Biomedical subjects

N R Alpert

Publications and source records attributed to N R Alpert.

At least 37 records · Page 2Linked to original sources

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↗

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

Myocardial force-frequency defect in mitral regurgitation heart failure is reversed by forskolin.

BACKGROUND: Postoperative ejection phase parameters and patient survival rates for mitral valve replacement surgery are considerably lower than for similar aortic valve surgery. While chordal transection probably is the major contributor to the lowered values, there is also evidence for decreased preoperative myocardial contractile reserve in mitral regurgitation patients. This study characterizes abnormalities in the force-frequency relation that may underlie impaired function of myocardium isolated from mitral regurgitation patients with New York Heart Association class II-III heart failure. METHODS AND RESULTS: Left ventricular epicardial myocardium was obtained by surgical biopsy during mitral valve replacement surgery in patients with mitral regurgitation heart failure (left ventricular ejection fraction, 0.64 +/- 0.05) and during coronary artery bypass surgery in patients with normal ventricular function. The steady-state twitch tension versus frequency relation was measured in myocardial strip preparations (37 degree C, 12 to 228 min-1) in the absence and presence of forskolin. Relative to normal function, peak isometric twitch tension in mitral regurgitation is depressed by 50% (P < .02) and 74% (P < .003) at contraction frequencies of 60 min-1 and 168 min-1, respectively. The slope of the tension-frequency curve is blunted and its peak is shifted to a lower frequency (mitral regurgitation: 134 min-1; normal function: 173 min-1; P < .02). The myosin heavy chain concentration did not differ between mitral regurgitation and normal function strips (53 +/- 4 versus 54 +/- 4 nmol/g blotted wt). Forskolin (0.5 mumol/L) completely reversed the tension depression, blunting, and the lowered peak frequency in the mitral regurgitation preparations. CONCLUSIONS: Preoperatively, myocardial tension generation in mitral regurgitation patients is severely depressed, and the force-frequency curve is blunted and has a negative slope in the exercise range of heart rates. The reversal of these defects by forskolin suggests that abnormal excitation-contraction coupling may underlie the decreased contractile reserve in mitral regurgitation patients.

Colforsin↗

PubMed1993

Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium.

Recent studies have shown that intracellular Ca2+ handling is abnormal in the myocardium of patients with end-stage heart failure. Muscles from the failing hearts showed a prolonged Ca2+ transient and a diminished capacity to restore a low resting Ca2+ level during diastole. Accordingly, we examined whether this defect in Ca2+ transport function is due to alterations in sarcoplasmic reticulum gene expression. We determined the messenger RNA (mRNA) levels of sarcoplasmic reticulum Ca2+ transport proteins in failing human hearts from 17 cardiac transplant recipients with a diagnosis of dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The expression levels of each mRNA were compared with each other and then correlated with that of atrial natriuretic factor (ANF) mRNA in the failing ventricle. The mRNA levels for the calcium release channel (ryanodine receptor, RYR2), Ca2+ uptake pump (Ca(2+)-ATPase, SERCA2 isoform), and phospholamban differed significantly between heart samples but showed an inverse relation with that of ventricular ANF mRNA. In contrast, calsequestrin mRNA levels remained unchanged in these failing hearts. In addition, beta-myosin and alpha-cardiac actin mRNA levels also showed an inverse relation with ANF mRNA levels. These changes were observed in both right and left ventricles of hearts with congestive heart failure due to dilated cardiomyopathy, primary pulmonary hypertension, or ischemic heart disease. The results are consistent with the hypothesis that abnormal calcium handling in the sarcoplasmic reticulum of failing hearts is due to the altered expression of the genes encoding sarcoplasmic reticulum proteins.

Adolescent↗

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

Contraction frequency dependence of twitch and diastolic tension in human dilated cardiomyopathy (tension-frequency relation in cardiomyopathy).

We studied isometric twitch tension and diastolic tension at 37 degrees C as a function of stimulation frequency (12-240 min-1) in very thin (.07-.5 mm2), parallel fibered strips of left-ventricular myocardium. Non-failing control tissue (C) was obtained from epicardial biopsies taken during myocardial revascularization surgery on patients with normal ventricular function. End-stage failing tissue was obtained from endocardial and epicardial biopsies from explanted hearts with idiopathic dilated cardiomyopathy (DCM). The methods and apparatus for biopsy and dissection of myocardium are described. Maximal peak twitch tension at optimal stimulation frequency of 163 +/- 5 min-1 was 41.8 +/- 10 mN/mm2 in non-failing myocardium and it was reduced by 70% (p less than .02) to 12.9 +/- 1.6 mN/mm2 at an optimal frequency of 72 +/- 17 min-1 in DCM. The peaks of the tension-frequency curves occurred at frequencies between 12 and 60 min-1 in most DCM strips (5/9), while in C most of the peaks (8/9) fell between 156 and 180 min-1. The peaks from four DCM hearts fell in an intermediate range of frequencies (96-144 min-1) which also included one non-failing peak at 132 min-1. Diastolic tension declined in both groups as stimulation frequency increased above 12 min-1 and it began increasing when stimulation frequency rose above optimal frequency by 19 +/- 5% and 110 +/- 50% in C and DCM, respectively. Total duration of the isometric twitch diminished with tachycardia remaining shorter than stimulation intervals up to 140 +/- 16 min-1 (3.1 +/- 1 times optimal frequency) in DCM and up to 161 +/- 14 min-1 (not different than optimal frequency) in C. Decline in peak twitch tension above optimal stimulation frequency was 4 to 6 times larger than the accompanying rise in diastolic tension in both groups. The premature decline in tension at lower than normal degrees of tachycardia in DCM does not arise from incomplete relaxation of the twitch response. The 70% deficit in tension generating ability of DCM may be a major contributor to heart failure. Moderate shift in the peak of the tension-frequency curves to lower frequencies (130 min-1) in C does not appear to predispose end-stage failure, but it may make the ventricle more susceptible to dilation.

