Biomedical subjects

B Pieske

Publications and source records attributed to B Pieske.

At least 55 records · Page 3Linked to original sources

PubMed1996

Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.

Post-rest contractile behavior of isolated myocardium indicates the capacity of the sarcoplasmic reticulum (SR) to store and release Ca2+. We investigated post-rest behavior in isolated muscle strips from nonfailing (NF) and endstage failing (dilated cardiomyopathy [DCM]) human hearts. At a basal stimulation frequency of 1 Hz, contractile parameters of the first twitch after increasing rest intervals (2-240 s) were evaluated. In NF (n = 9), steady state twitch tension was 13.7 +/- 1.8 mN/mm2. With increasing rest intervals, post-rest twitch tension continuously increased to maximally 29.9 +/- 4.1 mN/mm2 after 120s (P < 0.05) and to 26.7 +/- 4.5 mN after 240 s rest. In DCM (n = 22), basal twitch tension was 10.0 +/- 1.5 mN/mm2 and increased to maximally 13.6 +/- 2.2 mN/mm2 after 20 s rest (P < 0.05). With longer rest intervals, however, post-rest twitch tension continuously declined (rest decay) to 4.7 +/- 1.0 mN/mm2 at 240 s (P < 0.05). The rest-dependent changes in twitch tension were associated with parallel changes in intracellular Ca2- transients in NF and DCM (aequorin method). The relation between rest-induced changes in twitch tension and aequorin light emission was similar in NF and DCM, indicating preserved Ca(2-)-responsiveness of the myofilaments. Ryanodine (1 microM) completely abolished post-rest potentiation. Increasing basal stimulation frequency (2 Hz) augmented post-rest potentiation, but did not prevent rest decay after longer rest intervals in DCM. The altered post-rest behavior in failing human myocardium indicates disturbed intracellular Ca2- handling involving altered function of the SR.

Adult↗

PubMed1996

Calcium cycling proteins and force-frequency relationship in heart failure.

Myocardial function, intracellular calcium and levels of calcium cycling proteins were analyzed in failing and nonfailing human myocardium. Myocardial function was evaluated by the isometric force-frequency relation, and intracellular calcium was studied by aequorin light emission. When stimulation frequency was increased above 30 min-1, there was a continuous increase in isometric tension development in the nonfailing myocardium. In contrast, in failing myocardium, frequency potentiation of contractile force was blunted or inverse. As a consequence, at higher rates of stimulation, twitch tension was reduced significantly in failing compared to nonfailing human myocardium. Aequorin measurements indicated that the contractile deficit in the failing myocardium at higher rates of stimulation is associated with decreased free intracellular calcium concentration. Western blot analysis indicated that in the failing myocardium protein levels of SR-Ca(2+)- ATPase are significantly reduced and protein levels of Na(+)-Ca(2+)- exchanger are significantly increased. Levels of phospholamban are slightly reduced in the failing myocardium, and ryanodine receptor and calsequestrin protein levels are unchanged. There was a close positive correlation between the protein levels of SR-Ca(2+)-ATPase and frequency potentiation of contractile force. From these data, we conclude that in failing compared to nonfailing human myocardium 1) force-frequency relation is blunted or inverse. 2) Frequency-dependence of contractile force is closely correlated with frequency-dependence of intracellular calcium cycling. 3) Protein levels of SR-Ca(2+)-ATPase may determine frequency-dependence of sarcoplasmic reticulum calcium release. 4) Calcium elimination by an increased number of Na(+)-Ca2-exchanger molecules may be a compensatory mechanism to prevent diastolic calcium accumulation in failing myocardium with a reduced number of SR calcium pumps.

Calcium↗

PubMed1996

Ca2+ sensitization in idiopathic dilated human myocardium. Differential in vitro effects of (+)-(5-methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazoci ne-2,4-dione, a novel purely Ca2+sensitizing agent, and (+)-5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-meth yl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one on skinned fibres and isolated ventricular strips.

