ABSTRACT
BACKGROUND: About 20% of the German population have a migration background which might influence prevalence of preventable cardiovascular risk factors (CVRF). METHODS: We report data of the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of inhabitants of the City of Würzburg, Germany, aged 30 to 79â¯years. Individuals without migration background were defined as follows: German as native language, no other native language, and/or born in Germany. All other participants were defined as individuals with migration background. RESULTS: Of 2473 subjects (51% female, mean age 54⯱â¯12â¯years), 291 (12%) reported a migration background: nâ¯=â¯107 (37%) from a country within the EU, nâ¯=â¯117 (40%) from Russia, and nâ¯=â¯67 (23%) from other countries. Prevalence of hypertension, atherosclerotic disease, and diabetes mellitus was similar in individuals with and without migration background. By contrast, prevalence of obesity and metabolic syndrome was significantly higher in individuals with migration background, with the least favourable profile apparent in individuals from Russia (individuals without vs. with migration background: obesity 19 vs. 24%, pâ¯<â¯0.05; odds ratio: EU: 1.6, Russia: 2.2*, other countries: 0.6; metabolic syndrome 18 vs. 21%, pâ¯<â¯0.05; odds ratio: EU: 1.2, Russia: 1.7*, other countries: 1.5; *pâ¯<â¯0.05). CONCLUSION: Individuals with migration background in Germany might exhibit a higher CVRF burden due to a higher prevalence of obesity and metabolic syndrome. Strategies for primary prevention of heart failure may benefit from deliberately considering the migration background.
Subject(s)
Cardiovascular Diseases/ethnology , Risk Assessment/methods , Transients and Migrants , Adult , Aged , Female , Follow-Up Studies , Germany/epidemiology , Humans , Male , Middle Aged , Prevalence , Prospective Studies , Risk FactorsABSTRACT
AIMS: Cardiovascular disease, one of the most common causes of death in western populations, is characterized by changes in RNA splicing and expression. Circular RNAs (circRNA) originate from back-splicing events, which link a downstream 5' splice site to an upstream 3' splice site. Several back-splicing junctions (BSJ) have been described in heart biopsies from human, rat and mouse hearts (Werfel et al., 2016; Jakobi et al., 2016 ). Here, we use human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to identify circRNA and host gene dynamics in cardiac development and disease. In parallel, we explore candidate interactions of selected homologs in mouse and rat via RIP-seq experiments. METHODS AND RESULTS: Deep RNA sequencing of cardiomyocyte development and ß-adrenergic stimulation uncovered 4518 circRNAs. The set of circular RNA host genes is enriched for chromatin modifiers and GTPase activity regulators. RNA-seq and qRT-PCR data showed that circular RNA expression is highly dynamic in the hiPSC-CM model with 320 circRNAs showing significant expression changes. Intriguingly, 82 circRNAs are independently regulated to their host genes. We validated the same circRNA dynamics for circRNAs from ATXN10, CHD7, DNAJC6 and SLC8A1 in biopsy material from human dilated cardiomyopathy (DCM) and control patients. Finally, we could show that rodent homologs of circMYOD, circSLC8A1, circATXN7 and circPHF21A interact with either the ribosome or Argonaute2 protein complexes. CONCLUSION: CircRNAs are dynamically expressed in a hiPSC-CM model of cardiac development and stress response. Some circRNAs show similar, host-gene independent expression dynamics in patient samples and may interact with the ribosome and RISC complex. In summary, the hiPSC-CM model uncovered a new signature of potentially disease relevant circRNAs which may serve as novel therapeutic targets.
