard treatment for patients with mild-to-moderate heart failure. When patients receiving beta-blockers decompensate they often need treatment with a positive inotropic agent. The beta-agonist dobutamine may not produce much increase in cardiac output during full-dose beta-blocker treatment and may increase systemic vascular resistance via alpha-adrenergic stimulation. In contrast, phosphodiesterase inhibitors (PDEIs) such as milrinone or enoximone retain full hemodynamic effects during complete beta-blockade because the site of action of PDEIs is beyond the beta-adrenergic receptor and because beta-blockade reverses some of the desensitization phenomena that account for the attenuation of PDEI response in heart failure related to upregulation in G(alphai). Inotrope-requiring subjects with decompensated heart failure who are undergoing long-term therapy with beta-blocking agents should be treated with a type III-specific PDEI, not a beta-agonist such as dobutamine.
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Affiliation(s)
- M R Bristow
- Department of Cardiology, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262, USA
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Shakar SF, Bristow MR. Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving beta-blocking agents. Curr Cardiol Rep 2001; 3:224-31. [PMID: 11305977 DOI: 10.1007/s11886-001-0027-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
beta-blocking agents are now well established as a cornerstone therapy in mild to moderate heart failure. Patients with more advanced heart failure depend on adrenergic activation to maintain adequate myocardial function. This leads to significant difficulties in using beta-blockers in advanced or severe heart failure. In addition, recent data indicate that adrenergic withdrawal might be detrimental in some of these patients. In higher doses, positive inotropic agents have been shown to increase mortality when used alone in subsets with advanced heart failure. Preliminary data suggest that the combination of low-dose phosphodiesterase inhibitors and a beta-blocker may be better tolerated and does not appear to be associated with the adverse effects of either therapy used alone. We discuss the theoretic underpinning of this approach and the supportive clinical data.
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Affiliation(s)
- S F Shakar
- University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
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Abstract
UNLABELLED Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. The drug has an established role in the management of essential hypertension and angina pectoris, and more recently, in patients with chronic heart failure. The effects of metoprolol controlled-release/extended-release (CR/XL) in patients with stable, predominantly mild to moderate (NYHA functional class II to III) chronic heart failure have been evaluated in the large Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial and the much smaller Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Treatment with metoprolol CR/XL was initiated at a low dosage of 12.5 to 25 mg once daily and gradually increased at 2-weekly intervals until the target dosage (200 mg once daily) or maximal tolerated dosage had been attained in patients receiving standard therapy for heart failure. At 12 months, metoprolol CR/XL was associated with a 34% reduction in relative risk of all-cause mortality in patients with chronic heart failure due to ischaemic or dilated cardiomyopathy in the MERIT-HF trial. The incidence of sudden death and death due to progressive heart failure were both significantly decreased with metoprolol CR/XL. Similarly, a trend towards decreased mortality in the metoprolol CR/XL group compared with placebo was observed in the RESOLVD trial. Data from small numbers of patients with severe (NYHA functional class IV) heart failure indicate that metoprolol CR/XL is effective in this subset of patients. However, no firm conclusions can yet be drawn. Improvement from baseline values in NYHA functional class, exercise capacity and some measures of quality of life with metoprolol CR/XL or immediate-release metoprolol were significantly greater than those with placebo. The drug is well tolerated when treatment is initiated in low dosages and gradually increased at intervals of 1 to 2 weeks. CONCLUSIONS Metoprolol CR/XL effectively decreases mortality and improves clinical status in patients with stable mild to moderate (NYHA functional class II or III) chronic heart failure due to left ventricular systolic dysfunction, and the drug is effective in patients with ischaemic or dilated cardiomyopathy. Although limited data indicate that metoprolol CR/XL is effective in patients with severe (NYHA functional class IV) chronic heart failure, more data are needed to confirm these findings. Treatment with metoprolol CR/XL significantly reduced the incidence of sudden death and death due to progressive heart failure.
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Affiliation(s)
- A Prakash
- Adis International Limited, Mairangi Bay, Auckland, New Zealand.
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Abstract
Beta-adrenergic blocking agents are now standard treatment for mild to moderate chronic heart failure (CHF). However, although many subjects improve on beta blockade, others do not, and some may even deteriorate. Even when subjects improve on beta blockade, they may subsequently decompensate and need acute treatment with a positive inotropic agent. In the presence of full beta blockade, a beta agonist such as dobutamine may have to be administered at very high (> 10 micrograms/kg/min) doses to increase cardiac output, and these doses may increase afterload. In contrast, phosphodiesterase inhibitors (PDEIs) such as milrinone or enoximone retain their full hemodynamic effects in the face of beta blockade. This is because the site of PDEI action is beyond the beta-adrenergic receptor, and because beta blockade reverses receptor pathway desensitization changes, which are detrimental to PDEI response. Moreover, when the combination of a PDEI and a beta-blocking agent is administered long term in CHF, their respective efficacies are additive and their adverse effects subtractive. The PDEI is administered first to increase the tolerability of beta-blocker initiation by counteracting the myocardial depressant effect of adrenergic withdrawal. With this combination, the signature effects of beta blockade (a substantial decrease in heart rate and an increase in left ventricular ejection fraction) are observed, the hemodynamic support conferred by the PDEI appears to be sustained, and clinical results are promising. However, large-scale placebo-controlled studies with PDEIs and beta blockers are needed to confirm these results.
