| 1. |
- Fu, Michael, 1963, et al.
(författare)
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Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy.
- 1993
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Ingår i: The Journal of clinical investigation. - 0021-9738. ; 91:5, s. 1964-8
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Tidskriftsartikel (refereegranskat)abstract
- A peptide corresponding to the sequence 169-193 of the second extracellular loop of the human muscarinic acetylcholine receptor-2 was used as an antigen to screen sera from patients with idiopathic dilated cardiomyopathy (DCM, n = 36) and healthy blood donors (HBD, n = 40). The sera from 14 patients with DCM (38.8%) and 3 HBD (7.5%) recognized the muscarinic receptor peptide at dilutions varying from 1:20 to 1:160 in ELISA. A highly significant correlation (P = 0.006) was found between the presence of antimuscarinic receptor-2 autoantibodies and anti-beta-adrenoceptor-1 autoantibodies in the patients' sera. Affinity-purified autoantibodies from positive sera of patients with DCM recognized on the electrotransferred protein of rat ventricular membrane a major band of about 80 kD. Incubation of autoantibodies with membrane resulted not only in a decrease in the maximal binding sites (Bmax) but also in an increase in Kd of radioligand binding in a concentration-dependent manner. This suggests a mixed-type of inhibition. Moreover, preincubation with atropine abolished the inhibitory effect of autoantibodies on the receptor binding whereas carbachol appeared to have no effect on the activity of the autoantibodies. These data define a subgroup of patients with idiopathic DCM who have in their sera functionally active autoantibodies against muscarinic receptor-2.
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| 2. |
- Karason, Kristjan, 1962, et al.
(författare)
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Effect of growth hormone treatment on circulating levels of NT-proBNP in patients with ischemic heart failure.
- 2020
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Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1532-2238. ; 55
-
Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH) therapy in heart failure (HF) is controversial. We investigated the cardiovascular effects of GH in patients with chronic HF due to ischemic heart disease.In a double-blind, placebo-controlled trial, we randomly assigned 37 patients (mean age 66years; 95% male) with ischemic HF (ejection fraction [EF]<40%) to a 9-month treatment with either recombinant human GH (1.4mg every other day) or placebo, with subsequent 3-month treatment-free follow-up. The primary outcome was change in left ventricular (LV) end-systolic volume measured by cardiac magnetic resonance (CMR). Secondary outcomes comprised changes in cardiac structure and EF. Prespecified tertiary outcomes included changes in New York Heat Association (NYHA) functional class and quality of life (QoL), as well as levels of insulin-like growth factor-1 (IGF-1) and N-terminal pro-brain natriuretic peptide (NT-proBNP).No changes in cardiac structure or systolic function were identified in either treatment group; nor did GH treatment affect QoL or functional class. In the GH group, circulating levels of IGF-1 doubled from baseline (+105%; p<0.001) and NT-proBNP levels halved (-48%; p<0.001) during the treatment period, with subsequently a partial return of both towards baseline levels. No changes in IGF-1 or NT-proBNP were observed in the placebo group at any time during the study.In patients with chronic ischemic HF, nine months of GH treatment was associated with significant increases in levels of IGF-1 and reductions in levels of NT-proBNP, but did not affect cardiac structure, systolic function or functional capacity.
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| 3. |
- Larsson, Bengt, et al.
(författare)
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Molecular oxygen in the rho Ophiuchi cloud
- 2007
-
Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 466:3, s. 5-
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Molecular oxygen, O2, has been expected historically to be an abundant component of the chemical species in molecular clouds and, as such, an important coolant of the dense interstellar medium. However, a number of attempts from both ground and from space have failed to detect O2 emission.Aims: The work described here uses heterodyne spectroscopy from space to search for molecular oxygen in the interstellar medium. Methods: The Odin satellite carries a 1.1 m sub-millimeter dish and a dedicated 119 GHz receiver for the ground state line of O2. Starting in 2002, the star forming molecular cloud core ρ Oph A was observed with Odin for 34 days during several observing runs.Results: We detect a spectral line at v_LSR =+3.5 km s-1 with Δ v_FWHM=1.5 km s-1, parameters which are also common to other species associated with ρ Oph A. This feature is identified as the O2 (NJ = 11 - 1_0) transition at 118 750.343 MHz.Conclusions: The abundance of molecular oxygen, relative to H{2} , is 5 × 10-8 averaged over the Odin beam. This abundance is consistently lower than previously reported upper limits.Based on observations with Odin, a Swedish-led satellite project funded jointly by the Swedish National Space Board (SNSB), the Canadian Space Agency (CSA), the National Technology Agency of Finland (Tekes) and Centre National d'Étude Spatiale (CNES). The Swedish Space Corporation has been the industrial prime contractor and also is operating the satellite. Appendix A is only available in electronic form at http://www.aanda.org
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| 4. |
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| 5. |
- Andersson, Bert, 1952, et al.
(författare)
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Changes in early and late diastolic filling patterns induced by long-term adrenergic beta-blockade in patients with idiopathic dilated cardiomyopathy.
- 1996
-
Ingår i: Circulation. - 0009-7322. ; 94:4, s. 673-82
-
Tidskriftsartikel (refereegranskat)abstract
- beta-Blockers have been used in patients with idiopathic dilated cardiomyopathy to improve cardiac performance and theoretically would be beneficial to diastolic function. However, there are few reports on changes in diastolic function during chronic pharmacological treatment of congestive heart failure.The present study was a substudy in the international Metoprolol in Dilated Cardiomyopathy Trial. Transmitral Doppler echocardiography was used to evaluate diastolic function in 77 patients randomly assigned to placebo (n = 37) or metoprolol (n = 40). The patients were treated for 12 months. Changes in Doppler flow variables in the metoprolol group implied a less restrictive filling pattern, expressed as an increase in E-wave deceleration time (placebo, 185 +/- 126 to 181 +/- 64 ms; metoprolol, 152 +/- 63 to 216 +/- 78 ms; P = .01, placebo versus metoprolol). Maximal increase in deceleration time had occurred by 3 months, whereas systolic recovery was achieved gradually and maximal effect was seen by 12 months of treatment. Although deceleration time was correlated to heart rate at baseline, changes in deceleration time were not significantly correlated to changes in heart rate during treatment.During the first 3 months of treatment, maximal effects on diastolic variables were reached, whereas the most prominent effect on systolic function was seen late in the study. It is suggested that effects on diastolic filling account for subsequent later myocardial systolic recovery. The E-wave deceleration time, which in recent studies has been shown to be a powerful predictor of survival, was significantly improved in the metoprolol-treated patients.
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| 6. |
- Andersson, Bert, 1952, et al.
(författare)
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Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment.
