The Experts below are selected from a list of 2172 Experts worldwide ranked by ideXlab platform
Keld Kjeldsen - One of the best experts on this subject based on the ideXlab platform.
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regulation of Digitalis Glycoside receptors in digoxin treatment
2003Co-Authors: Thomas Andersen Schmidt, Keld KjeldsenAbstract:In myocardial samples from patients afflicted with heart failure, the Na,K-ATPase occupancy with digoxin as a result of digitalization amounted to 24–34%. Compared with myocardial tissue from human subjects not afflicted with heart failure, there were no indications of cardiac Glycoside receptor upregulation in heart failure patients as a result of longterm digoxin treatment. Heart failure reduced myocardial Na,K-ATPase concentration by 26–32%. In skeletal muscles digoxin occupancy was 9–13%. There was no indication of upregulation of skeletal muscle Na,K-ATPase during digitalization. In heart failure patients Na,K-ATPase was downregulated by 25–37%. Following digitalization the femoral venoarterial difference in plasma K increased 50–100% (p < 0.05) during exercise, and decreased 66–75% during recovery. The observations are of patophysiological importance and of importance for the clinical use of digoxin. It is concluded the digoxin should be used in nearly all heart failure patients that can obtain benefit.
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digoxin treatment and congestive heart failure in light of human cardiac and skeletal muscle Digitalis Glycoside receptor studies
1994Co-Authors: Thomas Andersen Schmidt, Henning Bundgaard, H L Olesen, Niels H Secher, Keld KjeldsenAbstract:Previous studies carried out on various in vitro systems (1,3,19) and experimental animals (2,18) have reported an increase in Na+/K+-ATPase as a result of cardiac Glycoside exposure, as have studies performed on human peripheral blood cells (4,11). This has engendered speculation about development of tolerance to the inotropic effect of cardiac Glycoside treatment: The idea being that inhibition of Na+/K+-ATPase obtained initially by digitalization would be counterbalanced by Na+/K+-ATPase upregulation. However, points of concern may be raised with regard to the methodology of the underlying studies for this hypothesis: 1) The concentrations of cardiac Glycoside applied to cell cultures were in micromolar concentration, i.e. toxic to humans 2) In vitro systems, peripheral blood cells and results obtained by digitalization of normal guinea pigs or rats need not mirror the effect of Digitalis treatment on human cardiac and skeletal muscle in heart failure. 3) Activity measurements performed on purified membrane fractions may not be applicable for studying quantitative aspects of Na+/K+-ATPase in muscle tissue (5). On this background it was our aim to evaluate the hypothesis that cardiac Glycoside treatment increases Digitalis receptors by performing appropriate measurements on the tissue of relevance, i.e. cardiac and skeletal muscle from patients with heart failure. In addition we wished to assess the distribution of specifically bound digoxin to human muscular tissue during digitalization.
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human skeletal muscle Digitalis Glycoside receptors na k atpase importance during digitalization
Cardiovascular Drugs and Therapy, 1993Co-Authors: Thomas Andersen Schmidt, Peter Holmnielsen, Keld KjeldsenAbstract:The aims of the present study were to evaluate in humans the putative importance of skeletal muscle Digitalis Glycoside receptors (Na,K-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause Digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125–187.5 µg daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated3H-ouabain binding increased 15% (p 0.30) before and after washing in specific dogoxin antibody fragments, respectively. Thus, the present study indicates a ~13% occupancy of skeletal muscle Digitalis Glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle Digitalis Glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p<0.005) Digitalis Glycoside receptor concentration in the vastus lateralis of the digitalized patients, which may be of importance for skeletal muscle incapacity in heart failure.