Subject(s)
Cardiomyopathy, Dilated/metabolism , Gene Expression Regulation , Induced Pluripotent Stem Cells/metabolism , Models, Cardiovascular , Muscle Proteins/biosynthesis , Myocytes, Cardiac/metabolism , RNA/metabolism , Animals , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Humans , Induced Pluripotent Stem Cells/pathology , Mice , Muscle Proteins/genetics , Myocytes, Cardiac/pathology , RNA/genetics , RNA, Circular , RatsABSTRACT
Perinatal hypoxia is a critical complication during delivery and is mostly studied in animal models of postnatal hypoxic-ischemic brain injury. We here studied the effects of postnatal hypoxic-ischemic brain injury in two different sub-strains of C57BL/6 mice, i.e. C57BL/6J and C57BL/6N mice. These two sub-strains show different metabolic properties, for instance an impaired glucose tolerance in C57BL/6J mice. Genetically, this was linked to differences in their nicotinamide nucleotide transhydrogenase (Nnt) genes: In C57BL/6J mice, exons 7-11 of the Nnt gene are deleted, resulting in the absence of functional Nnt protein. The mitochondrial Nnt-protein is one of several enzymes that catalyses the generation of NADPH, which in turn is important for the elimination of reactive oxygen species (ROS). As ROS is thought to contribute to the pathophysiology of hypoxia-ischemia, the lack of Nnt might indirectly increase ROS levels and therefore result in increased brain damage. We therefore hypothesize that lesion score and lesion size will increase in C57BL/6J mice as compared to C57BL/6N mice. Surprisingly, the results showed exactly the opposite: C57BL/6J mice showed a decrease in lesion score and size, associated with a reduced number of apoptotic cells and activated microglia. In contrast, the number of cells with ROS-induced DNA modifications (detected by 8OHdG) was higher in C57BL/6J than C57BL/6N mice. In conclusion, C57BL/6J mice showed reduced ischemic consequences after postnatal hypoxic-ischemic brain injury compared to C57BL/6N mice, with the exception of the amount of ROS-induced DNA-damage. These differences might relate to the lack of Nnt, but also to a modified metabolic setting (cardiovascular parameters, oxygen and glucose metabolism, immune function) in C57BL/6J mice.
Subject(s)
Hypoxia-Ischemia, Brain/physiopathology , Mice, Inbred Strains/metabolism , Animals , Brain/metabolism , Brain Injuries/physiopathology , Cerebrovascular Trauma/physiopathology , Exons , Glucose Intolerance/pathology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred Strains/genetics , NADP/genetics , NADP/metabolism , NADP Transhydrogenases/genetics , NADP Transhydrogenases/metabolism , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND AND PURPOSE: Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of adenosine A1 receptors following hypertrophic stimulation in vitro and in vivo. EXPERIMENTAL APPROACH: Pro-hypertrophic stimuli and adenosine A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, sc. drug administration, real-time PCR, (3) [H]-leucine-incorporation assay, immunostaining, tissue staining, Western blots, gravimetric analyses and echocardiography were applied in this study. KEY RESULTS: In neonatal rat cardiomyocyte cultures, phenylephrine, but not angiotensin II or insulin-like growth factor 1 (IGF1), up-regulated adenosine A1 receptors concentration-dependently. The hypertrophic phenotype (cardiomyocyte size, sarcomeric organization, total protein synthesis, c-fos expression) mediated by phenylephrine (10 µM), but not that by angiotensinII (1 µM) or IGF1 (20 ng·mL(-1) ), was counteracted by the selective A1 receptor agonist, N6-cyclopentyladenosine. In C57/BL6 mice, continuous N6-cyclopentyladenosine infusion (2 mg·kg(-1) ·day(-1) ; 21 days) blunted phenylephrine (120 mg·kg(-1) ·day(-1) ; 21 days) induced hypertrophy (heart weight, cardiomyocyte size and fetal genes), fibrosis, MMP 2 up-regulation and generation of oxidative stress - all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased expression of adenosine A1 receptors. CONCLUSIONS AND IMPLICATIONS: We have presented evidence for a negative feedback mechanism attenuating pathological myocardial hypertrophy following α1 -adrenoceptor stimulation. Our results suggest adenosine A1 receptors as potential targets for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure overload.
Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Adrenergic alpha-1 Receptor Agonists/adverse effects , Cardiomegaly/prevention & control , Fibrosis/prevention & control , Receptor, Adenosine A1/metabolism , Adenosine/analogs & derivatives , Adenosine/pharmacology , Angiotensin II/pharmacology , Animals , Animals, Newborn , Cell Culture Techniques , Dose-Response Relationship, Drug , Insulin-Like Growth Factor I/pharmacology , Male , Matrix Metalloproteinase 2/metabolism , Mice , Myocytes, Cardiac/metabolism , Oxidative Stress/drug effects , Phenylephrine/antagonists & inhibitors , Phenylephrine/pharmacology , Rats , Up-Regulation/drug effectsABSTRACT
Acute pulmonary embolism (PE) still represents a challenge regarding a rapid diagnosis and a risk-adapted therapy. In the 2014 guidelines of the European Society of Cardiology (ESC) on the diagnosis and management of acute PE, several new recommendations have been issued based on new study data. Some established scores for risk stratification were developed further and there is now good evidence for the use of age-adjusted D-dimer cut-off levels. For the risk stratification in patients without clinical features of shock, the utilization of the pulmonary embolism severity index (PESI) and simplified PESI (sPESI) scores is recommended. In patients with intermediate risk, right ventricular morphology and function can be evaluated by computer tomography or echocardiography and biomarkers facilitate further risk stratification. For the treatment of patients with venous thromboembolism with or without PE, the non-vitamin K-dependent oral anticoagulants (NOACs) are a safe alternative to the standard anticoagulation regimen with heparin and vitamin K antagonists. Systemic thrombolytic therapy should be restricted to patients with high risk or intermediate high risk with hemodynamic instability. Finally, new recommendations for the diagnosis and therapy of patients with chronic thromboembolic pulmonary hypertension (CTEPH), with cancer or during pregnancy are given.
Subject(s)
Cardiology/standards , Pulmonary Embolism/diagnosis , Pulmonary Embolism/therapy , Pulmonary Medicine/standards , Respiratory Function Tests/standards , Thrombolytic Therapy/standards , Acute Disease , Angiography/standards , Anticoagulants/administration & dosage , Europe , Humans , Practice Guidelines as Topic , Pulmonary Embolism/bloodABSTRACT
This review article summarizes results of a number of new clinical trials and registries in the field of cardiovascular medicine. Key presentations made at the 74th annual meeting of the German Cardiac Society, held in Mannheim, Germany, in March 2008 are reported. The data were presented by leading experts in the field with relevant positions in the trials and registries. These comprehensive summaries should provide the readers with the most recent data on diagnostic and therapeutic developments in cardiovascular medicine.
Subject(s)
Cardiology , Clinical Trials as Topic , Registries , Ablation Techniques/statistics & numerical data , Angina Pectoris/therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Coronary Artery Disease/therapy , Drug-Eluting Stents , Equipment Design , Germany , Heart Failure/prevention & control , Humans , Myocardial Infarction/therapy , Paclitaxel/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Societies, MedicalABSTRACT
The primary target in preoperative risk evaluation is not to classify patients as operable or inoperable but rather to reduce perioperative morbidity and mortality. Indications for perioperative diagnostic and therapeutic procedures are mostly the same as for patients without subsequent non-cardiac surgery. However, the time schedule often depends on cofactors such as urgency and severity of surgical interventions. Perioperative risk management requires exceedingly good communication and collaboration between surgeons, anesthesiologists and internists and offers the chance to diagnose and treat perioperative risk factors in a justifiable time and cost context.
Subject(s)
Heart Failure/diagnosis , Heart Failure/surgery , Preoperative Care/methods , Risk Assessment/methods , Germany , Humans , Patient Selection , Practice Patterns, Physicians' , Prognosis , Risk FactorsSubject(s)
Cardiovascular Diseases/diagnosis , Heart Failure/diagnosis , Hernia, Ventral/surgery , Myocarditis/complications , Parvoviridae Infections/complications , Parvovirus B19, Human , Preoperative Care , Abdominal Pain/etiology , Adult , Cardiovascular Diseases/etiology , Heart Failure/etiology , Hernia, Ventral/etiology , Humans , Male , Myocarditis/virology , Parvoviridae Infections/virology , Parvovirus B19, Human/isolation & purification , Risk Assessment , Soccer/physiology , Weight Lifting/injuries , Weight Lifting/physiologySubject(s)