- 1994
-
Ingår i: Journal of the American College of Cardiology. - 0735-1097. ; 23:6, s. 1397-404
-
Tidskriftsartikel (refereegranskat)abstract
- This study was performed to investigate exercise hemodynamic status in a double-blind, placebo-controlled trial and was a substudy in the Metoprolol in Dilated Cardiomyopathy Trial.Previous open studies have shown beneficial effects on exercise hemodynamic status after beta-adrenergic blocking agent therapy in patients with congestive heart failure.The study included 41 patients with idiopathic dilated cardiomyopathy with ejection fraction < 0.40 (metoprolol, 20 patients; placebo, 21 patients) whose hemodynamic status was investigated at rest and during supine submaximal exercise, at baseline and after 6 and 12 months of treatment. Myocardial metabolism was evaluated in a subset of 19 patients.Metoprolol-treated patients responded favorably, as expressed by improved exercise cardiac index ([mean +/- SD] placebo 4.8 +/- 1.6 to 4.7 +/- 1.8 liters/min per m2, metoprolol 4.3 +/- 1.1 to 5.4 +/- 1.9 liters/min per m2, p = 0.0001) and stroke work index (placebo 44 +/- 20 to 41 +/- 27 g.m/m2, metoprolol 35 +/- 16 to 58 +/- 28 g.m/m2, p < 0.0001). Exercise systolic arterial pressure increased (placebo 161 +/- 25 to 151 +/- 23 mm Hg, metoprolol 155 +/- 29 to 165 +/- 37 mm Hg, p = 0.0003) as well as exercise oxygen consumption index (placebo 463 +/- 194 to 474 +/- 232 ml/min per m2, metoprolol 406 +/- 272 to 507 +/- 298 ml/min per m2, p = 0.045). There was a significant increase in exercise duration in the metoprolol group (63 +/- 38 s) compared with the placebo group (-24 +/- 42 s) (p = 0.01). Net myocardial lactate extraction increased in the metoprolol group, suggesting less myocardial ischemia (placebo 17 +/- 22 to 9.5 +/- 6.4 mmol/min, metoprolol -32 +/- 100 to 42 +/- 45 mmol/min, p = 0.03). Peripheral levels of norepinephrine tended to decrease at rest and during exercise, whereas myocardial net spillover was unchanged.Metoprolol improved hemodynamic status in patients with dilated cardiomyopathy at rest and had a more pronounced effect during exercise. These positive effects were achieved along with improved or stable myocardial metabolic data.
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| 7. |
- Ballegaard, Soren, et al.
(författare)
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In Ischemic Heart Disease, Reduced Sensitivity to Pressure at the Sternum Accompanies Lower Mortality after Five Years: Evidence from a Randomized Controlled Trial
- 2023
-
Ingår i: JOURNAL OF CLINICAL MEDICINE. - 2077-0383. ; 12:24
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Autonomic nervous system dysfunction (ANSD) is associated with negative prognosis of ischemic heart disease (IHD). Elevated periosteal pressure sensitivity (PPS) at the sternum relates to ANSD and sympathetic hyperactivity. Two previous observational case-control studies of the effect of reduction of PPS suggested lower all-cause mortality from IHD and stroke. We now used a specific daily, adjunct, non-pharmacological program of reduction of elevated PPS to test the hypothetical association between the intervention and reduced all-cause mortality in patients with stable IHD in a randomized controlled trial (RCT). Methods: We completed active (n = 106) and passive interventions (n = 107) and compared the five-year mortalities. We also compared the five-year individual all-cause mortality of each participant to approximately 35.000 members of the general population of Denmark. Pooling the mortality data from the active group of the RCT with the two preliminary studies, we registered the mortality following active intervention of 1.168 person-years, compared to 40 million person-years of the pooled general population. Results: We recorded fewer deaths of the active RCT intervention group than of the corresponding control group from the general population (p = 0.01), as well as of the passive RCT intervention group (p = 0.035). The meta-analysis of the three studies together demonstrated reduced 4.2-year all-cause mortality of 60% (p = 0.007). Conclusions: The test of the hypothetical effect of an intervention aimed at the attenuation of ANSD accompanied by a lowered PPS revealed reduced all-cause mortality in patients with stable IHD.
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| 8. |
- Batty, J. A., et al.
(författare)
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An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy
- 2014
-
Ingår i: Clinical Pharmacology & Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 95:3, s. 321-330
-
Tidskriftsartikel (refereegranskat)abstract
- To explore the pharmacogenetic effects of the cytochrome P450 (CYP) 2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional * 4 allele (1846G> A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6* 4 allele (EM: * 1* 1, 60.4%; IM: * 1* 4, 35.8%; and PM: * 4* 4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6* 4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.
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| 9. |
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| 10. |
- Bengtson, Ann, 1947, et al.
(författare)
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Cardiovascular and psychosomatic symptoms among relatives of patients waiting for possible coronary revascularization.
- 1996
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Ingår i: Heart & Lung: Journal of Acute & Critical Care. - : Mosby, Inc.. - 0147-9563 .- 1527-3288. ; 25:6, s. 438-43
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the consequences for close family members of patients on a waiting list for possible coronary revascularization. BACKGROUND: An increasing number of patients with symptomatic ischemic heart disease require evaluation for possible revascularization. Many of these patients must wait a long time before receiving treatment. The negative consequences of this long wait for patients and their relatives have not been satisfactorily evaluated previously. DESIGN: Cross-sectional descriptive study. SETTING: All hospitals in Southwestern Sweden. STUDY POPULATION: One hundred relatives of patients referred for possible revascularization and a sex- and age-matched reference group. The convenience sample consisted of 85% (n = 76) women and 15% (n = 13) men. OUTCOME MEASURES: Frequency of cardiovascular and psychosomatic symptoms. EVALUATION: One hundred relatives and 100 members of the control group were sent a questionnaire to evaluate their clinical condition; working situation; use of tobacco, alcohol and sedatives; and cardiovascular and psychosomatic symptoms. RESULTS: Family members had a significantly higher frequency of anxiety, depression, and irritability compared with the control group. Furthermore, family members reported sleeping disorders, including difficulty waking, tiredness due to lack of sleep, and restless sleep, more frequently than did the control group. CONCLUSION: Close family members of patients waiting for coronary revascularization have particular difficulties, and these difficulties should receive more attention.
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| 11. |
- Bengtson, Ann, 1947, et al.
(författare)
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Complications prior to revascularization among patients waiting for coronary artery bypass grafting and percutaneous transluminal coronary angioplasty
- 1996
-
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 17:12, s. 1846-1851
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To describe the occurrence of death, development of acute myocardial infarction and need for hospitalization among patients on the waiting list for coronary artery by pass grafting and percutaneous transluminal coronary angioplasty. PATIENTS AND METHODS: All the patients on the waiting list for possible coronary revascularization in September 1990 in western Sweden. RESULTS: Of 718 patients waiting for either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, 15 (2.1%) died between the actual week in September 1990 and prior to revascularization and 12 (1.7%) developed a non-fatal acute myocardial infarction during the same period. All 15 patients who died before undergoing revascularization died a cardiac death. Death and/or the development of an acute myocardial infarction was significantly more frequent among the elderly, among patients with a low ejection fraction and among patients with a history of diabetes mellitus. In all, 29% required hospitalization prior to the procedure. The most common reason was symptoms of angina pectoris requiring hospitalization in 23% of the patients. CONCLUSION: Among patients on the waiting list before either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, 15 (2.1%) died prior to the procedure and 1.7% developed a non-fatal acute myocardial infarction. The risk of either death or developing an acute myocardial infarction was highest among patients in the older age groups, among patients with a history of diabetes mellitus and among patients with a lower ejection fraction.
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| 12. |
- Bengtson, Ann, 1947, et al.
(författare)
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Distress correlates with the degree of chest pain: a description of patients awaiting revascularisation.