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Human skeletal muscle Digitalis Glycoside receptors (Na,K-ATPase)—Importance during digitalization
Cardiovascular Drugs and Therapy, 1993Co-Authors: Thomas Andersen Schmidt, Peter Holm-nielsen, Keld KjeldsenAbstract:The aims of the present study were to evaluate in humans the putative importance of skeletal muscle Digitalis Glycoside receptors (Na,K-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause Digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125–187.5 µg daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated^3H-ouabain binding increased 15% (p0.30) before and after washing in specific dogoxin antibody fragments, respectively. Thus, the present study indicates a ~13% occupancy of skeletal muscle Digitalis Glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle Digitalis Glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p
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No upregulation of Digitalis Glycoside receptor (Na,K-ATPase) concentration in human heart left ventricle samples obtained at necropsy after long term Digitalisation.
Cardiovascular research, 1991Co-Authors: Thomas Andersen Schmidt, Peter Holm-nielsen, Keld KjeldsenAbstract:Study objective — The aim was to evaluate the hypothesis that Digitalis Glycosides increase the concentration of their specific receptor (Na,K-ATPase) in human myocardial tissue, thereby possibly reducing the inotropic effect of long term Digitalis treatment. Design — Intact samples of left ventricle were obtained at necropsy from patients who had been on long term treatment with digoxin and from patients not previously given digoxin. Digitalis Glycoside receptors were quantified using vanadate facilitated 3H-ouabain binding before and after washing samples in buffer containing excess digoxin antibody fragments for 16 h at 30°C. This washing procedure has previously been shown to reduce prior specific digoxin binding in human left ventricle by 95% and to allow subsequent vanadate facilitated complete quantification of 3H-ouabain binding sites. In this context it was performed to reduce occupancy of Digitalis Glycoside receptors by digoxin, caused by Digitalisation before 3H-ouabain binding. Subjects — 11 patients who had been on long term treatment with digoxin and eight who had not previously been given digoxin were studied. Left ventricle samples were obtained at necropsy at around 15 h after death. Measurements and main results — Standard 3H-ouabain binding was 39% less in samples from Digitalised than from unDigitalised subjects (p 0.10) in patients exposed to digoxin compared to left ventricle samples from individuals unexposed to Digitalis Glycoside treatment. Calculating 3H-ouabain binding relative to dry ventricular muscle weight confirmed the results obtained using wet weight as reference. Conclusions — The results suggest that digoxin treatment in life is associated with a 34% occupancy of Digitalis Glycoside receptors with digoxin. In the human heart there was no evidence for upregulation of Digitalis Glycoside receptor concentration due to long term Digitalisation. Thus at receptor level there was no evidence for development of tolerance to digoxin therapy. The lower Digitalis Glycoside receptor concentration in the left ventricle observed in the heart failure patients may support the report of a relationship between Na,K-ATPase concentration as evaluated by 3H-ouabain binding and left ventricular function.
Thomas Andersen Schmidt - One of the best experts on this subject based on the ideXlab platform.
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regulation of Digitalis Glycoside receptors in digoxin treatment
2003Co-Authors: Thomas Andersen Schmidt, Keld KjeldsenAbstract:In myocardial samples from patients afflicted with heart failure, the Na,K-ATPase occupancy with digoxin as a result of digitalization amounted to 24–34%. Compared with myocardial tissue from human subjects not afflicted with heart failure, there were no indications of cardiac Glycoside receptor upregulation in heart failure patients as a result of longterm digoxin treatment. Heart failure reduced myocardial Na,K-ATPase concentration by 26–32%. In skeletal muscles digoxin occupancy was 9–13%. There was no indication of upregulation of skeletal muscle Na,K-ATPase during digitalization. In heart failure patients Na,K-ATPase was downregulated by 25–37%. Following digitalization the femoral venoarterial difference in plasma K increased 50–100% (p < 0.05) during exercise, and decreased 66–75% during recovery. The observations are of patophysiological importance and of importance for the clinical use of digoxin. It is concluded the digoxin should be used in nearly all heart failure patients that can obtain benefit.
