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C Holubarsch

Publications and source records attributed to C Holubarsch.

At least 37 records · Page 2Linked to original sources
PubMed1995

Effect of peri-operative diltiazem on myocardial ischaemia and function in patients receiving mammary artery grafts.

A prospective, randomized study was performed with 66 patients undergoing elective coronary bypass surgery involving internal mammary artery (IMA) grafts to the left anterior descending artery (LAD). Patients received a continuous peri-operative infusion of either diltiazem (0.1 mg.kg-1 h-1, n = 32) or nitroglycerin (1 microgram.kg-1 min-1, n = 34) for 24 h. The aim of this study was to define the effect of the calcium channel blocker diltiazem on peri-operative ischaemia, arrhythmias and myocardial function in patients receiving arterial bypass grafts by preventing transient vasospasm. The study patients did not differ with respect to pre-operative, operative and haemodynamic data. Patients treated with diltiazem had lower numbers of ventricular premature beats/hour (8.1 +/- 7.8 vs 20.5 +/- 11.2; P < 0.05). The anti-ischaemic efficacy of peri-operative diltiazem in patients receiving IMA grafts significantly reduced the incidence and duration of transient ischaemic events (0 vs 5). Additionally, patients receiving IMA grafts and diltiazem showed significantly lower peak levels of ischaemia-sensitive laboratory parameters, as compared to IMA graft patients receiving only nitroglycerin: CK-MB: 17.3 +/- 7.7 vs 23.5 +/- 11.0, (P < 0.05); MB-M: 29.4 +/- 14.7 vs 43.1 +/- 27.4, (P < 0.05); troponin-T: 0.88 +/- 0.6 vs 1.41 +/- 0.9, (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diltiazem↗
PubMed1995

Myocyte reorganization in hypertrophied and failing hearts.

In hypertrophied and failing hearts there are major changes in the overall contractile performance. We present a review of our previous work relating the alterations in myocardial force, work, power and relaxation, that lead to changes in overall ventricular performance, to changes in the actin-myosin cross-bridge cycle characteristics along with the degree of activation and inactivation (calcium cycling). Tissues from hypertrophied rabbit and failing human (volume overload, dilated cardiomyopathy) heart were used in these studies. Myocardial peak twitch tension (mN.mm-2) was reduced in dilated cardiomyopathy (human) (25.9 +/- 3.9 vs 13.9 +/- 2.0, 37 degrees C), volume overload (human) (44.0 +/- 11.7 vs 19.9 +/- 3.7, 21 degrees C) and pressure overload (rabbit) (46.1 +/- 2.6 vs 41.7 +/- 5.0, 21 degrees C). We used myothermal and mechanical data to analyse the average cross-bridge force time integral and the amount of calcium cycled per gram per beat. Tension-dependent Heat (mJ.g-1) (TDH) (cross-bridge cycling) and tension-independent heat (mJ.g-1) (TIH) were reduced in all of the experimental preparations (dilated cardiomyopathy, human, 37 degrees C: TDH, 3.39 +/- 0.59 vs 1.34 +/- 0.22; TIH 1.51 +/- 0.02 vs 0.16 +/- 0.03) (volume overload, human 21 degrees C: TDH, 7.23 +/- 2.22 vs 1.92 +/- 0.25; TIH, 0.75 +/- 0.19 vs 0.39 +/- 0.04) (pressure overload, rabbit, 21 degrees C: TDH, 6.60 +/- 0.75 vs 3.05 +/- 0.46; TIH, 1.00 +/- 0.17 vs 0.41 +/- 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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

Positive inotropism and myocardial energetics: influence of beta receptor agonist stimulation, phosphodiesterase inhibition, and ouabain.