Cardiovascular Diseases/diagnosis , Preoperative Care/methods , Cardiovascular Diseases/etiology , Echocardiography , Electrocardiography , Exercise Test , Humans , Natriuretic Peptide, Brain , Nerve Tissue Proteins/blood , Peptide Fragments/blood , Preoperative Care/economics , Risk Assessment , Risk FactorsSubject(s)
Cardiovascular Diseases/therapy , Preoperative Care/methods , Adrenergic beta-Antagonists/therapeutic use , Algorithms , Angioplasty, Balloon, Coronary , Anti-Arrhythmia Agents/therapeutic use , Antihypertensive Agents/therapeutic use , Cardiotonic Agents/therapeutic use , Cardiovascular Diseases/diagnosis , Coronary Artery Bypass , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Risk Assessment , Risk FactorsABSTRACT
In patients with coronary artery disease undergoing noncardiac surgery, beta-blockers decrease perioperative mortality and nonfatal myocardial infarction. It is presently unknown whether beta-blockers reduce perioperative risk in patients with chronic heart failure. Thus, data of the CIBIS II study were analyzed regarding the effect of bisoprolol on perioperative outcome in patients with moderate to severe heart failure. A total of 2647 patients with heart failure in New York Heart Association (NYHA) class III-IV and left ventricular ejection fraction < or =35% were randomized to bisoprolol or placebo in a double-blind randomized study. Of these patients, 165 underwent surgery (bisoprolol, n = 87; placebo, n = 78). In patients undergoing surgery, mortality was not different between the placebo- and bisoprolol-treated group (7.7% vs 5.8%, p = 0.76). Neither postoperative hospital admission (placebo, 24.4%; bisoprolol, 34.5%, p = 0.17) nor time to postoperative hospital admission (placebo, < or =30 days, n = 2; 31-180 days, n=11; >180 days, n = 6; bisoprolol, n = 9/ 10/11; p = 0.14) were reduced by bisoprolol. Compared to coronary artery disease, perioperative beta-blockade has little effect in patients with chronic heart failure. Therefore, a controlled randomized trial with perioperative beta-blocker treatment in heart failure patients is warranted to further test this hypothesis.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Bisoprolol/pharmacology , Heart Failure/complications , Intraoperative Complications/prevention & control , Surgical Procedures, Operative , Adrenergic beta-Antagonists/administration & dosage , Adrenergic beta-Antagonists/therapeutic use , Adult , Aged , Aged, 80 and over , Bisoprolol/administration & dosage , Bisoprolol/therapeutic use , Data Interpretation, Statistical , Double-Blind Method , Female , Heart Failure/drug therapy , Heart Failure/mortality , Hospitalization , Humans , Intraoperative Complications/mortality , Length of Stay , Male , Middle Aged , Placebos , Risk Factors , Stroke Volume , Surgical Procedures, Operative/mortality , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: This study investigates the effects of a change of beta-adrenergic blocking agent treatment from metoprolol to carvedilol and vice versa in patients with heart failure (HF). BACKGROUND: Beta-blockers improve ventricular function and prolong survival in patients with HF. It has recently been suggested that carvedilol has more pronounced effects on left ventricular ejection fraction (LVEF) compared with metoprolol. It is uncertain whether a change from one beta-blocker to the other is safe and leads to any change of left ventricular function. METHODS: Forty-four patients with HF due to ischemic (n = 17) or idiopathic cardiomyopathy (n = 27) that had responded well to long-term treatment with either metoprolol (n = 20) or carvedilol (n = 24) were switched to an equivalent dose of the respective other beta-blocker. Before and six months after crossover of treatment, echocardiography, radionuclide ventriculography and dobutamine stress echocardiography were performed. RESULTS: Six months after crossover of beta-blocker treatment, LVEF had further improved with both carvedilol and metoprolol (carvedilol: 32 +/- 3% to 36 +/- 4%; metoprolol: 27 +/- 4% to 30 +/- 5%; both p < 0.05 vs. baseline), without interindividual differences. There were no changes in either New York Heart Association functional class or any other hemodynamic parameters at rest. Dobutamine stress echocardiography revealed a more pronounced increase of heart rate after dobutamine infusion in metoprolol- compared with carvedilol-treated patients. After dobutamine infusion, LVEF increased in the carvedilol- but not in the metoprolol-treated group. CONCLUSIONS: When switching treatment from one beta-blocker to the other, improvement of LVEF in patients with HF is maintained. Despite similar long-term effects on hemodynamics at rest, beta-adrenergic responsiveness is different in both treatments.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Carbazoles/therapeutic use , Heart Failure/drug therapy , Metoprolol/therapeutic use , Propanolamines/therapeutic use , Ventricular Function, Left , Carbazoles/pharmacology , Carvedilol , Chronic Disease , Cross-Over Studies , Female , Heart Failure/physiopathology , Hemodynamics , Humans , Male , Metoprolol/pharmacology , Middle Aged , Propanolamines/pharmacology , Prospective Studies , Stroke Volume , Ventricular Function, Left/drug effectsABSTRACT