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digoxin treatment and congestive heart failure in light of human cardiac and skeletal muscle Digitalis Glycoside receptor studies
1994Co-Authors: Thomas Andersen Schmidt, Henning Bundgaard, H L Olesen, Niels H Secher, Keld KjeldsenAbstract:Previous studies carried out on various in vitro systems (1,3,19) and experimental animals (2,18) have reported an increase in Na+/K+-ATPase as a result of cardiac Glycoside exposure, as have studies performed on human peripheral blood cells (4,11). This has engendered speculation about development of tolerance to the inotropic effect of cardiac Glycoside treatment: The idea being that inhibition of Na+/K+-ATPase obtained initially by digitalization would be counterbalanced by Na+/K+-ATPase upregulation. However, points of concern may be raised with regard to the methodology of the underlying studies for this hypothesis: 1) The concentrations of cardiac Glycoside applied to cell cultures were in micromolar concentration, i.e. toxic to humans 2) In vitro systems, peripheral blood cells and results obtained by digitalization of normal guinea pigs or rats need not mirror the effect of Digitalis treatment on human cardiac and skeletal muscle in heart failure. 3) Activity measurements performed on purified membrane fractions may not be applicable for studying quantitative aspects of Na+/K+-ATPase in muscle tissue (5). On this background it was our aim to evaluate the hypothesis that cardiac Glycoside treatment increases Digitalis receptors by performing appropriate measurements on the tissue of relevance, i.e. cardiac and skeletal muscle from patients with heart failure. In addition we wished to assess the distribution of specifically bound digoxin to human muscular tissue during digitalization.
-
human skeletal muscle Digitalis Glycoside receptors na k atpase importance during digitalization
Cardiovascular Drugs and Therapy, 1993Co-Authors: Thomas Andersen Schmidt, Peter Holmnielsen, Keld KjeldsenAbstract:The aims of the present study were to evaluate in humans the putative importance of skeletal muscle Digitalis Glycoside receptors (Na,K-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause Digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125–187.5 µg daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated3H-ouabain binding increased 15% (p 0.30) before and after washing in specific dogoxin antibody fragments, respectively. Thus, the present study indicates a ~13% occupancy of skeletal muscle Digitalis Glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle Digitalis Glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p<0.005) Digitalis Glycoside receptor concentration in the vastus lateralis of the digitalized patients, which may be of importance for skeletal muscle incapacity in heart failure.
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Human skeletal muscle Digitalis Glycoside receptors (Na,K-ATPase)—Importance during digitalization
Cardiovascular Drugs and Therapy, 1993Co-Authors: Thomas Andersen Schmidt, Peter Holm-nielsen, Keld KjeldsenAbstract:The aims of the present study were to evaluate in humans the putative importance of skeletal muscle Digitalis Glycoside receptors (Na,K-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause Digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125–187.5 µg daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated^3H-ouabain binding increased 15% (p0.30) before and after washing in specific dogoxin antibody fragments, respectively. Thus, the present study indicates a ~13% occupancy of skeletal muscle Digitalis Glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle Digitalis Glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p
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No upregulation of Digitalis Glycoside receptor (Na,K-ATPase) concentration in human heart left ventricle samples obtained at necropsy after long term Digitalisation.
Cardiovascular research, 1991Co-Authors: Thomas Andersen Schmidt, Peter Holm-nielsen, Keld KjeldsenAbstract:Study objective — The aim was to evaluate the hypothesis that Digitalis Glycosides increase the concentration of their specific receptor (Na,K-ATPase) in human myocardial tissue, thereby possibly reducing the inotropic effect of long term Digitalis treatment. Design — Intact samples of left ventricle were obtained at necropsy from patients who had been on long term treatment with digoxin and from patients not previously given digoxin. Digitalis Glycoside receptors were quantified using vanadate facilitated 3H-ouabain binding before and after washing samples in buffer containing excess digoxin antibody fragments for 16 h at 30°C. This washing procedure has previously been shown to reduce prior specific digoxin binding in human left ventricle by 95% and to allow subsequent vanadate facilitated complete quantification of 3H-ouabain binding sites. In this context it was performed to reduce occupancy of Digitalis Glycoside receptors by digoxin, caused by Digitalisation before 3H-ouabain binding. Subjects — 11 patients who had been on long term treatment with digoxin and eight who had not previously been given digoxin were studied. Left ventricle samples were obtained at necropsy at around 15 h after death. Measurements and main results — Standard 3H-ouabain binding was 39% less in samples from Digitalised than from unDigitalised subjects (p 0.10) in patients exposed to digoxin compared to left ventricle samples from individuals unexposed to Digitalis Glycoside treatment. Calculating 3H-ouabain binding relative to dry ventricular muscle weight confirmed the results obtained using wet weight as reference. Conclusions — The results suggest that digoxin treatment in life is associated with a 34% occupancy of Digitalis Glycoside receptors with digoxin. In the human heart there was no evidence for upregulation of Digitalis Glycoside receptor concentration due to long term Digitalisation. Thus at receptor level there was no evidence for development of tolerance to digoxin therapy. The lower Digitalis Glycoside receptor concentration in the left ventricle observed in the heart failure patients may support the report of a relationship between Na,K-ATPase concentration as evaluated by 3H-ouabain binding and left ventricular function.