- 1996
-
Ingår i: Heart. - : B M J Group. - 1355-6037 .- 1468-201X. ; 75:3, s. 257-260
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To describe various symptoms other than pain among consecutive patients on the waiting list for possible coronary revascularisation in relation to estimated severity of chest pain. DESIGN: All patients were sent a postal questionnaire for symptom evaluation. SUBJECTS: All patients in western Sweden on the waiting list in September 1990 who had been referred for coronary angiography or coronary revascularisation (n = 904). RESULTS: 88% of the patients reported chest pain symptoms that limited their daily activities to a greater or lesser degree. Various psychological symptoms including anxiety and depression were strongly associated with the severity of pain (P < 0.001), as were sleep disturbances (P < 0.001), and dyspnoea and various psychosomatic symptoms (P < 0.001). Nevertheless only 44% of the patients reported chest pain as the major disruptive symptom, whereas the remaining 56% reported uncertainty about the future, fear, or unspecified symptoms as being the most disturbing. CONCLUSIONS: In a consecutive series of patients on the waiting list for possible coronary revascularisation, half the participants reported that uncertainty and fear were more disturbing than chest pain.
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| 13. |
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| 14. |
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| 15. |
- Biver, N., et al.
(författare)
-
Radio observations of Comet 9P/Tempel 1 before and after Deep Impact
- 2007
-
Ingår i: Icarus. - : Elsevier BV. - 1090-2643 .- 0019-1035. ; 191:2, s. 494-512
-
Tidskriftsartikel (refereegranskat)abstract
- Comet 9P/Tempel 1 was the target of a multi-wavelength worldwide investigation in 2005. The NASA Deep Impact mission reached the comet on 4.24 July 2005, delivering a 370-kg impactor which hit the comet at 10.3 km s -1 . Following this impact, a cloud of gas and dust was excavated from the comet nucleus. The comet was observed in 2005 prior to and after the impact, at 18-cm wavelength with the Nançay radio telescope, in the millimeter range with the IRAM and CSO radio telescopes, and at 557 GHz with the Odin satellite. OH observations at Nançay provided a 4-month monitoring of the outgassing of the comet from March to June, followed by the observation of H 2 O with Odin from June to August 2005. The peak of outgassing was found to be around 1 × 10 28 molec. s -1 between May and July. Observations conducted with the IRAM 30-m radio telescope in May and July 2005 resulted in detections of HCN, CH 3 OH and H 2 S with classical abundances relative to water (0.12, 2.7 and 0.5%, respectively). In addition, a variation of the HCN production rate with a period of 1.73 ± 0.10 days was observed in May 2005, consistent with the 1.7-day rotation period of the nucleus. The phase of these variations, as well as those of CN seen in July by Jehin et al. [Jehin, E., Manfroid, J., Hutsemékers, D., Cochran, A.L., Arpigny, C., Jackson, W.M., Rauer, H., Schulz, R., Zucconi, J.-M., 2006. Astrophys. J. 641, L145-L148], is consistent with a rotation period of the nucleus of 1.715 days and a strong variation of the outgassing activity by a factor 3 from minimum to maximum. This also implies that the impact took place on the rising phase of the "natural" outgassing which reached its maximum ≈4 h after the impact. Post-impact observations at IRAM and CSO did not reveal a significant change of the outgassing rates and relative abundances, with the exception of CH 3 OH which may have been more abundant by up to one order of magnitude in the ejecta. Most other variations are linked to the intrinsic variability of the comet. The Odin satellite monitored nearly continuously the H 2 O line at 557 GHz during the 38 h following the impact on the 4th of July, in addition to weekly monitoring. Once the periodic variations related to the nucleus rotation are removed, a small increase of outgassing related to the impact is present, which corresponds to the release of ≈ 5000 ± 2000 tons of water. Two other bursts of activity, also observed at other wavelengths, were seen on 23 June and 7 July; they correspond to even larger releases of gas. © 2006 Elsevier Inc. All rights reserved.
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| 16. |
- Biver, N., et al.
(författare)
-
Radio observations of Comet 9P/Tempel 1 before and after Deep Impact
- 2007
-
Ingår i: Icarus. - : Elsevier BV. - 1090-2643 .- 0019-1035. ; 187:1, s. 253-271
-
Tidskriftsartikel (refereegranskat)abstract
- Comet 9P/Tempel 1 was the target of a multi-wavelength worldwide investigation in 2005. The NASA Deep Impact mission reached the comet on 4.24 July 2005, delivering a 370-kg impactor which hit the comet at 10.3 km s -1 . Following this impact, a cloud of gas and dust was excavated from the comet nucleus. The comet was observed in 2005 prior to and after the impact, at 18-cm wavelength with the Nançay radio telescope, in the millimeter range with the IRAM and CSO radio telescopes, and at 557 GHz with the Odin satellite. OH observations at Nançay provided a 4-month monitoring of the outgassing of the comet from March to June, followed by the observation of H 2 O with Odin from June to August 2005. The peak of outgassing was found to be around 1 × 10 28 molec. s -1 between May and July. Observations conducted with the IRAM 30-m radio telescope in May and July 2005 resulted in detections of HCN, CH 3 OH and H 2 S with classical abundances relative to water (0.12, 2.7 and 0.5%, respectively). In addition, a variation of the HCN production rate with a period of 1.73 ± 0.10 days was observed in May 2005, consistent with the 1.7-day rotation period of the nucleus. The phase of these variations, as well as those of CN seen in July by Jehin et al. [Jehin, E., Manfroid, J., Hutsemékers, D., Cochran, A.L., Arpigny, C., Jackson, W.M., Rauer, H., Schulz, R., Zucconi, J.-M., 2006. Astrophys. J. 641, L145-L148], is consistent with a rotation period of the nucleus of 1.715 days and a strong variation of the outgassing activity by a factor 3 from minimum to maximum. This also implies that the impact took place on the rising phase of the "natural" outgassing which reached its maximum ≈4 h after the impact. Post-impact observations at IRAM and CSO did not reveal a significant change of the outgassing rates and relative abundances, with the exception of CH 3 OH which may have been more abundant by up to one order of magnitude in the ejecta. Most other variations are linked to the intrinsic variability of the comet. The Odin satellite monitored nearly continuously the H 2 O line at 557 GHz during the 38 h following the impact on the 4th of July, in addition to weekly monitoring. Once the periodic variations related to the nucleus rotation are removed, a small increase of outgassing related to the impact is present, which corresponds to the release of ≈ 5000 ± 2000 tons of water. Two other bursts of activity, also observed at other wavelengths, were seen on 23 June and 7 July; they correspond to even larger releases of gas. © 2006 Elsevier Inc. All rights reserved.
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| 17. |
- Bollano, Entela, 1970, et al.
(författare)
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Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure.
- 2003
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Ingår i: Heart (British Cardiac Society). - 1468-201X. ; 89:6, s. 621-4
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Tidskriftsartikel (refereegranskat)abstract
- To determine whether patients with congestive heart failure on different beta adrenoreceptor blocking drugs have similar haemodynamic responses to dobutamine.Single centre, single blind, randomised, two period crossover study comparing carvedilol with metoprolol CR/XL.Ten patients with stable chronic congestive heart failure (ejection fraction < 40%) on chronic treatment with metoprolol CR/XL.Patients were treated with carvedilol or metoprolol CR/XL (target dose 50 mg twice daily and 200 mg once daily, respectively) for eight weeks. Stress echocardiography was undertaken at the end of each maintenance period, using dobutamine 5 and 15 microg/kg/min.No significant haemodynamic differences were seen at rest on the two treatments. There was a more pronounced increase in heart rate and cardiac output during dobutamine infusion when the patients were on metoprolol than when they were on carvedilol. Mean arterial pressure increased significantly when the patients were on carvedilol, and cardiac output increased during low dose dobutamine, without further change during high dose dobutamine. During the dobutamine infusion, there was no significant difference in ejection fraction between carvedilol and metoprolol treatment.Patients with congestive heart failure on a non-selective beta adrenoreceptor blocker or beta1 selective blocker responded differently to the inotropic drug dobutamine: the beta1 blockade caused by metoprolol could be counteracted by dobutamine, whereas with carvedilol a low dose of dobutamine increased cardiac output, and a higher dose of dobutamine caused a pressor effect. These findings may be clinically relevant when choosing an inotropic drug.