Intrinsic activity and beta(1)-selectivity are important features of beta-blockers in the treatment of patients with coronary syndromes and heart failure. In human myocardium, intrinsic activity and beta(1)-selectivity of the novel beta-adrenoceptor antagonist nebivolol have not yet been determined. The study examines intrinsic activity, beta-adrenoceptor-G-protein coupling and beta(1)-selectivity of nebivolol and bisoprolol in human ventricular myocardium. Furthermore, intrinsic activity of both compounds is compared to the one of bucindolol, carvedilol and metoprolol in human atrial myocardium. Radioligand binding studies ([(125)I]-lodocyanopindolol) were performed on membrane preparations of human failing and nonfailing myocardium and on COS-7 cells transfected with human beta(1)- and beta(2)-adrenoceptors, respectively. Functional experiments were carried out on isolated muscle preparations of human left ventricular and right atrial myocardium from failing and nonfailing hearts. Radioligand binding studies reveal 3 - 4 fold beta(1)-selectivity for nebivolol and 16 - 20 fold beta(1)-selectivity for bisoprolol in human myocardium. In COS-7-cells, beta(1)-selectivity is 3 fold for nebivolol and 15 fold for bisoprolol. Neither the binding of nebivolol nor of bisoprolol is affected by the presence of guanylylimidodiphosphate (Gpp(NH)p). Nebivolol and bisoprolol exert similar inverse agonist activity in human ventricular as well as atrial myocardium. In atrial myocardium, inverse agonism of both compounds is higher compared to bucindolol, equal to carvedilol and lower compared to metoprolol. Favourable haemodynamic effects of nebivolol in humans are not due to beta(1)-selectivity or partial agonist activity of this agent. Other mechanisms, i.e. the production of nitric oxide, may thus be responsible for its unique haemodynamic profile.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Benzopyrans/pharmacology , Ethanolamines/pharmacology , GTP-Binding Protein alpha Subunits, Gs/drug effects , Heart/drug effects , Receptors, Adrenergic, beta-1/drug effects , Animals , COS Cells , GTP-Binding Protein alpha Subunits, Gs/genetics , Guanylyl Imidodiphosphate/pharmacology , Humans , Imidazoles/pharmacology , In Vitro Techniques , Iodocyanopindolol , Isoproterenol/pharmacology , Myocardial Contraction/drug effects , Myocardium/metabolism , Nebivolol , Propanolamines/pharmacology , Radioligand Assay , Receptors, Adrenergic, beta-1/genetics , TransfectionABSTRACT
OBJECTIVE: beta-Blockers improve cardiac function and survival in heart failure patients. The underlying mechanisms are not completely elucidated. Differences between agents might be important for the development of more specific therapeutical approaches. This study investigated whether metoprolol or carvedilol alter beta-adrenergic signaling differently. METHODS: beta-Adrenoceptor density and systolic function were determined in rat adult ventricular cardiac myocytes. RESULTS: 12 h isoprenaline-treatment (Iso, 1 micromol/l) reduced beta-adrenoceptor density by 33% (P<0.01). The effect was abolished by incubation with isoprenaline plus metoprolol (3 micromol/l), but was more pronounced after coincubation with carvedilol (0.003 micromol/l, P<0.05 Carv vs. Iso). Metoprolol alone had no effect on beta-adrenoceptor density, but carvedilol induced a decrease in receptor density even in absence of isoprenaline (P<0.05 Carv vs. ctr.). The isoprenaline (0.0003-10 micromol/l) induced concentration-dependent increase in myocyte shortening was blunted after 12 h preincubation with Iso (1 micromol/l, P<0.001). This reduction was abolished or partly prevented by coincubation with metoprolol or carvedilol, respectively. Carvedilol decreased the number of receptors which had to be occupied by isoprenaline in order to obtain 50% and 90% increase in myocyte cell shortening. Comparison of guanine nucleotide-dependent binding characteristics of isoprenaline, carvedilol and metoprolol revealed beta-receptor agonist like binding characteristics for carvedilol, but antagonist like binding characteristics for metoprolol. CONCLUSION: Metoprolol but not carvedilol prevents isoprenaline-induced downregulation of myocyte beta-adrenoceptors. The difference might be due to specific binding properties of the beta-blockers. Restoration of isoprenaline responsiveness by carvedilol might be due to improved coupling of beta-receptors to postreceptor effects.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Carbazoles/pharmacology , Isoproterenol/pharmacology , Metoprolol/pharmacology , Myocardium/metabolism , Propanolamines/pharmacology , Receptors, Adrenergic, beta/metabolism , Analysis of Variance , Animals , Carvedilol , Cell Size/drug effects , Cells, Cultured , Electric Stimulation , Guanylyl Imidodiphosphate , Male , Microscopy, Phase-Contrast , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Regression AnalysisABSTRACT