Scott D Solomon - One of the best experts on this subject based on the ideXlab platform.
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effects of sacubitril valsartan in the paradigm hf trial prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure according to background therapy
Circulation-heart Failure, 2016Co-Authors: Naoki Okumura, Pardeep S Jhund, Jianjian Gong, Martin P Lefkowitz, Adel R Rizkala, Jean L Rouleau, Karl Swedberg, Michael R Zile, Scott D SolomonAbstract:Background— In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitor enalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy. Methods and Results— We examined the effect of study treatment in the following subgroups: diuretics (yes/no), Digitalis Glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no), and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399) were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval, 0.73–0.87; P <0.001) and for cardiovascular death was 0.80 (0.71–0.89; P <0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death ranged from 0.75 to 0.89, with no treatment-by-subgroup interaction. Conclusions— The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previous coronary revascularization or β-blocker dose. Clinical Trial Registration— URL: . Unique identifier: [NCT01035255][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01035255&atom=%2Fcirchf%2F9%2F9%2Fe003212.atom
Karl Swedberg - One of the best experts on this subject based on the ideXlab platform.
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effects of sacubitril valsartan in the paradigm hf trial prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure according to background therapy
Circulation-heart Failure, 2016Co-Authors: Naoki Okumura, Pardeep S Jhund, Jianjian Gong, Martin P Lefkowitz, Adel R Rizkala, Jean L Rouleau, Karl Swedberg, Michael R Zile, Scott D SolomonAbstract:Background— In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitor enalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy. Methods and Results— We examined the effect of study treatment in the following subgroups: diuretics (yes/no), Digitalis Glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no), and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399) were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval, 0.73–0.87; P <0.001) and for cardiovascular death was 0.80 (0.71–0.89; P <0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death ranged from 0.75 to 0.89, with no treatment-by-subgroup interaction. Conclusions— The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previous coronary revascularization or β-blocker dose. Clinical Trial Registration— URL: . Unique identifier: [NCT01035255][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01035255&atom=%2Fcirchf%2F9%2F9%2Fe003212.atom
Naoki Okumura - One of the best experts on this subject based on the ideXlab platform.
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effects of sacubitril valsartan in the paradigm hf trial prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure according to background therapy
Circulation-heart Failure, 2016Co-Authors: Naoki Okumura, Pardeep S Jhund, Jianjian Gong, Martin P Lefkowitz, Adel R Rizkala, Jean L Rouleau, Karl Swedberg, Michael R Zile, Scott D SolomonAbstract:Background— In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitor enalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy. Methods and Results— We examined the effect of study treatment in the following subgroups: diuretics (yes/no), Digitalis Glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no), and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399) were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval, 0.73–0.87; P <0.001) and for cardiovascular death was 0.80 (0.71–0.89; P <0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death ranged from 0.75 to 0.89, with no treatment-by-subgroup interaction. Conclusions— The benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previous coronary revascularization or β-blocker dose. Clinical Trial Registration— URL: . Unique identifier: [NCT01035255][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01035255&atom=%2Fcirchf%2F9%2F9%2Fe003212.atom