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G Hasenfuss

Publications and source records attributed to G Hasenfuss.

At least 19 recordsLinked to original sources
PubMed1998

Frequency-dependent changes in contribution of SR Ca2+ to Ca2+ transients in failing human myocardium assessed with ryanodine.

We tested the influence of blocking sarcoplasmic reticulum (SR) function with ryanodine (1 microM) on stimulation rate-dependent changes of intracellular Ca2+ transients and twitch force in failing human myocardium. Isometrically contracting, electrically stimulated muscle strips from ventricles of 10 end-stage failing human hearts were used. Muscles were loaded with the intracellular Ca2+ indicator aequorin. At stimulation rates from 0.5-3 Hz, intracellular Ca2+ transients and twitch force were simultaneously recorded before and after ryanodine exposure (37 degrees C). Ryanodine significantly reduced twitch force at 1 Hz by 46 +/- 9% and aequorin light by 57 +/- 10% in failing human myocardium (P < 0.05). The blunted or inverse aequorin light- and force-frequency relation became positive after ryanodine: in failing human myocardium, twitch force and aequorin light before ryanodine did not increase with increasing frequency and force decreased significantly at 3 Hz (P < 0.05). After ryanodine, twitch force (P < 0.05) and aequorin light increased with increasing stimulation frequency and were maximum at 2 Hz. The data indicate that inhibition of SR function significantly reduces twitch force and Ca2+ transients in failing human myocardium, but converts the blunted or inverse Ca(2+)- and force-frequency relation into a positive one. We infer that Ca2+ responsible for approximately 50% of twitch force is derived from the SR and approximately 50% from sarcolemmal Ca2+ influx in failing human myocardium. This sarcolemmal component increases at higher stimulation frequencies.

Calcium↗
PubMed1998

Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations.

Diastolic dysfunction at high heart rates may be associated with increased myocardial energy consumption. Frequency-dependent changes of isometric force and oxygen consumption (MVO2) were investigated in strip preparations from endstage failing human hearts exhibiting various degrees of diastolic dysfunction. MVO2 was determined by a new method which was validated. When stimulation rate was increased from 40 to 200 min-1 (n=7), developed force decreased from 16.5+/-4.3 to 7.9+/-2.9 mN/mm2 (P<0.01), diastolic force increased from 15.9+/-3.2 to 22.0+/-3.0 mN/mm2 (P<0.01), and total MVO2 increased from 2.6+/-0.6 to 4.7+/-0.9 ml/min/100 g (P<0.025). Resting MVO2 and resting force were 1.8+/-0.4 ml/min/100 g and 15.9+/-3.0 mN/mm2, respectively. After addition of 30 mm 2,3-butanedione monoxime (BDM) to inhibit crossbridges, resting MVO2 and resting force decreased by 46% (P<0.05) and 15% (P<0.01), respectively, indicating the presence of active force generation in unstimulated failing human myocardium. In each muscle preparation, there was a significant correlation between force-time integral (FTI) and total MVO2 (r=0.96+/-0.01). The strength of these correlations did not vary with the contribution of diastolic FTI to total FTI. The ratio of activity related MVO2 to developed FTI, an inverse index of the economy of contraction, increased depending on the rise of diastolic FTI at higher stimulation rates. In conclusion, in failing human myocardium, diastolic force development is occurring at the same energy expenditure as systolic force generation. Therefore, in muscle preparations with disturbed diastolic function economy of contraction decreases with higher stimulation rates, depending on the rise of diastolic force.

Biomechanical Phenomena↗
PubMed1998

The trabecula culture system: a novel technique to study contractile parameters over a multiday time period.

In the intact heart, various triggers induce alterations in gene expression that impact on contractile function. Because changes in gene expression reflect altered protein expression patterns after 12-48 h, we developed a system in which intact twitching cardiac trabeculae can be studied for multiday periods. Right ventricular trabeculae from pentobarbital sodium anesthetized rabbits were mounted in a sterile, closed muscle chamber. Over the first 48 h, developed force (Fdev) did not significantly change: 102.3 and 98.9% of the initial Fdev was observed after 24 and 48 h, respectively (n = 8). Also, neither diastolic force, time from peak to 50% relaxation (RT50), nor protein synthesis measured by a [3H]leucine incorporation assay changed significantly over time. Contractile response after > 48 h to an increase in extracellular calcium concentration (1.8 to 2.5 mM; Fdev increased 43.5%, n = 2) or to 1 microM isoproterenol (Fdev increased 138.6% and RT50 decreased 34.9%, n = 2) was similar to those observed in freshly dissected preparations. In conclusion, this system can investigate contractile function of multicellular preparations under well-defined physiological conditions after events that alter gene and consequent protein expression.