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| 18. |
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| 19. |
- Caro, J. J., et al.
(författare)
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Economic implications of extended-release metoprolol succinate for heart failure in the MERIT-HF trial: a US perspective of the MERIT-HF trial
- 2005
-
Ingår i: J Card Fail. - 1071-9164. ; 11:9, s. 647-56
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The MERIT-HF trial demonstrated improved survival and fewer hospitalizations for worsening heart failure with extended-release (ER) metoprolol succinate in patients with heart failure. This study sought to estimate the economic implications of this trial from a US perspective. METHODS AND RESULTS: A discrete event simulation was developed to examine the course of patients with heart failure. Characteristics of the population modeled, probabilities of hospitalization and death with standard therapy, and risk reductions with ER metoprolol succinate were obtained from Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) and evaluated in weekly cycles. Direct medical costs were estimated from US databases in 2001 US dollars. Uncertainty in inputs was incorporated and analyses were carried out to estimate events prevented total and net costs. The model predicts that ER metoprolol succinate will prevent approximately 7 deaths and 15 hospitalizations from heart failure per 100 patients over 2 years. Compared with standard therapy alone, this translates to a cost reduction between $395 and $1112 per patient, depending on whether the costs of hospitalizations for other causes are included. Savings were maintained in 90% of the simulations. CONCLUSION: This analysis predicts that the positive effect of ER metoprolol succinate on mortality and morbidity demonstrated in MERIT-HF leads to substantial savings.
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| 20. |
- Cleland, J. G. F., et al.
(författare)
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Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials
- 2018
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 39:1, s. 26-35
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Tidskriftsartikel (refereegranskat)abstract
- Aims Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF >= 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 >= 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF >= 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF >= 50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conculations Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.
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| 21. |
- Cleland, John G F, et al.
(författare)
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Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).
- 2009
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 1558-3597 .- 0735-1097. ; 54:20, s. 1850-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. BACKGROUND: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. METHODS: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. CONCLUSIONS: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin.
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| 22. |
- Crovisier, J., et al.
(författare)
-
The chemical composition of 9P/tempel 1 from radio observations
- 2009
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Ingår i: ESO Astrophysics Symposia. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 1431-2433 .- 1611-6143. - 9783540769583 ; 2009, s. 243-248
-
Konferensbidrag (refereegranskat)abstract
- In 2005, as part of a world-wide multi-wavelength investigation of comet 9P/Tempel 1 in support to the Deep Impact mission, we conducted radio spectroscopic observations with the Nançay radio telescope, the Odin satellite, the CSO 10-m and the IRAM 30-m telescopes. We report here our results concerning the chemical composition of the comet. The relative abundances of the detected species (H2O, CH3OH, H2S, HCN) or their upper limits (CO, H2CO, CS) are comparable to the mean values observed in other comets. No significant changes of the outgassing rates (except possibly for CH3OH) or of the molecular abundances were observed following the impact.
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| 23. |
- Elies, Rozenn, et al.
(författare)
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Immunochemical and functional characterization of an agonist-like monoclonal antibody against the M2 acetylcholine receptor.
- 1998
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Ingår i: European journal of biochemistry / FEBS. - 0014-2956. ; 251:3, s. 659-66
-
Tidskriftsartikel (refereegranskat)abstract
- Monoclonal antibodies were raised against a peptide corresponding to the second extracellular loop of the M2 acetylcholine receptor. One of the monoclonal antibodies, B8E5, was selected for further characterization on the basis of its high yield, its isotype (IgG2a), its dissociation kinetics and its agonist-like activity. The epitope recognized by B8E5 corresponded to the N-terminal part of the second extracellular loop of the receptor (V-R-T-V-E-) as determined by competition immunoassays and epitope scanning. The KA of B8E5 for the target peptide was assessed by surface plasmon resonance (SPR) to be 6.5x10(7) M(-1) by equilibrium and 3.7x10(7) M(-1) by kinetic analysis. B8E5 recognized the M2 acetylcholine receptor on rat cardiac tissue. It only recognized the non-reduced receptor in immunoblots. The antibody had no effect on antagonist binding but decreased the affinity for the agonist carbachol. B8E5 decreased the beating frequency of neonatal rat cardiomyocytes. The effect was specific since it was blocked by the target peptide and the antagonist atropine. The EC50 of the antibody corresponded to the KA measured by surface plasmon resonance. The physiological effect of the antibody did not lead to desensitization. The Fab fragments had no physiological effect; subsequent addition of anti-mouse IgG however restored the physiological effect. These results confirm that the N-terminus of the second extracellular loop is a functional target for antibodies against the M2 acetylcholine receptor. They suggest that the functional epitope is only accessible in the non-reduced receptor. The antibodies act through a functional dimerization of the receptor.
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| 24. |
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| 25. |
- Fu, Michael, 1963, et al.
(författare)
-
Activity of receptors coupled to guanine nucleotide binding regulatory protein in doxorubicin induced cardiomyopathy.
- 1991
-
Ingår i: Cardiovascular research. - 0008-6363. ; 25:2, s. 145-50
-
Tidskriftsartikel (refereegranskat)abstract
- STUDY OBJECTIVE--The aim was to study the activity of receptors coupled to guanine nucleotide binding regulatory proteins (G proteins) in doxorubicin induced cardiomyopathy, with special attention to G proteins, beta adrenoceptors, muscarinic receptors, and adenylyl cyclase. DESIGN--Messenger RNA of G proteins, densities and high affinity agonist binding of beta adrenoceptors and muscarinic receptors, activity of adenylyl cyclase, calcium influx, and in vivo lipid peroxidation were determined before, in the early stage, and in the later stage of doxorubicin cardiomyopathic heart failure. SUBJECTS--Sprague-Dawley rats between 150-200 g were used. Doxorubicin was given intravenously at two doses of 4 mg.kg-1 and 6 mg.kg-1 every third week (1st, 4th, 7th week) for nine weeks. Doxorubicin treated rats plus corresponding controls were killed at 3 weeks (n = 7), 6 weeks (n = 7), and 9 weeks (n = 6), respectively. MEASUREMENTS AND MAIN RESULTS--Northern blot and dot blot hybridisations of the total RNA revealed that messenger RNA of both stimulatory and inhibitory G proteins were identical between doxorubicin treated rats and controls. No alterations in the densities of beta adrenoceptors and muscarinic receptors were observed, neither did the high affinity agonist binding of beta adrenoceptors and muscarinic receptors change. Furthermore, modulation of adenylyl cyclase was unimpaired. In contrast, Ca(2+)-ATPase and serum water soluble fluorescent substance, a product of in vivo lipid peroxidation, were shown to increase dramatically in doxorubicin treated rats (4 mg.kg-1 for 6 and 9 weeks, 6 mg.kg-1 for 3, 6 and 9 weeks) as compared with corresponding controls. CONCLUSIONS--The findings suggest that, despite increased calcium influx and lipid peroxidation in doxorubicin induced cardiomyopathy, the activity of receptors coupled to G proteins remained normal.
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| 26. |
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| 27. |
- Fu, Michael, 1963, et al.
(författare)
-
Autoantibodies against cardiac G-protein-coupled receptors define different populations with cardiomyopathies but not with hypertension.