(+)-(5-Methyl-6-phenyl)-1,3,5,6-tetrahydro-3,6-methano-1, 5-benzodiazocine-2,4-dione (CAS 165755-40-8, CGP 48506) is a novel Ca2+ sensitizing agent devoid of any other positive inotropic mechanism, particularly phosphodiesterase (PDE) III inhibition. 5-(1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-met hyl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one (CAS 120223-04-3, EMD 53998) is a PDE III inhibitor with a Ca2+ sensitizing activity residing in its (+)-enantiomer, EMD 57033 (CAS 147527-31-9). In skinned fibres and electrically stimulated left ventricular strips from idiopathic dilated human hearts, New York Heart Association (NYHA) class IV, the Ca2+ sensitizing and inotropic effects of the benzodiazocine CGP 48506 and the thiadiazinones EMD 53998 or EMD 57033 were compared. Both CGP 48506 and EMD 53998 induce a left shift of the Ca2+ activation curve of force towards lower Ca2+ concentrations in skinned fibres, which indicates Ca2+ sensitization. Only EMD 53998, but not CGP 48506, increases skinned fibre force at both minimum (resting) and maximally activating Ca2+ concentrations. This is taken as an argument for a principal difference in the mechanisms of the Ca2+ sensitizing actions of the two compounds. CGP 48506 is shown not to influence the amplitude of the Ca2+ transient in rat cardiomyocytes. On the other hand, both CGP 48506 and EMD 57033 show comparable, though quantitatively different, positive inotropic effects in electrically stimulated left ventricular strip preparations. It is unclear whether the PDE III inhibitory component of the profile of actions of EMD 57033 may play a role in preventing the increase in diastolic tension as expected from the skinned fibre experiments. It is noteworthy that both Ca2+ sensitizing agents act as positive inotropic compounds in the end-stage failing human heart where other inotropic agents like beta 1-adrenergic agonists or PDE inhibitors have been described to fail.

Aniline Compounds↗

PubMed1995

Positive and negative inotropic effects of DL-sotalol and D-sotalol in failing and nonfailing human myocardium under physiological experimental conditions.

BACKGROUND: DL-Sotalol has class III antiarrhythmic activity through prolongation of the repolarization phase of the action potential as well as beta-adrenoceptor-blocking properties. Although the former effect was found to exert positive inotropic effects in animal experimental studies, the latter may be detrimental in heart failure due to negative inotropism. In contrast to DL-sotalol, D-sotalol is suggested to exert only positive inotropic effects, which were never tested in isolated human myocardium. METHODS AND RESULTS: Therefore, we investigated the effects of racemic DL-sotalol and its enantiomer D-sotalol in human right atrial muscle strip preparations and in left ventricular muscle strip preparations from nonfailing and end-stage failing human hearts. DL-sotalol and D-sotalol significantly (P < .01) increased peak developed force in atrial preparations by 14.0 +/- 3.4% and 16.7 +/- 3.8%, respectively, but had no effect in ventricular myocardium. In nonfailing ventricular myocardium, both DL-sotalol and D-sotalol shifted the dose-response curve for isoproterenol to higher concentrations (P < .01); however, DL-sotalol was 100-fold more effective than D-sotalol. In non-failing myocardium, a positive force-frequency relation was found between 30 and 120 beats per minute, but isoproterenol was much more powerful in its inotropic effects. In failing myocardium, reduction in stimulation rate from 120 to 30 beats per minute increased peak developed force more pronounced than did the application of isoproterenol. CONCLUSIONS: (1) D-Sotalol has no relevant beta-adrenoceptor-blocking activity compared with DL-sotalol. (2) Neither DL-sotalol nor D-sotalol exhibit positive inotropic effects in human left ventricular myocardium. (3) Heart rate reduction increases contractile force in end-stage failing human myocardium due to an inverse force-frequency relation and thereby counteracts the potential negative inotropic properties of beta-blockade.

Adrenergic beta-Agonists↗

PubMed1995

Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy.