Animals↗
PubMed1997

Ca(2+)-dependent and Ca(2+)-independent regulation of contractility in isolated human myocardium.

UNLABELLED: Changes in contractile force of the myocardium may depend on changes in the intracellular Ca2+ concentration, changes in the responsiveness of the myofibrils for Ca2+, or a combination of both. We investigated in isolated muscle strip preparations from human nonfailing and endstage failing hearts the influence of physical (changes in preload, stimulation rate, or rhythm), and pharmacological interventions (alpha- or beta-adrenoceptor-stimulation, endothelin) on developed force of contraction and the corresponding intracellular Ca2+ transients. METHODS: Isometric contraction, electrical stimulation, 37 degrees C. Simultaneous registration of force of contraction and intracellular Ca2+ transients (aequorin method). RESULTS: Increases in preload, alpha- and endothelin-receptor stimulation resulted in increases in force of contraction without increasing aequorin light emission. Increasing stimulation rate or increasing rest intervals resulted in parallel increases (nonfailing myocardium) or decreases (failing myocardium) of force of contraction and aequorin light emission. beta-Adrenoceptor-stimulation exerted inotropic and lusitropic effects in human failing myocardium associated with a large, overproportional increase in aequorin light emission. CONCLUSION: The human heart regulates intrinsic contractility via several subcellular mechanisms. Increases in preload (Frank-Starling-mechanism) and alpha- or endothelin-receptor-stimulation enhance myocardial contractility by increasing the Ca2+ responsiveness of the myofilaments; rate- and rhythm-dependent modulation of the contractile state directly depend on changes in the intracellular Ca(2+)-transients; beta-adrenoceptor stimulation results in an overproportional large increase in intracellular Ca2+ transients, probably due to additional cAMP-dependent Ca(2+)-desensitizing effects on the level of the myofibrils.

Calcium↗
PubMed1997

Calcium handling proteins in the failing human heart.

There is accumulating evidence that disturbed calcium homeostasis may play a key role in the pathophysiology of human heart failure. Because disturbed calcium handling could result from altered protein expression, levels of calcium handling proteins were quantitated by Western Blot analysis in failing and nonfailing human myocardium from hearts with endstage failing dilated or ischemic cardiomyopathy. Protein levels of the sarcoplasmic reticulum calcium release channel (ryanodine receptor) and of calcium storage proteins (calsequestrin and calreticulin) were similar in failing and nonfailing human myocardium. However, proteins involved in calcium removal from the cytosol were significantly altered in the failing human heart: 1) SR-Ca(2+)-ATPase, relevant for removal of calcium from the cytosol into the lumen of the sarcoplasmic reticulum, was decreased; 2) phospholamban, which inhibits the SR-Ca(2+)-ATPase in the basal unphosphorylated state, was slightly decreased; 3) the ratio of SR-Ca(2+)-ATPase to phospholamban was decreased; 4) the sarcolemmal Na(+)-Ca(2+)-exchanger, relevant for transsarcolemmal calcium extrusion was increased in the failing hearts. In summary, altered levels of proteins involved in calcium removal from the cytosol suggest an increase in transsarcolemmal calcium elimination relative to sarcoplasmic reticulum calcium removal. These findings support the concept that reduced function of the sarcoplasmic reticulum to accumulate calcium may reflect a major defect in excitation-contraction coupling in human heart failure.

Calcium↗
PubMed1997

[Successful treatment of fulminant myocarditis with the biventricular MEDOS Assist System (MEDOS HIA-VAD)].