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Affiliation(s)
- B D Lowes
- Division of Cardiology, University of Colorado Health Sciences Center, Denver 80262, USA
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Post SR, Hammond HK, Insel PA. Beta-adrenergic receptors and receptor signaling in heart failure. Annu Rev Pharmacol Toxicol 1999; 39:343-60. [PMID: 10331088 DOI: 10.1146/annurev.pharmtox.39.1.343] [Citation(s) in RCA: 112] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cardiac beta-adrenergic receptors, which respond to neuronally released and circulating catecholamines, are important regulators of cardiac function. Congestive heart failure, a common clinical condition, is associated with a number of alterations in the activation and deactivation of beta-adrenergic receptor pathways. Studies with failing hearts from humans and animals indicate that such alterations include changes in the expression or function of beta-adrenergic receptors, G-proteins, adenylyl cyclases, and G-protein receptor kinases. The net effect of these alterations is the substantial blunting of beta-adrenergic receptor-mediated cardiac response. An important unanswered question is whether the loss of cardiac beta-adrenergic receptor responsiveness is a contributing cause, or a result, of ventricular dysfunction. Even though this question remains unanswered, the concept of targeting the beta-adrenergic pathway in the failing heart is becoming increasing popular and several new therapeutic strategies are in development.
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Affiliation(s)
- S R Post
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington 40536-0284, USA.
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Nomura A, Saitoh H, Atarashi H, Hayakawa H. [Possible contribution of alpha-adrenergic abnormalities to cerebral ischemia in the patients with sinus bradycardia. Analysis by pharmacologic autonomic nervous test]. NIHON IKA DAIGAKU ZASSHI 1999; 66:119-26. [PMID: 10339990 DOI: 10.1272/jnms.66.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Syncope of patients with bradyarrhythmia is perceived as severe sign of low cardiac output caused by bradycardia and as a major criteria for pacemaker implantation (PMI). However, it has been reported that PMI can not always prevent syncope; it has been suggested that not bradycardia but an abnormality of the autonomic nervous system plays a part in syncope. PURPOSE To investigate the relation between autonomic nervous dysfunction and syncope in cases of sinus bradycardia (SB). SUBJECTS Thirty-nine patients with SB were divided into two groups according to the presence (group S, n = 16, 46.9 +/- 20.0 years) or absence (group N, n = 23, 40.4 +/- 17.6 years) of syncope or presyncope. METHODS Corrected sinus node recovery time (CSNRT) was measured by electrophysiologic study. Pharmacologic autonomic nervous tests were performed as follows in a quiet room. Increased HR by application of 0.04 mg/kg atropine (para-tone), and by 0.004 microgram/kg/min isoproterenol divided by 0.004 (beta-sens) were evaluated, beta-tone was obtained by subtracting HR after application of propranolol (0.2 mg/kg) from that of atropine. Basal beta-sympathetic activity was evaluated by beta-sec that was obtained by beta-tone/beta-sens. Increased SBP by application of 0.4 microgram/kg/min phenylephrine divided by 0.4 (alpha-sens) was evaluated. alpha-tone was obtained by subtracting minimum SBP after 0.2 mg/kg phentolamine from SBP after application of propranolol. Basal alpha-sympathetic activity was evaluated by alpha-sec, that was obtained by alpha-tone/alpha-sens. RESULT There were no significant differences in basal clinical characteristics (age, sex, cardiac function) between the groups. The parameters of the functions of parasympathetic and beta-sympathetic receptors (para-tone, beta-sens, beta-tone, beta-sec) showed no significant differences between the groups, alpha-sens was attenuated (P < 0.01) and alpha-sec was augmented (P < 0.0001) significantly in group S. CONCLUSION It was suggested that syncope or presyncope in SB patients could be attributed to failure of vasoconstriction mediated by alpha-sympathetic receptor but to severity of sinus node dysfunction.