BACKGROUND: The present study was performed to test the hypothesis that the altered force-frequency relation in human failing dilated cardiomyopathy may be attributed to alterations in intracellular calcium handling. METHODS AND RESULTS: The force-frequency relation was investigated in isometrically contracting ventricular muscle strip preparations from 5 nonfailing human hearts and 7 hearts with end-stage failing dilated cardiomyopathy. Intracellular calcium cycling was measured simultaneously by use of the bioluminescent photoprotein aequorin. Stimulation frequency was increased stepwise from 15 to 180 beats per minute (37 degrees C). In nonfailing myocardium, twitch tension and aequorin light emission rose with increasing rates of stimulation. Maximum average twitch tension was reached at 150 min-1 and was increased to 212 +/- 34% (P < .05) of the value at 15 min-1. Aequorin light emission was lowest at 15 min-1 and was maximally increased at 180 min-1 to 218 +/- 39% (P < .01). In the failing myocardium, average isometric tension was maximum at 60 min-1 (106 +/- 7% of the basal value at 15 min-1, P = NS) and then decreased continuously to 62 +/- 9% of the basal value at 180 min-1 (P < .002). In the failing myocardium, aequorin light emission was highest at 15 min-1. At 180 min-1, it was decreased to 71 +/- 7% of the basal value (P < .01). Including both failing and nonfailing myocardium, there was a close correlation between the frequencies at which aequorin light emission and isometric tension were maximum (r = .92; n = 19; P < .001). Action potential duration decreased similarly with increasing stimulation frequencies in nonfailing and end-stage failing myocardium. Sarcoplasmic reticulum 45Ca2+ uptake, measured in homogenates from the same hearts, was significantly reduced in failing myocardium (3.60 +/- 0.51 versus 1.94 +/- 0.18 (nmol/L).min-1.mg protein-1, P < .005). CONCLUSIONS: These data indicate that the altered force-frequency relation of the failing human myocardium results from disturbed excitation-contraction coupling with decreased calcium cycling at higher rates of stimulation.

Action Potentials↗

PubMed1995

Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy.

BACKGROUND: Previous studies provide considerable evidence that excitation-contraction coupling may be disturbed at the level of the sarcoplasmic reticulum (SR) in the failing human heart. Disturbed SR function may result from altered expression of calcium-handling proteins. METHODS AND RESULTS: Levels of SR proteins involved in calcium release (ryanodine receptor), calcium binding (calsequestrin, calreticulin), and calcium uptake (calcium ATPase, phospholamban) were measured by Western blot analysis in nonfailing human myocardium (n = 7) and in end-stage failing myocardium due to dilated cardiomyopathy (n = 14). The levels of the ryanodine receptor, calsequestrin, and calreticulin were not significantly different in nonfailing and failing human myocardium. Phospholamban protein levels (pentameric form) normalized per total protein were decreased by 18% in the failing myocardium (P < .05). However, phospholamban protein levels were not significantly different in failing and nonfailing myocardium when normalization was performed per calsequestrin. Protein levels of SR calcium ATPase, normalized per total protein or per calsequestrin, were decreased by 41% (P < .001) or 33% (P < .05), respectively, in the failing myocardium. Furthermore, SR calcium ATPase was decreased relative to ryanodine receptor by 37% (P < .05) and relative to phospholamban by 28% (P < .05). CONCLUSIONS: Levels of SR proteins involved in calcium binding and release are unchanged in failing dilated cardiomyopathy. In contrast, protein levels of calcium ATPase involved in SR calcium uptake are reduced in the failing myocardium. Moreover, SR calcium ATPase is decreased relative to its inhibitory protein, phospholamban.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗

PubMed1995

Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics.

Calcium sensitizers may influence myocardial energetics by their action on calcium turnover and on crossbridge behavior. Using a myothermal method, the effects of the Ca2+ sensitizer EMD-53998 on calcium cycling, crossbridge behavior, and myocardial energy turnover were compared with the effects of an increase in extracellular calcium from 1.25 to 7.5 mM and with the effects of the catecholamine isoproterenol. All three inotropic interventions increased isometric force development in right ventricular rabbit papillary muscles. Relaxation time was decreased with isoproterenol, unchanged with high calcium, and increased with EMD 53998. Calcium cycling-related energy consumption, as measured by tension-independent heat, increased by 234% with high calcium, by 439% with isoproterenol, and by 77% with EMD 53998. In contrast to high calcium and isoproterenol, EMD 53998 increased economy of crossbridge cycling by increasing the force-time integral of the individual crossbridge cycle. The data indicate that EMD 53998 acts by phosphodiesterase inhibition and myofilament calcium sensitization. The latter effect is in part mediated by alteration of crossbridge behavior. Because of its effects on calcium cycling and crossbridge function myocardial energy turnover was reduced significantly with EMD 53998, whereas energy turnover was unchanged with high calcium and was increased with isoproterenol. The new calcium sensitizer levosimendan was investigated in isolated failing human myocardium. Levosimendan dose-dependently increased isometric tension. The inotropic effect was associated with increased rate of relaxation and reduced relaxation time. Measurements of intracellular calcium using the photoprotein aequorin suggest that levosimendan acts by increasing myofilament calcium sensitivity and by increasing cAMP due to phosphodiesterase inhibition. However, the contribution of the cAMP system to the action of levosimendan appears to be rather small. Therefore, the finding of a positive lusitropic effect of levosimendan may be consistent with the notion that levosimendan binds to troponin-C and increases calcium sensitivity only at high (systolic) intracellular calcium concentrations.