BACKGROUND: Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the new MEDOS HIA ventricular assist device. METHODS AND RESULTS: We used the MEDOS assist system to support a 30-year-old woman with profound circulatory impairment caused by acute myocarditis. The device provided adequate hemodynamics and recovery of myocardial function. Despite anticoagulation therapy we had to change either the left or right ventricular pump chamber because of clot formation on the surface of the outflow tract. On the 14th postoperative day a surgical reintervention was necessary for bleeding from the cannulation site of the pulmonary artery. After 17 days the myocardial function had recovered and we could remove the assist system. The following parameters were measured before implantation of the MEDOS assist system and after weaning from circulatory support: ejection fraction 15 vs. 45%, cardiac index 0.7 vs. 2.6 L/min/m2, arterial pressure (systolic/diastolic/mean) 81/55/66 vs. 113/66/82 mm Hg, pulmonary artery pressure 33/25/29 vs. 34/20/28 mm Hg, pulmonary capillary wedge pressure 24 vs. 19 mm Hg. CONCLUSIONS: Despite severe cardiac failure in fulminant myocarditis requiring biventricular mechanical support full recovery of the myocardium is possible.

Adult↗
PubMed1996

Influence of isoproterenol and ouabain on excitation-contraction coupling, cross-bridge function, and energetics in failing human myocardium.

BACKGROUND: In patients with heart failure, long-term treatment with catecholamines and phosphodiesterase inhibitors, both of which increase cyclic AMP levels, may be associated with increased mortality, whereas mortality may not be increased with glycoside treatment. Differences in clinical benefit between cyclic AMP-dependent inotropic agents and cardiac glycosides may be related to differences of these drugs on calcium cycling and myocardial energetics. METHODS AND RESULTS: Isometric heat and force measurements were used to investigate the effects of isoproterenol and ouabain on myocardial performance, cross-bridge function, excitation-contraction coupling, and energetics in myocardium from end-stage failing human hearts. Isoproterenol (1 mumol/L) increased peak twitch tension by 55% and decreased time to peak tension and relaxation time by 30% and 26%, respectively (P < .005). Ouabain (0.38 +/- 0.11 mumol/L) increased peak twitch tension and relaxation time by 41% and 20%, respectively, and decreased time to peak tension by 12% (P < .05). With isoproterenol, the amount of excitation-contraction coupling-related heat evolution (tension-independent heat) increased by 246% (P < .05) and the economy of excitation-contraction coupling decreased by 61% (P < .05). Ouabain increased tension-independent heat by only 61% (P < .05) and did not significantly influence economy of excitation-contraction coupling. The effects of isoproterenol on excitation-contraction coupling resulted in a 21% (P < .005) decrease of overall contraction economy, which was not significantly changed with ouabain. Neither isoproterenol nor ouabain influenced energetics of cross-bridge cycling or recovery metabolism. CONCLUSIONS: Major differences between the effects of isoproterenol and ouabain in failing human myocardium are related to calcium cycling with secondary effects on myocardial energetics.

Cardiomyopathies↗
PubMed1996

Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels.

BACKGROUND: The Frank-Starling mechanism is one of the most important physiological principles for regulation of contractile performance. We therefore studied the question of whether this mechanism may be absent or attenuated in end-stage failing human left ventricular myocardium. METHODS AND RESULTS: Different methodological approaches were used to analyze the effects of this mechanism on the organ, tissue, and sarcomere levels: (1) In excised human whole left ventricles (2 donor hearts, 5 failing hearts), diastolic and systolic pressure-volume relationships were obtained. (2) In isolated muscle strip preparations from the left ventricular wall of donor hearts (n = 14) and failing hearts from patients with idiopathic dilated cardiomyopathy (n = 21) and ischemic cardiomyopathy (n = 11), peak developed force was measured at different muscle lengths of the preparation. (3) Skinned fiber preparations were obtained from failing right and left ventricles (n = 12). In all three studies, we clearly observed the existence of the Frank-Starling mechanism: (1) In isolated failing human left ventricles, peak developed isometric pressure is increased when the preload is elevated. (2) Peak developed tension is increased by approximately 50% to 70% (P < .01) in left ventricular preparations of failing and nonfailing ventricles when the muscles are stretched from 90% to 100% optimum length. (3) An increase in sarcomere length leads to a sensitization of contractile proteins of ventricular skinned fiber preparations from failing human hearts. At 1.9-microns sarcomere length, the EC50 value was 5.56 +/- 0.06, and at 2.3 microns it was 5.70 +/- 0.05 (P < .01; n = 7). CONCLUSIONS: The Frank-Starling mechanism is maintained in end-stage failing human hearts, whereas significant alterations of diastolic myocardial distensibility are evident in chronic heart failure.

Analysis of Variance↗
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

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↗