- 1994
-
Ingår i: Clinical immunology and immunopathology. - 0090-1229. ; 72:1, s. 15-20
-
Tidskriftsartikel (refereegranskat)abstract
- It was previously shown that the second extracellular loop of cardiovascular G-protein-coupled receptors is an antigenic target for pharmacologically active autoantibodies in patients with idiopathic dilated cardiomyopathy. To extend these observations to cover patients with the same disease from different geographical origins or to patients with other cardiac diseases, peptides corresponding to the sequences of the second extracellular loops of the human M2 muscarinic receptors and beta adrenoceptors were used as antigens in an enzyme immunoassay. Sera from patients from Sweden and Japan with idiopathic dilated cardiomyopathy (DCM, n = 32), hypertrophic cardiomyopathy (HCM, n = 23), malignant essential hypertension (MEH, n = 11), malignant secondary hypertension (MSH, n = 10), and sera from healthy blood donors (HBD, n = 49) were tested. Sera from patients with DCM recognized the muscarinic receptor peptide in 38% of cases and the beta 1 adrenoceptor peptide in 31% of cases. In 50% of the positive patients, autoantibodies against both peptides coexisted as shown by competition experiments using both peptides as inhibitors. In HCM patients, there was a lower frequency of autoantibodies but with a higher but not significant predominance against the M2 peptide. No autoantibodies were detected in sera from patients with MEH or MSH. Autoantibodies against the M2 muscarinic receptors, affinity-purified from positive patients, displayed pharmacological activity as demonstrated by changes in the affinity and number of radioligand binding sites. In contrast, antibodies purified from positive HBD had no effect. These results confirm that autoantibodies displaying pharmacological activity against G-protein-coupled cardiovascular receptors are mainly restricted to patients with idiopathic dilated cardiomyopathy and that different autoantibody populations are responsible for the recognition of the different receptors.
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| 28. |
- Fu, Michael, 1963, et al.
(författare)
-
Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.
- 2000
-
Ingår i: Journal of hypertension. - 0263-6352. ; 18:7, s. 945-53
-
Tidskriftsartikel (refereegranskat)abstract
- Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.
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| 29. |
- Fu, Michael, 1963, et al.
(författare)
-
Characterization of anti-peptide antibodies directed against an extracellular immunogenic epitope on the human alpha 1-adrenergic receptor.
- 1994
-
Ingår i: Clinical and experimental immunology. - 0009-9104. ; 97:1, s. 146-51
-
Tidskriftsartikel (refereegranskat)abstract
- A synthetic peptide corresponding to amino acids 192-218 of the second extracellular loop of the human alpha 1A-adrenergic receptor was used to raise antibodies in rabbits. Affinity-purified antibodies specifically recognized main bands with a molecular weight of about 68, 40 and 37 kD on the electrotransferred membrane proteins of rat ventricle membranes. The incubation of these antibodies with rat myocardial membranes resulted in a decrease in the number of binding sites for the specific radiolabelled alpha 1-antagonist prazosin. These antibodies were also able to mimic the effects of agonist stimulation as demonstrated by a positive chronotropic effect on cultured cardiomyocytes. These results constitute the first immunochemical evidence of the presence of both the A and B subtypes of the alpha 1-adrenergic receptor in the heart. They also confirm that the second extracellular loop of the alpha 1-adrenergic receptors is an immunologically and functionally important domain.
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| 30. |
- Fu, Michael, 1963, et al.
(författare)
-
Decreased density of mesenteric arteries but not of myocardial endothelin receptors and function in rats with chronic ischemic heart failure.
- 1993
-
Ingår i: Journal of cardiovascular pharmacology. - 0160-2446. ; 22:2, s. 177-82
-
Tidskriftsartikel (refereegranskat)abstract
- Mesenteric artery and cardiac ventricular endothelin receptors and endothelin-1-induced pressor responses were studied in normal rats and rats with chronic congestive heart failure induced by myocardial ischemia (4 weeks after coronary artery ligation). In mesenteric arteries of rats with chronic ischemic heart failure, endothelin receptor density was significantly decreased by 59%, whereas the dissociation constant was increased 2.8-fold, as compared with controls. There were, however, no changes in endothelin-receptor density or the dissociation constant in cardiac ventricular membrane preparations from rats with congestive heart failure as compared with controls. In pithed rats with congestive heart failure there was a reduced pressor response to a bolus injection of endothelin-1 (800 pmole/kg body weight), while the vasodilatory response was unaltered as compared with sham-operated controls. These results demonstrate that there is a decreased vascular endothelin-receptor function due to a down-regulated endothelin receptor. The in vivo data indicate that this is due to impaired endothelin A but not endothelin B receptor function. Thus, there is an impaired arterial but not cardiac ventricular endothelin receptor-mediated signalling system in the rat with chronic ischemic heart failure.
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| 31. |
- Fu, Michael, 1963, et al.
(författare)
-
Diabetes-induced changes in the Gi-modulated muscarinic receptor-adenylyl cyclase system in rat myocardium.
- 1994
-
Ingår i: Pharmacology & toxicology. - 0901-9928. ; 75:3-4, s. 186-93
-
Tidskriftsartikel (refereegranskat)abstract
- The inhibitory guanine nucleotide binding regulatory protein (Gi)-mediated muscarinic receptor-adenylyl cyclase system was studied in myocardium from adult male Wistar rats with 10 weeks of diabetes induced by a single intravenous injection of streptozotocin (60 mg/kg). Neither the messenger ribonucleic acid level nor the amount of Gi was changed in the streptozotocin diabetic group as compared to the control group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate was decreased by 48% in the streptozotocin diabetic group whereas stimulated activities of adenylyl cyclase by sodium fluoride and forskolin remained unchanged. The inhibition of forskolin-stimulated adenylyl cyclase activity by carbachol was more potent in membranes from the streptozotocin diabetic group than that in membranes from the control group. The competition binding curve between (3H)- quinuclidinyl benzilate and carbachol obtained from the streptozotocin diabetic group was shifted to the left as compared to the control group. These results suggest that the myocardium of streptozotocin-induced diabetic rats exhibited an increase in Gi function as demonstrated by the increased inhibition of guanyliminodiphosphate-mediated adenylyl cyclase and the superhigh affinity for carbachol of the muscarinic receptors. As there were signs, similar to those seen in clinical heart failure, in the streptozotocin diabetic group, these results demonstrate that functional alteration of Gi might underlie, at least in part, the cardiac dysfunction that is associated with diabetes.
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| 32. |
- Fu, Michael, 1963, et al.
(författare)
-
Effect of metoprolol on activity of beta-adrenoceptor coupled to guanine nucleotide binding regulatory proteins in adriamycin-induced cardiotoxicity.