Adrenergic beta-Agonists↗

PubMed1994

Functional significance of angiotensin receptors in human myocardium. Significant differences between atrial and ventricular myocardium.

We studied the effects of angiotensin (Ang) I and II in a variety of isolated human cardiac tissues contracting under physiological conditions (37 degrees C, 60 beats.min-1). Ang I and II consistently increased the peak developed force of human atrial muscles by 30-40%, an effect that was completely blocked by 10(-6) M saralasine, but not by the combination of prazosin and propranolol. However, neither Ang I or II had significant inotropic effects in right and left ventricular human preparations. We were also able to demonstrate that the positive inotropic effect of Ang II in human right atrial tissue is mediated by the AT1 receptor subtype but not the AT2 receptor subtype.

Angiotensin I↗

PubMed1994

Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy.

In isolated human myocardium it was shown that a positive force-frequency relationship occurs in non-failing myocardium; however, the force-frequency relationship was found to be inverse in myocardium from failing human hearts. In order to investigate the clinical relevance of these experimental findings, the influence of heart rate changes on haemodynamics and left ventricular function was studied in eight patients without heart failure and in nine with failing dilated cardiomyopathy (NYHA II-III). Right ventricular pacing was performed at a rate slightly above sinus rate and at 100, 120 and 140 beats.min-1. Haemodynamic parameters were obtained by right heart catheterization and by high-fidelity left ventricular pressure measurements. Left ventricular angiography was performed at basal pacing rate and at 100 and 140 beats.min-1. With increasing heart rate, cardiac index increased in patients with normal left ventricular function from 2.9 +/- 0.2 to 3.5 +/- 0.21.min-1.m-2 (P < 0.01) and decreased continuously in patients with dilated cardiomyopathy from 2.6 +/- 0.1 to 2.2 +/- 0.1 l.min-1. m-2 (P < 0.05). With increasing heart rate, the maximum rate of left ventricular pressure rise increased in non-failing hearts from 1388 +/- 86 to 1671 +/- 88 mmHg.s-1 (P < 0.01) and did not change in failing hearts. Ejection fraction decreased from 27 +/- 3% to 19 +/- 2% in patients with dilated cardiomyopathy (P < 0.05) when the pacing rate was changed from 84 +/- 2 beats.min-1 to 140 beats.min-1, which was associated with a significant increase in end-systolic volume without significant changes in end-diastolic volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium.

Expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase was shown to be reduced in failing human myocardium. The functional relevance of this finding, however, is not known. We investigated the relation between myocardial function and protein levels of SR Ca(2+)-ATPase in nonfailing human myocardium (8 muscle strips from 4 hearts) and in myocardium from end-stage failing hearts with dilated (10 muscle strips from 9 hearts) or ischemic (7 muscle strips from 5 hearts) cardiomyopathy. Myocardial function was evaluated by the force-frequency relation in isometrically contracting muscle strip preparations (37 degrees C, 30 to 180 min-1). In nonfailing myocardium, twitch tension rose with increasing rates of stimulation and was 76% higher at 120 min-1 compared with 30 min-1 (P < .02). In failing myocardium, there was no significant increase in average tension at stimulation rates above 30 min-1. At 120 min-1, twitch tension was decreased by 59% (P < .05) in dilated cardiomyopathy and 76% (P < .05) in ischemic cardiomyopathy compared with nonfailing myocardium. Protein levels of SR Ca(2+)-ATPase, normalized per total protein or per myosin, were reduced by 36% (P < .02) or 32% (P < .05), respectively, in failing compared with nonfailing myocardium. SR Ca(2+)-ATPase protein levels were closely related to SR Ca2+ uptake, measured in homogenates from the same hearts (r = .70, n = 16, and P < .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

[Use of enoximone in patients with acute and subacute heart failure in the intensive care unit].