OBJECTIVE: The aim was to study the effect of three positive inotropic interventions on myocardial force development and heat production in guinea pig papillary muscles in order to investigate the energetic consequences. METHODS: The positive inotropic agents used were epinine (beta adrenoceptor stimulation), E-1020 (phosphodiesterase inhibition), and ouabain (sodium-potassium ATPase inhibition). Heat measurements were accomplished using antimony-bismuth thermopiles, and initial heat was separated into tension dependent and tension independent heat using the butanedione-monoxime (BDM) and the shortening methods. RESULTS: Optimal concentrations of epinine, E-1020, and ouabain increased peak developed force from 20.0(SD 6.6) to 55.5(9.3) (n = 5; p < 0.01), from 20.9(9.1) to 27.2(7.2) (n = 6; p < 0.05), and from 23.4(9.2) to 44.9(18.0) mN.mm-2 (n = 6; p < 0.01), respectively. Epinine and E-1020 decreased the tension-time integral per unit initial heat, ie, the economy of isometric contraction, from 5.5(1.4) to 3.6(0.5) (p < 0.01) and from 5.5(1.4) to 3.1(0.9) N.m.s.J-1 (p < 0.01), respectively; no significant change was observed with ouabain [6.7(1.4) to 8.3(0.5) N.m.s.J-1]. The tension independent heat (calcium turnover) was measured in two different ways using BDM or shortening to abolish force production. It was increased significantly by epinine (by 141-243%), E-1020 (by 77-114%), and ouabain (by 23-38%). The first measurement in brackets is the BDM estimate, the second is the shortening estimate. From the tension-time integral and the tension dependent heat the crossbridge force-time integral was analysed: epinine and E-1020 decreased the crossbridge force-time integral from 0.46(0.16) to 0.31(0.06) pN.s (p < 0.01) and from 0.50(0.19) to 0.31(0.08) pN.s (p < 0.01), respectively, while ouabain left the force-time integral unchanged [0.59(0.27) to 0.63(0.20) pN.s]. CONCLUSIONS: (1) The inotropic effect of ouabain results from an increase in muscle activation with no change in crossbridge kinetics; (2) epinine and E-1020 increase the tension independent heat and decrease the crossbridge force-time integral, both effects reducing the overall economy; and (3) the shortening and BDM methods for measuring the tension independent heat give qualitatively similar but quantitatively different results.

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↗
PubMed1993

Optimization of myocardial function.

Under normal conditions the cardiac output is designed to meet the metabolic needs of the organism. Thus, the demands imposed on the heart muscle can range from low values at rest to an order of magnitude greater values during exercise. The heart uses a number of strategies to meet the short- and long-term changes in demand. These strategies are of general biological interest and employ similar mechanisms to those responsible for the differences in muscle performance seen between muscle from various species and diverse muscle types within a given animal. This review deals with the heart's utilization of these strategies to meet a broad range of requirements. Tortoise (TM) and rat soleus (RS) muscles are slow, have high economy and develop low power. In contrast (FM) and rat extensor digitorum longus (REDL) are fast, have low economy and have a high power output. These differences are explainable in terms of the characteristics of the myosin head cross-bridge cycle (Cross-bridge tension-time integral: FM/FT = 0.024; REDL/RS = 0.16. Myosin ATPase activity: FM/TM = 15; RDEL/RS = 2.3) and excitation contraction coupling system (time to peak tension: FM/TM = 0.2; REDL/RS = 0.4). Heart muscle employs similar strategies (cross-bridge cycle; excitation contraction coupling) to meet short (catecholamine) and long (hypertrophy secondary to pressure overload or thyrotoxicosis) term changes in demand. In the presence of catecholamine power is increased while economy is decreased. This difference between control (C) and isoproterenol treated hearts (I) is explainable in terms of the contractile and excitation contraction coupling systems (Cross-bridge tension-time integral: I/C = 0.4. Tension independent heat: I/C = 2.0. Tension independent heat rate: I/C = 2.5). A persistent increase in the demand on the heart results in myocardial hypertrophy that is associated with intracellular reorganization. Hyperthyroidism (T) and pressure overload (PO) were used to produce myocardial hypertrophy. In T hearts the economy is decreased while the power is increased; in PO hearts oppositely directed changes occur. These alterations are attributable to changes in the performance of the contractile and excitation contraction coupling systems (Cross-bridge force-time integral: T/C/PO = 0.5/1.0/2.6. Tension independent heat: T/C/PO = 1.4/1.0/0.4. Tension independent heat rate: T/C/PO = 1.4/1.0/0.3). Thus it is clear that in meeting changes in demand, the heart uses strategies comparable to those seen between species and muscle types within a given muscle.