- 1991
-
Ingår i: Basic research in cardiology. - 0300-8428. ; 86:2, s. 117-26
-
Tidskriftsartikel (refereegranskat)abstract
- Prevention of cardiotoxicity without interfering with the therapeutic efficacy of adriamycin is a very crucial question. We have investigated the activity of beta-adrenoceptor coupled to guanine nucleotide binding regulatory proteins (G-proteins) and Ca(2+)-ATPase activity in experimental adriamycin-induced cardiotoxicity and the influence of metoprolol treatment on these variables. Adriamycin was administered to rats intravenously as a single dose of 6 mg/kg, and metoprol was continuously given by means of implanted osmotic pumps. beta-Adrenoceptor characteristics were measured by radioligand-binding experiments and by basal and stimulated adenylyl cyclase activity. Northern blot and dot blot analysis was used to quantify G-protein mRNA. It was shown that adriamycin did not induce any change in the total beta-adrenoceptor density, nor did the high affinity agonist binding to beta-adrenoceptor change. Adriamycin did not induce any alteration in the amount of mRNA encoding for stimulatory (Gs) or inhibitory (Gi) G-proteins. Also, basal and stimulated adenylyl cyclase activities were identical in the different experimental groups. In contrast, the Ca(2+)-ATPase was shown to increase in adriamycin-treated rats compared to control rats (45 +/- 3.8 versus 23 +/- 1.2 mumol Pi/mg/h, P less than .01). Metoprolol was shown to normalize this increase (29 +/- 2.1 mumol Pi/mg/h). Thus, it may be concluded that in experimental adriamycin-induced cardiotoxicity, despite Ca(2+)-overloading, the beta-adrenoceptor-G protein-adenylyl cyclase system remains intact. Metoprolol seems to prevent Ca(2+)-overloading independently of the beta-adrenoceptors studied here.
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| 33. |
- Fu, Michael, 1963, et al.
(författare)
-
Free radical scavenging enzymes and G protein mediated receptor signalling systems in ischaemically preconditioned porcine myocardium.
- 1993
-
Ingår i: Cardiovascular research. - 0008-6363. ; 27:4, s. 612-6
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Increased antioxidant defence and altered G protein mediated receptor signalling systems could be expected in myocardial preconditioning. The myocardial antioxidant defence and the integrity of the G protein mediated receptor signalling systems were therefore examined in normal and preconditioned myocardium. METHODS: Preconditioning in the porcine heart was induced by two occlusions of the mid left anterior descending coronary artery for 10 min, with a 30 min reperfusion interval. Left ventricular biopsies were obtained from control and preconditioned regions 30 min after the last occlusion. RESULTS: In biopsies from the preconditioning region, neither the activities of superoxide dismutase of glutathione peroxidase, nor the content of malondialdehyde were changed. There were no alterations in either the number of receptors (beta adrenergic, muscarinic and endothelin receptors) or the amount of G proteins. Furthermore, the activity of adenylyl cyclase remained unchanged. CONCLUSIONS: No change in the antioxidant defence was demonstrated in preconditioned myocardium. This finding does not support the hypothesis that increased antioxidant defence could contribute to the cardioprotection of preconditioning. Additionally, an intact G protein mediated receptor signalling system was found in preconditioned myocardium with regard to beta adrenergic, muscarinic, and endothelin receptors.
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| 34. |
- Fu, Michael, 1963, et al.
(författare)
-
Functional autoimmune epitope on alpha 1-adrenergic receptors in patients with malignant hypertension.
- 1994
-
Ingår i: Lancet. - 0140-6736. ; 344:8938, s. 1660-3
-
Tidskriftsartikel (refereegranskat)abstract
- Because of the growing evidence that hypertensive disease is accompanied by immunological dysfunction, we have investigated autoimmunity in patients with malignant hypertension. Peptides corresponding to the sequence of the second extracellular loops of the human alpha 1-adrenergic receptor and the M2-muscarinic receptor were used as antigens in an ELISA. Serum from 4 (12%) of 33 healthy controls, 3 (20%) of 15 patients with malignant essential hypertension, and 7 (64%) of 11 with secondary hypertension showed positive responses in the ELISA for the alpha 1-adrenergic receptor peptide. Positive responses were significantly more common among the patients with secondary hypertension than in the other two groups (p < 0.01). By contrast, no autoantibodies against the M2-muscarinic receptor peptide were detected in either hypertensive group. Autoantibodies against the alpha 1-adrenergic receptor, affinity-purified from patients with positive responses, specifically recognised bands with molecular masses of 68, 40, and 37 kDa on immunoblotted membrane proteins of rat ventricles. The patients' autoantibodies caused a decrease in tritiated prazosin binding sites and an increase in heart beating frequency of neonatal cultured rat cardiomyocytes; antibodies purified from the controls had no effect. Circulating autoantibodies against the alpha 1-adrenergic receptor are present in a subgroup of patients with malignant hypertension. These autoantibodies have pharmacological activity in vitro, which suggests that they may be involved in the pathogenesis of malignant hypertension.
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| 35. |
- Fu, Michael, 1963, et al.
(författare)
-
Gi-mediated muscarinic adenylyl cyclase inhibition in timolol-treated stunned porcine myocardium.
- 1994
-
Ingår i: Acta physiologica Scandinavica. - 0001-6772. ; 151:3, s. 291-9
-
Tidskriftsartikel (refereegranskat)abstract
- The Gi-mediated muscarinic receptor-adenylyl cyclase system was examined in stunned myocardium induced by either three or five brief ischaemic periods after beta-adrenoceptor blockade by timolol (0.1 mg kg-1). The mid-left anterior descending coronary artery was occluded for 2, 10 and 2 min in four pigs, and for 2, 2, 5, 10 and 2 min in four other pigs. All the ischaemic periods were separated by 30 min of reperfusion and the biopsies were obtained 60 min after the last ischaemic period. Segment length function was measured in the ischaemic region and in the control region supplied by the left circumflex artery. In the two groups, the percentage systolic shortening was reduced equally, to 59 +/- 9 and 58 +/- 10% of control in the region subjected to ischaemia and only minimally in the control region. The biopsies from the stunned region from both groups showed: (1) no change in either the affinity for carbachol or the number of binding sites of the muscarinic receptors; (2) no alterations in messenger RNA encoding for the alpha subunit-2 of the inhibitory guanine nucleotide binding protein, as demonstrated by northern blot and solution hybridization; (3) no change in membrane-bound inhibitory guanine nucleotide binding protein, as shown by enzyme immunoassay utilizing a specific anti-peptide antibody, and (4) unchanged inhibition of stimulated adenylyl cyclase activity. These results suggest that there is an intact inhibitory guanine nucleotide binding protein-mediated muscarinic receptor adenylyl cyclase system in the stunned porcine myocardium.
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| 36. |
|
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| 37. |
- Fu, Michael, 1963, et al.
(författare)
-
Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat.
- 1993
-
Ingår i: Cardiovascular research. - 0008-6363. ; 27:11, s. 2065-70
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim was to study the Gi protein mediated muscarinic signalling system in the myocardium of rats with chronic ischaemic heart failure. METHODS: Chronic ischaemic heart failure was induced by myocardial ischaemia (four weeks after coronary artery ligation) in rats. The densities and agonist affinities of muscarinic receptors, and the functional activity and concentration of Gi proteins were studied. RESULTS: In failing hearts, the activity of adenylyl cyclase stimulated by guanyliminodiphosphate (Gpp(NH)p) was decreased by 46%. Stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin, however, remained unchanged. Carbachol depressed forskolin stimulated adenylyl cyclase more in membranes from failing hearts than those from normal hearts. The functional level of Gs protein as measured by a reconstitution assay in sarcolemmal membrane did not differ between the two groups. Furthermore, muscarinic receptors exhibited superhigh and low affinities for agonist in failing hearts whereas those in control hearts displayed only high and low affinities. No significant difference in the peptide equivalent amount of membrane bound Gi protein was found in either group. CONCLUSIONS: The experimental chronic failing heart due to myocardial ischaemia showed a depressed myocardial adenylyl cyclase signalling system. This may be due to the hypersensitivity of the Gi protein mediated muscarinic receptor-adenylyl cyclase system as shown by the increased inhibition of Gpp(NH)p mediated adenylyl cyclase, more potent inhibition of stimulated adenylyl cyclase by carbachol, and the superhigh affinity of the muscarinic receptors for carbachol.