The phosphodiesterase inhibitor enoximone has both vasodilating and positive inotropic pharmacological properties. The balance between vasodilation and positive inotropism may be different between the various types of heart failure as well as the various stages of heart failure. Therefore, we investigated the effect of intravenous application of enoximone (1 mg/kg body weight) in a cohort of patients (n = 10) suffering from acute or subacute heart failure mainly due to ischemia or hypoxia. All patients had high left ventricular filling pressure, low cardiac output and were pretreated with intravenous dobutamine. Enoximone increased cardiac output from 3.2 +/- 1.2 to 5.5 +/- 2.2 l/min, increased heart rate from 94 +/- 20 to 100 +/- 18 beats/min, decreased systemic peripheral resistance from 1770 +/- 861 to 931 +/- 340 dyn.sec.cm-5 and decreased pulmonary wedge pressure from 24 +/- 5 to 20 +/- 6 mmHg, significantly. However, systolic aortic pressure, systolic pulmonary pressure and right atrial pressure were not significantly altered. We conclude that in a selected group of patients enoximone-given intravenously and acutely in the intensive care unity-can induce beneficial effects on central hemodynamics without critical falls in perfusion pressure.

Aged↗

PubMed1993

Excitation-contraction coupling and contractile protein function in failing and nonfailing human myocardium.

Isometric force, heat output, and aequorin light emission were measured in isolated muscle strips from nonfailing human hearts and from hearts with endstage failing dilated cardiomyopathy (37 degrees C; 30-180 beats per minute (bpm)). In nonfailing myocardium, peak twitch tension increased with higher rates of stimulation, whereas the force-frequency relation was inverse in the failing myocardium. At 60 bpm and at higher rates of stimulation, peak twitch tension was reduced significantly in the failing myocardium. Myothermal measurements, performed at 60 bpm, indicated that the number of crossbridge interactions and the amount of calcium cycling are reduced significantly in the failing myocardium. Furthermore, aequorin light transients indicated that the inverse force-frequency relation in failing myocardium results from altered calcium cycling; with increasing rates of stimulation aequorin light emission increased continuously in the nonfailing and decreased continuously in the failing myocardium. The data suggest that impaired myocardial performance in failing human myocardium may result primarily from disturbed excitation-contraction coupling processes with a reduced amount of calcium cycling and, thus, a decreased activation of contractile proteins.

Biomechanical Phenomena↗

PubMed1993

Angiotensin I and II exert inotropic effects in atrial but not in ventricular human myocardium. An in vitro study under physiological experimental conditions.

BACKGROUND: The renin-angiotensin system with its renal-humoral and local myocardial components plays an important role in the development and progression of chronic heart failure. Whereas angiotensin receptors have been found in atrial and ventricular myocardium of different species including humans, its influence on myocardial contractility is not yet defined in human failing myocardium and especially in human nonfailing myocardium. METHODS AND RESULTS: We measured force development of right atrial and right and left ventricular myocardial preparations of patients with a variety of cardiac diseases. To evaluate the physiological effects of angiotensin, experimental temperature and stimulation rates were 37 degrees C and 60 beats per minute, respectively. Angiotensin I and II increased peak developed force in atrial myocardial preparations obtained from patients without heart failure in a concentration-dependent manner. At optimal concentrations, peak developed force is increased from 10.2 +/- 1.8 to 12.3 +/- 1.9 mN/mm2 by angiotensin I (P < .05) and from 15.4 +/- 2.1 to 20.5 +/- 3.3 mN/mm2 by angiotensin II (P < .05). This effect was not influenced by pretreatment with propranolol (10(-6) mol/L) and prazosin (10(-5) mol/L) but was completely blocked by saralasin (10(-6) mol/L). The positive inotropic effect of angiotensin I could be blocked by enalaprilate (10(-5) mol/L). Neither angiotensin I nor angiotensin II had any effect in preparations of the left ventricle from patients with idiopathic dilated cardiomyopathy, mitral valve stenosis, and incompetence or in patients with no significant heart disease. Additionally, no effect could be seen when angiotensin II was applied to right ventricular preparations from infants undergoing reconstructive heart surgery for tetralogy of Fallot. CONCLUSIONS: Angiotensin I and II exert positive inotropic effects via angiotensin receptors in atrial preparations but not in right or left ventricular preparations. Furthermore, the existence of a local myocardial angiotensin converting enzyme with functional importance is shown.