Animals↗
PubMed1993

Myocardial adaptation to stress from the viewpoint of adaptation and development.

Myocardial adaptation to stress and development includes reorganization of subcellular systems. Using a myothermal method, changes in the contractile protein system were investigated across species (rat, rabbit, human myocardium) and in consequence of hemodynamic (volume overload human, pressure overload rabbit myocardium) or hormonal stresses (hypothyroid rat, hyperthyroid rabbit myocardium). Mechanical and myothermal measurements were performed in isometrically contracting right or left ventricular muscle strips and the force-time integral of the individual crossbridge cycle was calculated from heat and force data. Within species, crossbridge force-time integral increased by 85% from control human to volume overload human myocardium. Crossbridge force-time integral increased by 100% from control to hypothyroid rat myocardium. In rabbit myocardium, crossbridge force-time integral increased by 164% in pressure overload and decreased by 47% in hyperthyroid compared to control myocardium. Across species, crossbridge force-time integral was smallest in control rat myocardium (0.16 +/- 0.01 pNs) and increased in the order: control rat < hyperthyroid rabbit < hypothyroid rat, control rabbit < control human < pressure overload rabbit < volume overload human myocardium (0.96 +/- 0.01 pNs). Within and across species, crossbridge force-time integral was positively correlated with time to peak tension (r = 0.86; p < 0.05) and negatively correlated with maximum rate of tension rise (r = -0.85; p < 0.05) and maximum rate of tension fall (r = -0.78; p < 0.05). Furthermore, there were significant correlations between crossbridge force-time integral and total activity related heat (r = -0.81; p < 0.05) as well as total activity related heat per tension-time integral (r = -0.89; p < 0.005). Thus, the close relationship between crossbridge force-time integral and myocardial function within and across species demonstrates that alterations of crossbridge force-time integral reflect an important mechanism of subcellular adaptation to stress from a mechanical point of view. Moreover, alterations of the crossbridge force-time integral have pronounced effects on energy consumption in the different types of myocardium.

Adaptation, Physiological↗
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

Contractile protein function in failing and nonfailing human myocardium.

Isometric heat and force measurements were used to relate mechanical performance to function of contractile proteins in muscle strips from failing and nonfailing human hearts (37 degrees C, 60 beats per minute). Compared to control myocardium, crossbridge behavior was altered in myocardium from hearts with end-stage failing dilated and ischemic cardiomyopathy, resulting in increased crossbridge force-time integral by 33% and 36%, respectively. Peak isometric twitch tension was reduced significantly by 46% in muscle strips from hearts with dilated cardiomyopathy. In myocardium from hearts with ischemic cardiomyopathy peak isometric twitch tension was comparable to values from nonfailing hearts. Including all three types of myocardium, there was a close correlation between the number of crossbridge interactions during the isometric twitch (tension-dependent heat) and peak twitch tension (r = 0.88; p less than 0.001). Compared to control, in failing myocardium from dilated cardiomyopathic hearts, tension-independent heat (calcium cycling) was significantly reduced. This indicates that in dilated cardiomyopathy reduced peak twitch tension results from decreased calcium activation of contractile proteins with reduced number of crossbridge interactions during the isometric twitch. In ischemic cardiomyopathy mechanisms different from those observed in dilated cardiomyopathy seem to be involved in the development of heart failure.

Actomyosin↗
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↗