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Affiliation(s)
- A Nomura
- First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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Müller FU, Bokník P, Knapp J, Neumann J, Vahlensieck U, Oetjen E, Scheld HH, Schmitz W. Identification and expression of a novel isoform of cAMP response element modulator in the human heart. FASEB J 1998; 12:1191-9. [PMID: 9737722 DOI: 10.1096/fasebj.12.12.1191] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In end-stage human heart failure, excessive beta-adrenergic stimulation of the cAMP-dependent signaling pathway due to enhanced endogenous catecholamines is hypothesized to contribute to expressional alterations of myocardial regulatory proteins. The cAMP response element modulator (CREM) regulates the transcription of cAMP-responsive genes and might be involved in the regulation of cardiac gene expression. Using the reverse transcription polymerase chain reaction, we identified a novel CREM mRNA, CREM-Ib deltaC-X, in the human heart. Overexpression of CREM-Ib deltaC-X decreased cAMP response element (CRE) -mediated gene transcription in HIT-T15 cells, and this activity was assigned to the part of the sequence encoding putative internally translated proteins. Two of three possible internally translated proteins were immunologically identified in cells overexpressing CREM-Ib deltaC-X tagged with the hemagglutinin epitope of the influenza virus. Both proteins were expressed in bacteria and showed CRE-specific DNA binding, formation of heterodimers with the cAMP response element binding protein (CREB), and inhibition of CREB's binding to the CRE. CREM expression was detected on the mRNA and protein levels in the human heart. We conclude that CREM-Ib deltaC-X generates internally translated repressors of CRE-mediated gene transcription, suggesting the first example for the existence and function of human cardiac CREM.
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Affiliation(s)
- F U Müller
- Institut für Pharmakologie und Toxikologie, Universität Münster, Germany.
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Affiliation(s)
- M R Bristow
- Division of Cardiology, School of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA
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Böhm M, Deutsch HJ, Hartmann D, Rosée KL, Stäblein A. Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J Am Coll Cardiol 1997; 30:992-6. [PMID: 9316529 DOI: 10.1016/s0735-1097(97)00248-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES This study tested the hypothesis that metoprolol restores the reduction of the inotropic effect of the cyclic adenosine monophosphate (cAMP)-phosphodiesterase inhibitor milrinone, which is cAMP dependent but beta-adrenoceptor independent. BACKGROUND Treatment with beta-adrenergic blocking agents has been shown to lessen symptoms and improve submaximal exercise performance and left ventricular ejection fraction in patients with heart failure. Restoration of the number of down-regulated beta-adrenoceptors has been suggested to be one mechanism of beta-blocker effectiveness. However, the reversal of postreceptor events, namely, an increase in inhibitory G-protein alpha-subunit concentrations, could also play a role. METHODS Fifteen patients with heart failure due to dilated cardiomyopathy (left ventricular ejection fraction 24.6 +/- 1.5% [mean +/- SD], New York Heart Association functional class II or III) were treated with metoprolol (maximal dose 50 mg three times daily) for 6 months. Before and after metoprolol treatment, inotropic responses to milrinone (5 to 10 micrograms/kg body weight per min) were measured echocardiographically. For comparison, responses to milrinone were determined under control conditions and after accelerated application of 150 mg of metoprolol to inactivate beta-adrenoceptors in subjects with normal left ventricular function. RESULTS In subjects with normal left ventricular function, treatment with metoprolol did not alter the increase in fractional shortening or pressure/dimension ratio of circumferential fiber shortening after application of milrinone. In patients with heart failure, treatment with metoprolol significantly increased left ventricular ejection fraction, fractional shortening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrations and functional class. After metoprolol treatment, milrinone increased fractional shortening but had no effect before beta-blocker treatment. CONCLUSIONS Milrinone increases inotropic performance independently of beta-adrenoceptors in vivo. Metoprolol treatment restores the blunted inotropic response to milrinone in patients with heart failure, indicating that postreceptor events (e.g., increase in inhibitory G-protein) are favorably influenced. This mechanism could contribute to the beneficial effects observed in the study patients and represents an important mechanism of how beta-blocker treatment influences the performance of the failing heart.
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Affiliation(s)
- M Böhm
- Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany.
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Müller FU, Bokník P, Knapp J, Lüss H, Neumann J, Vahlensieck U, Böhm M, Deng MC, Scheld HH, Schmitz W. Quantification of the cAMP response element binding protein in ventricular nuclear protein from failing and nonfailing human hearts. Biochem Biophys Res Commun 1997; 236:351-4. [PMID: 9240439 DOI: 10.1006/bbrc.1997.6971] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Alterations in the expression of myocardial regulatory proteins (e.g. beta-adrenoceptor, inhibitory G-proteins) in human heart failure are associated with excessive stimulation of the cAMP signalling pathway by endogenous catecholamines. The transcription factor cAMP response element binding protein (CREB) mediates cAMP-dependent transcriptional activation and is expressed in the human heart. Here, CREB protein was immunologically quantified in ventricular nuclear protein preparations from nonfailing donor hearts (n = 8) and from failing hearts transplanted due to dilative (n = 10) or ischemic cardiomyopathy (n = 6). CREB expression was unchanged in ventricular nuclei from failing hearts compared to the nonfailing controls suggesting that expressional alterations in human heart failure cannot be explained by altered expression of CREB.
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Affiliation(s)
- F U Müller
- Institut für Pharmakologie und Toxikologie, Universität Münster, Germany.
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