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| 38. |
- Fu, Michael, 1963, et al.
(författare)
-
Immunocytochemical localization of M2 muscarinic receptors in rat ventricles with anti-peptide antibodies.
- 1994
-
Ingår i: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. - 0022-1554. ; 42:3, s. 337-43
-
Tidskriftsartikel (refereegranskat)abstract
- We produced antibodies against a synthetic peptide corresponding to amino acids 168-192 of the second extracellular loop of the M2 human muscarinic receptor in rabbits. In immunoblot, affinity-purified antibodies specifically recognized a major band of rat ventricular muscarinic receptor protein with a molecular weight of about 80 KD. This recognition could be blocked by pre-incubation with peptide. Moreover, with both light (LM) and electron microscopic (EM) immunocytochemistry techniques, muscarinic receptors were detected on sarcolemma and T-tubules of rat cardiomyocytes. In addition, immunoreactions were localized in membranes of capillaries. Likewise, these reactivities were abolished by pre-incubation with peptide. These results suggest that the antibodies against the second extracellular loop of human M2 muscarinic receptor could specifically recognize rat ventricular muscarinic receptor protein and could be a powerful tool to study the fate of this receptor under different pathological or physiological conditions.
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| 39. |
- Fu, Michael, 1963, et al.
(författare)
-
Immunohistochemical localization of angiotensin II receptors (AT1) in the heart with anti-peptide antibodies showing a positive chronotropic effect.
- 1998
-
Ingår i: Receptors & channels. - 1060-6823. ; 6:2, s. 99-111
-
Tidskriftsartikel (refereegranskat)abstract
- Antibodies were produced against a synthetic peptide corresponding to amino acids (165-191) of the second extracellular loop of the human angiotensin II receptor subtype 1 (AT1) in rabbits. The purified antibodies had an apparent affinity of about 1 nM and were monospecific for the AT1-receptor peptide. Chemical modification of the carboxyl groups (glu at positions 173 and 185) and the sulfhydryl group (cys at position 180) of the AT1-receptor peptide did not alter the relative affinity of the coated AT1-receptor peptide to antibodies. The antibodies specifically stained CHO cells expressing the rat AT1a receptor. Immunoblots on rat kidney revealed that the antibody recognized a protein band of 59 +/- 3 kDa in a dose-dependent manner and this band was no longer detected after preincubating the antibodies with AT1-receptor peptide. Using electron microscopic and immunofluorescence immunocytochemistry techniques, angiotensin II receptors were detected in (1) the sarcolemma, T-tubules and nuclei of rat cardiomyocytes, (2) the transluminal side of endothelial cells and (3) fibroblast cells. These localizations are specific, as the immunostaining did not appear when preimmune rabbit serum was used and was blocked after preincubating antibodies with antigenic peptide. Functionally, these antibodies did not affect the ligand binding properties of the receptors but displayed agonist-like activity as shown by dose-dependent increases in beating frequency in cultured neonatal cardiomyocytes. These results suggest that the antibodies against the second extracellular loop of human AT1 receptors were able to specifically recognize AT1 receptors. In addition, they extend the observation that the second extracellular loop of the G-protein coupled membrane receptors is a specific target for antibodies with agonist-like activity.
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| 40. |
- Fu, Michael, 1963, et al.
(författare)
-
Increase in functional activity rather than in amount of Gi-alpha in failing human heart with dilated cardiomyopathy.
- 1992
-
Ingår i: Cardiovascular research. - 0008-6363. ; 26:10, s. 950-5
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim was to investigate whether or not increased pertussis toxin catalysed ADP ribosylation correlates with increased amount of Gi-alpha in failing human heart. DESIGN: Antisera raised against unique synthetic peptides corresponding to alpha subunits of Gs and Gi 1-3 were used in immunoblotting and ELISA to determine amounts of various G proteins. Adenylyl cyclase activity, beta adrenoceptors, and muscarinic receptors were then measured in cardiomyopathic hearts (n = 6) obtained at transplant in order to study whether or not an altered expression of G proteins has relevance to the integrity and function of the receptor--adenylyl cyclase system. Six non-failing control hearts were also studied. RESULTS: No significant differences in the peptide equivalent amounts of either Gs or Gi were found in the failing human heart as compared to the non-failing heart. However, functional activity of Gi was shown to increase significantly since there was a decrease in basal (57%), isoprenaline stimulated (60%), and guanyliminodiphosphate stimulated (52%) adenylyl cyclase activity. In contrast the density of beta adrenoceptors was markedly decreased (51%) in failing human heart in comparison to non-failing hearts. Neither the density nor the affinity of muscarinic receptors changed in the failing human heart. CONCLUSION: These results suggest that in the failing human heart, there is an increase in functional activity rather than in amount of Gi, and an important part of functional expression of Gi-alpha may be regulated at the post-translational level.
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| 41. |
- Fu, Michael, 1963, et al.
(författare)
-
Myocardial hypertrophy in transgenic mice overexpressing the bovine growth hormone (bGH) gene.
- 2000
-
Ingår i: Journal of internal medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 247:5, s. 546-52
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The main purpose of the present study was to characterize cardiac muscle hypertrophy using both qualitative and quantitative microscopy in mice overexpressing the bovine growth hormone. RESULTS: Measurements of 30 fibres from each group revealed that fibre diameter in transgenic hearts was significantly larger than in control hearts. There was a significant decrease in interfibrillar space in transgenic hearts as compared with control hearts. The enlarged transgenic hearts displayed unchanged organelles such as normal myofibrils and mitochondria in a normal pattern, suggesting balanced growth. Myelin structures were occasionally observed between normal myofibrils. Moreover, myocardial beta-adrenergic receptors and muscarinic receptors in the hearts of transgenic mice overproducing GH were studied to see whether they are involved in the hypertrophic process. It was shown that the density of muscarinic receptors had decreased and the super-high affinity of muscarinic receptors was lost, without any significant changes in either the density or the affinity of beta-adrenergic receptors, as compared with controls. CONCLUSIONS: These results demonstrate that a GH excess was able to induce significant myocardial hypertrophy and that there was a downregulation of muscarinic receptors.
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| 42. |
- Fu, Michael, 1963, et al.
(författare)
-
Oxygen free radical injury and Gs mediated signal transduction in the stunned porcine myocardium.
- 1992
-
Ingår i: Cardiovascular research. - 0008-6363. ; 26:5, s. 449-55
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim was to investigate involvement of oxygen free radicals and any changes in the Gs mediated beta adrenergic signalling system of stunned porcine myocardium. METHODS: Myocardial stunning was induced in eight pentobarbitone anaesthetised pigs by brief occlusions of the distal left anterior descending coronary artery for periods of up to 10 min. Segment length function was measured in the ischaemic region and in a control region supplied by the circumflex artery. Left ventricular biopsies were obtained from the two regions 1 h after the last occlusion for ultrastructural and biochemical studies. Timolol has been used to prevent arrhythmia during ischaemia. RESULTS: At the time when biopsies were obtained, percent systolic shortening was reduced to 58% in the region subjected to ischaemia and was only minimally reduced in the control region. In the biopsies from the stunned region: (1) electron microscopy showed mild and reversible intracellular changes in the stunned myocardium; (2) the activities of superoxide dismutase and glutathione peroxidase were decreased by 66% and 52%, respectively; (3) the content of malondialdehyde was increased by 49%; (4) neither density nor affinity of beta adrenoceptors showed any changes; (5) there were no alterations in messenger RNA encoding for the alpha subunit of the stimulatory guanine nucleotide binding protein (Gs), demonstrated by northern and dot-blot hybridisations; (6) ELISA technique utilising a specific antipeptide antibody showed no quantitative change in Gs; (7) the activity of adenyl cyclase was unchanged. CONCLUSIONS: Even though the stunned porcine myocardium showed substantial evidence of free radical injury, the beta adrenergic signalling system was intact.