The human heart contains at least four distinct beta-adrenoceptor subtypes, three of which have been cloned. However, the binding properties of beta-blockers to the different beta-adrenoceptor subpopulations are not yet thoroughly characterized. Human beta1-, beta2- and beta3-adrenoceptors were expressed in COS-7 cells and [125I]iodocyanopindolol saturation binding, and competition experiments with commonly used beta-blockers were performed in the respective membrane preparations. Atenolol and metoprolol were about fivefold selective for beta1- versus beta2- and beta3-adrenoceptors. Bisoprolol was approximately 15-fold selective for beta1- versus beta2- and approximately 31-fold selective for beta1- versus beta3-adrenoceptors. Carvedilol was nonselective for any beta-adrenoceptor subtype. We conclude that the beta1-selectivities of atenolol, metoprolol, and bisoprolol are lower in COS cell membranes compared with previous investigations performed in native membranes. All beta-blockers investigated bind to beta3-adrenoceptors. Differential binding properties to beta3-adrenoceptors might imply different responses as to body weight, cardiac contractility, heart rate, and growth regulation. This might imply differential indications for the drugs investigated.
Subject(s)
Adrenergic beta-Antagonists/metabolism , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Adrenergic, beta-3/metabolism , Animals , Binding, Competitive/drug effects , COS Cells , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Humans , In Vitro Techniques , Iodocyanopindolol/metabolism , Myocardium/metabolism , Radioligand Assay , Receptors, Adrenergic, beta-1/drug effects , Receptors, Adrenergic, beta-1/genetics , Receptors, Adrenergic, beta-2/drug effects , Receptors, Adrenergic, beta-2/genetics , Receptors, Adrenergic, beta-3/drug effects , Receptors, Adrenergic, beta-3/genetics , TransfectionABSTRACT
1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Carbazoles/pharmacology , Heart Failure/drug therapy , Metoprolol/pharmacology , Propanolamines/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Adult , Aged , Carvedilol , Catecholamines/physiology , Female , Guanylyl Imidodiphosphate/pharmacology , Heart Failure/physiopathology , Humans , In Vitro Techniques , Iodocyanopindolol/metabolism , Male , Middle Aged , Myocardial Contraction/drug effectsABSTRACT
Sympathetic activation is a significant predictor of a poor prognosis in heart failure. Excessive stimulation with norepinephrine produces apoptosis, tachycardia and arrhythmias thereby leading to progression of left ventricular dysfunction and worsening of outcome. Beta-blockers reduce morbidity and improve cardiac function. They have been shown to improve survival (MERIT-HF, CIBIS II and US-Carvedilol Trials). A careful uptitration of dosages is achievable with a low rate of side effects. The mechanism of beta-blocker effects in heart failure are cardiac protection from beta1-adrenoceptor overstimulation, antiarrhythmic effects, reduction in heart rate and positive energetic effects or a combination thereof.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Cardiac Output, Low/drug therapy , Cardiac Output, Low/mortality , Cardiac Output, Low/physiopathology , Hemodynamics/drug effects , Humans , Neurosecretory Systems/physiopathology , Outcome Assessment, Health Care , Physical Endurance/drug effects , Ventricular Function/drug effects , Ventricular Remodeling/drug effectsABSTRACT
This study explores the main changes gained from Guided Imagery and Music (GIM) therapy as described by former clients. It also explores whether gains are integrated into the clients' lives and if those changes stabilize over periods of time after finishing GIM therapy. Questionnaires were sent to GIM therapists who forwarded them to former GIM clients. Twenty-five former GIM clients returned questionnaires directly to the researcher. Results show that the main gains reported by former clients of GIM therapy are (a) getting more in touch with one's emotions, (b) gaining insights into some problems, (c) spiritual growth, (d) increased relaxation, and (e) discovering new parts of oneself. Results also show that GIM therapy might be helpful for clients with symptoms of anxiety and/or fear, and for clients who want to increase their self-esteem. Changes gained during GIM therapy appear to stabilize over a period of time after finishing GIM therapy. They improved after termination of therapy, especially in the mental and transpersonal areas.