Aged↗

PubMed1992

Alterations of the force-frequency relationship in the failing human heart depend on the underlying cardiac disease.

We investigated the force-frequency relationship (0.5-3 Hz) in non-failing human myocardium and in end-stage failing human myocardium due to dilated cardiomyopathy or subacute myocarditis. In non-failing myocardium, force of contraction increased with increasing stimulation frequency. In end-stage heart failure, the force-frequency relationship was inverse in myocardium from dilated cardiomyopathy, but was similar to control in myocardium from subacute myocarditis. After increasing extracellular Ca(2+)-concentration from 2.5 to 7.2 mM, the shape of the force-frequency relationship was not changed in nonfailing myocardium. In dilated cardiomyopathy, the decline in force with increasing frequencies was even more pronounced at 7.2 mM compared to 2.5 mM extracellular Ca2+. In subacute myocarditis, at Ca2+ 7.2 mM, increasing frequencies increased force in the lower frequency range (less than 1.75 Hz) only, whereas at higher stimulation rates force declined again. These results indicate that (1.) alterations of the force-frequency relationship in the failing human heart depend on the underlying cardiac disease and/or the time-course of the disease, and (2.) an increase in the extracellular Ca(2+)-concentration aggravates changes in the force-frequency relationship in the failing myocardium.

Calcium↗

PubMed1992

Energetics of calcium cycling in nonfailing and failing human myocardium.

Using sensitive antimony-bismuth thermopiles, isometric force and heat output were measured in muscle strips from nonfailing human hearts and from failing dilated cardiomyopathic hearts at a stimulation rate of 60 beats per minute (37 degrees C). This frequency was chosen because analysis of the force-frequency relation showed significant differences in isometric force between failing and nonfailing human myocardium at 60 beats per minute and at higher frequencies, whereas at lower rates of stimulation (30 beats per minute) force of contraction was similar in failing and nonfailing myocardium. The liberated initial heat was partitioned into its two components, tension-dependent heat and tension-independent heat from high-energy phosphate hydrolysis by contractile proteins and excitation-contraction coupling processes, respectively. Tension-dependent heat reflects the total number of crossbridge interactions, and tension-independent heat is an index of the amount of calcium cycling during the contraction-relaxation cycle. In failing compared to nonfailing human myocardium, peak twitch tension, maximum rate of tension rise and maximum rate of tension fall were reduced significantly. Reduced mechanical performance was associated with reduced liberation of both tension-dependent and tension-independent heat in the failing heart. The reduction of tension-dependent heat by 61% and of tension-independent heat by 69% indicate considerable decreases in the number of crossbridge interactions activated and calcium ions cycled during the isometric twitch. In addition, the rate of calcium removal was reduced in the failing human heart as is indicated by a 71% reduction in tension-independent heat rate. The efficiency of excitation-contraction coupling with respect to crossbridge activation was similar in failing and nonfailing myocardium. These data indicate that impaired myocardial performance in dilated cardiomyopathy may result from disturbed excitation-contraction coupling with reduced amount of calcium cycling and reduced rate of calcium removal.

Calcium↗

PubMed1991

The heart in heart failure. Ventricular and myocardial alterations.

In heart failure, many alterations occur in the ventricle as a whole, as well as in the myocardial cell. In the first part of this review we report on the macroscopic structure of the left ventricle by analysing the relation between left ventricular dilatation and left ventricular hypertrophy in terms of ventricular wall stress. Peak systolic stress in dilated ventricles of patients with compensated heart failure does not differ from values obtained in normal ventricles, whereas the systolic stress-time integral is increased by more than 40%. The stress-time integral is a major determinant of myocardial oxygen consumption, and its reduction by peripheral vasodilation leads to a proportional decrease in left ventricular oxygen consumption. In contrast, the phosphodiesterase inhibitor, enoximone, decreases the stress-time integral without a proportional decrease in myocardial oxygen consumption, due to the competition between positive inotropic effect with increased oxygen consumption and a vasodilating effect with decreased oxygen consumption. Beta-1 adrenoceptor agonists increase myocardial oxygen consumption. In the second part of this review we report on the functional alterations of the following subcellular and molecular structures in the failing myocardium: (1) adrenoceptors and G-proteins; (2) sarcoplasmic reticulum with an altered force-frequency relationship; (3) the acto-myosin system with decreased velocity of shortening and increased economy of force generation. On the basis of these alterations, a disadvantageous chain of events develops in the failing myocardial cell.