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| 43. |
- Fu, Michael, 1963, et al.
(författare)
-
Properties of G-protein modulated receptor-adenylyl cyclase system in myocardium of spontaneously hypertensive rats treated with adriamycin.
- 1994
-
Ingår i: International journal of cardiology. - 0167-5273. ; 44:1, s. 9-18
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Tidskriftsartikel (refereegranskat)abstract
- Properties of the receptor--G protein--adenylyl cyclase system were studied in spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) treated with adriamycin (ADR, 1 mg/kg per week) for 12 weeks. An identical dosing schedule caused a significantly greater decline in body weight gain and a marked elevation of plasma norepinephrine level in SHR than in WKY. A significant increase in the messenger RNA encoding Gi-alpha 2 was found in SHR+ADR group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate [Gpp(NH)p] was decreased by 49% in SHR and 73% in SHR+ADR. However, stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin remained unchanged. Functional level of stimulatory G-protein (Gs) as measured by reconstitution assay in sarcolemmal membrane was unaltered among different groups. Furthermore, the density of beta-adrenoceptor was significantly decreased without change of its affinity. Muscarinic receptors exhibited a three-site affinity distribution in SHR+ADR whereas other groups displayed only two-site affinity distribution. These results suggest that SHR exhibited a depressed myocardial adenylyl cyclase signaling system which may not be due to the functional uncoupling of beta-adrenoceptors from Gs but to the increased inhibitory G-protein (Gi) activity as demonstrated by the increased mRNA of Gi-alpha 2, increased inhibition of Gpp(NH)p-mediated adenylyl cyclase and the super high affinity for carbachol of the muscarinic receptors. Decreased beta-adrenoceptor density and functional alteration of Gi might be regarded as the predisposing factors for the increased susceptibility of myocardium of SHR to ADR.
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| 44. |
- Ghali, Jalal K, et al.
(författare)
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The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF).
- 2009
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Ingår i: Journal of cardiac failure. - : Elsevier BV. - 1532-8414 .- 1071-9164. ; 15:4, s. 310-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF). METHODS AND RESULTS: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) < 45 mL/min per 1.73 m(2) body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups. CONCLUSIONS: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.
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| 45. |
- Gullestad, L., et al.
(författare)
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What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF)
- 2005
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Ingår i: J Am Coll Cardiol. - 0735-1097. ; 45:2, s. 252-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The goal of this study was to explore the question: what resting heart rate (HR) should one aim for when treating patients with heart failure with a beta-blocker? BACKGROUND: The interaction of pretreatment and achieved resting HR with the risk-reducing effect of beta-blocker treatment needs further evaluation. METHODS: Cardiovascular risk and risk reduction were analyzed in five subgroups defined by quintiles (Q) of pretreatment resting HR in the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). RESULTS: Mean baseline HR in the 5 Qs were 71, 76, 81, 87, and 98 beats/min; achieved HR 63, 66, 68, 72, and 75 beats/min; and net change -8, -10, -11, -13, and -14 beats/min, respectively. Baseline HR was related to a number of baseline characteristics. Cardiovascular risk was no different in Q1 to Q4 (placebo groups) but increased in Q5 (HR above 90 beats/min). No relationship was observed between the risk-reducing effect of metoprolol controlled release/extended release (CR/XL) and baseline HR in the five Qs of baseline HR, or achieved HR, or change in HR during follow-up, respectively. CONCLUSIONS: Metoprolol CR/XL significantly reduced mortality and hospitalizations independent of resting baseline HR, achieved HR, and change in HR. Achieved HR and change in HR during follow-up were closely related to baseline HR; therefore, it was not possible to answer the question posed. Instead, one has to apply a very simple rule: aim for the target beta-blocker dose used in clinical trials, and strive for the highest tolerated dose in all patients with heart failure, regardless of baseline and achieved HR.
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| 46. |
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| 47. |
- Herlitz, Johan, 1949, et al.
(författare)
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5-year mortality rate in patients with suspected acute myocardial infarction in relation to early diagnosis.
- 1988
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Ingår i: Cardiology. - 0008-6312. ; 75:4, s. 250-9
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Tidskriftsartikel (refereegranskat)abstract
- In 1,395 patients admitted to hospital between 1976 and 1981 due to suspected acute myocardial infarction, the 5-year mortality rate was related to whether they developed infarction or not during the first 3 days. In all, patients with definite myocardial infarction had a 5-year mortality rate of 33.4% as compared with 13.3% in patients not fulfilling the criteria for this diagnosis (p less than 0.001). When separately analyzing patients with no previous myocardial infarction before admission and discharged from hospital, the corresponding mortality rate was 24.1% for myocardial infarction patients versus 8.1% in nonmyocardial infarction patients (p less than 0.001). Among all patients with nonconfirmed myocardial infarction, those who partly fulfilled the criteria (possible myocardial infarction) had a 5-year mortality rate of 16.7% as compared with 12.0% in those in whom myocardial infarction was completely ruled out (p = 0.18). Independent risk factors for death among patients not developing early infarction were high age and a clinical history of previous myocardial infarction and smoking. We conclude that in this study the long-term prognosis among patients admitted to hospital due to suspected acute myocardial infarction was clearly related to whether they developed an infarction or not during the first 3 days in hospital.
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| 48. |
- Herlitz, Johan, 1949, et al.
(författare)
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Body temperature in acute myocardial infarction and its relation to early intervention with metoprolol.
- 1988
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Ingår i: International Journal of Cardiology. - 0167-5273. ; 20:1, s. 65-71
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Tidskriftsartikel (refereegranskat)abstract
- In a subsample of 223 patients participating in a double-blind trial with metoprolol in suspected acute myocardial infarction, body temperature during the first 5 days in hospital was recorded. Patients developing infarction had a mean temperature of 37.3 degrees C compared with 36.8 degrees C for those with no infarction (P less than 0.001). A positive association was observed between enzyme-estimated infarct size and body temperature (P less than 0.001). Patients given metoprolol had a mean temperature of 37.0 degrees C as compared with 37.2 degrees C in those given placebo (P = 0.03). The most marked difference between metoprolol and placebo was observed among those treated very early. We conclude that early treatment with metoprolol in suspected acute myocardial infarction appears to lower body temperature during the following days. This might reflect limitation of the infarct size.
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| 49. |
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| 50. |
- Herlitz, Johan, 1949, et al.
(författare)
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Delay time between onset of myocardial infarction and start of thrombolysis in relation to prognosis.
- 1993
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Ingår i: Cardiology. - : S. Karger AG. - 0008-6312 .- 1421-9751. ; 82:5, s. 347-53
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Tidskriftsartikel (refereegranskat)abstract
- In 292 patients with suspected acute myocardial infarction given thrombolytic agents, we describe the delay time between the onset of pain and the start of thrombolysis and relate the observations to the prognosis. In 3%, treatment was started 1 h or less and in 22% 2 h or less after onset of symptoms. The median delay time between onset of symptoms and arrival in hospital was 1 h 38 min, and the median delay time between the arrival in hospital and start of thrombolysis was 1 h 25 min. A very strong association between delay time to thrombolysis and mortality during 2 weeks and 1 year of follow-up was observed.
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