Cardiomegaly↗

PubMed1991

Different beta-adrenoceptor-effector coupling in human ventricular and atrial myocardium.

To examine whether the downregulation of beta-adrenoceptors is accompanied by reduced beta-adrenoceptor-mediated effects in atrial as well as in ventricular myocardium, we investigated the beta-adrenoceptor-effector coupling in atrial and papillary muscle strips from patients with terminal heart failure (heart transplantation because of dilated cardiomyopathy; New York Heart Association Class IV, NYHA IV) and moderate heart failure (mitral valve replacement, NYHA II-III) and in tissue from non-failing hearts. The isometric force of contraction induced by isoprenaline (0.001-1 mumoll-1) or Ca2+ (1.8-15 mmoll-1) in atrial muscle strips and papillary muscle strips has been measured. We also examined the number of beta-adrenoceptors in both tissues by radioligand binding. The degree of heart failure affected neither the potency (EC50: control: 0.01 (0.001-0.082) mumoll-1; NYHA II-III: 0.01 (0.001-0.125) mumoll-1; NYHA IV: 0.01 (0.001-0.160) mumoll-1) nor the efficacy (NYHA IV: 7.8 +/- 1.0 mN; NYHA II-III: 6.1 +/- 0.7 mN; control: 7.7 +/- 0.9 mN) of the isoprenaline-mediated increase in force of contraction in atrial muscle strips. This is in spite of a reduced number of beta-adrenoceptors in moderately (NYHA II-III) and terminally (NYHA IV) failing atrial myocardium compared to non-failing atrial myocardium (P less than 0.05). In contrast, in papillary muscle strips increasing degrees of heart failure were accompanied by a progressive reduction of the isoprenaline-mediated increase in force of contraction (P less than 0.05) as well as by a progressive decrease of beta-adrenoceptors (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium.

Previous studies have shown reduced effects of cAMP-dependent positive inotropic agents in the failing human myocardium; thus other cAMP-independent mechanisms of action may be useful to increase force of contraction in this condition. The purpose of this investigation was to determine whether a positive inotropic effect of the cAMP-phosphodiesterase (PDE) inhibitor pimobendan is observed in the failing human myocardium and to study whether other factors, such as an increase in the Ca2+ sensitivity of myofilaments, play a functional role in the increase in force of contraction. Pimobendan produced a positive inotropic effect in isolated preparations from nonfailing donor hearts; however, in moderately (New York Heart Association class II-III, NYHA II-III) and severely (NYHA IV) failing myocardium, this effect was reduced. In addition, in NYHA IV specimens pimobendan inhibited the crude cAMP-PDE (crude PDE) and the isoenzymes I-III (PDE I-III) in a concentration-dependent way. As judged from the IC50 values found in this tissue for the inhibition of PDE III and of crude PDE, the potency of the compound was 18.1 times greater on PDE III. Consistent with a cAMP-PDE-dependent mechanism of action, the positive inotropic effect was potentiated by isoproterenol and inhibited by adenosine in failing myocardium. In failing myocardium, pimobendan also increased the sensitivity of skinned cardiac fibers to Ca2+ and shifted the Ca(2+)-tension relation to the left. This sensitizing effect began at 0.01 mumol/l in NYHA II-III and NYHA IV and rose to about 200% at 300 mumol/l in both groups. In contrast, the demethylated metabolite UD-CG 212 Cl failed to produce positive inotropic effects in failing myocardium alone, but in the presence of isoproterenol, it exerted an increase in force of contraction. The potency of UD-CG 212 Cl for PDE III inhibition in NYHA IV was greater than that of pimobendan. The metabolite pronouncedly decreased the sensitivity of skinned cardiac fibers to Ca2+ at 30-300 mumol/l in NYHA II-III and NYHA IV. It is concluded that in the failing human heart pimobendan inhibited PDE III and sensitized contractile proteins for Ca2+. Both effects appear to be involved in the positive inotropic effect of the compound, because its metabolite, UD-CG 212 Cl, had no effect on force of contraction and on the Ca2+ sensitivity of skinned cardiac fibers but inhibited PDE III even more potently than pimobendan.(ABSTRACT TRUNCATED AT 400 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