Adult↗

PubMed1992

Dynamic calcium requirements for activation of human ventricular muscle calculated from tension-independent heat.

The heat and tension generated by strips of human left ventricle taken from nonfailing hearts were measured at 30 C before and after partial inhibition of ATP splitting by the contractile proteins. We used 2, 3-butanedione monoxime (BDM) (4mM) as the chemical inhibition agent and alterations in solution calcium concentration and stimulus frequency to estimate the heat associated with calcium cycling for a wide range of activation levels. Tension-independent heat (TIH) was used to calculate the total calcium cycled per twitch by assuming that two-thirds of TIH was due to ATP splitting by the sarcoplasmic reticulum CA2+ ATPase with a coupling ratio of 2 Ca2+/ATP split and that one-third of TIH was due to ATP splitting by the sarcolemmal Na+ -K+ ATPase supporting the Na+ -Ca2+ exchanger (1 Ca2+/ATP). The enthalpy of creatine phosphate hydrolysis buffering ATP was taken as -34 KJ/mol. There was a highly positive correlation between TIH and mechanical activation during steady-state and nonsteady-state stimulation. The estimated total calcium turnover per twitch at 39% activation (0.3 Hz pacing rate and 2.5 mM Calcium) was approximately 0.17 nmol/g wet weight. This estimate is less than that calculated from biochemical data describing the cellular content and Ca2+ affinity of major Ca2+ buffers, but is similar to values calculated from recent electron probe microanalysis experiments.

Adenosine Triphosphate↗

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

The regulation of calcium cycling in stressed hearts.

Myothermal measurements of tension-independent heat are used to calculate the quantity of calcium released during isometric contraction and the rate at which it is removed in control, thyrotoxic and pressure-overloaded rabbit hearts. Experiments were carried out at 30 degrees C. In control rabbit hearts 41.0 +/- 7.0 nmoles/g Ca++ was released into the cytosol for each beat, while the rate at which the Ca++ was removed from the cytosol was 24.4 +/- 4.4 nmoles/g sec. In the presence-overloaded preparations, the amount of calcium released and the rate of calcium removal were 41% and 40% of control values. This reduction was correlated with the mRNA levels for the sarcoplasmic reticulum (SR) Ca++ ATPase, phospholamban and the ryanodine receptor. The depression was also correlated with a reduction in SR Ca++ ATPase protein expression. In thyrotoxic hearts compared with controls, with each activation there is an increase in the amount of calcium liberated into the cytosol (39%) and the rate of calcium removal (31%). This increase is correlated with an increase in the mRNA and protein expression for the SR Ca++ ATPase as well as the mRNA for the ryanodine receptor. Calsequestrin mRNA was unchanged in all of the experimental preparations. It is suggested that the alteration in the calcium cycling proteins offers at least a partial explanation for the changes in calcium cycling measured in response to the stresses applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

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↗

PubMed1992

The reorganization of the human and rabbit heart in response to haemodynamic overload.

A myothermal/mechanical analysis on non-failing and failing human hearts and normal and pressure overloaded rabbit hearts is reported. Heat production is partitioned into tension-dependent and tension-independent components together with force measurements to provide information about calcium and cross-bridge cycling. In the non-failing human heart the cross-bridge force-time integral is 0.51 +/- 0.06 (ns). This value is increased to 0.97 +/- 0.09 (P less than 0.05 s) in failing hearts. In control as compared to pressure-overload rabbit hearts the cross-bridge force-time integral increases from 0.36 +/- 0.02 to 0.96 +/- 0.11 (P less than 0.05 s). The increase in force-time integral allows the heart muscle to develop force with greater economy (less high energy phosphate hydrolysis) but at the expense of velocity and power. The amount of calcium cycled following activation in non-failing human hearts is 32.2 +/- 8.17 nmoles.g-1.-beat-1. In the failing preparations calcium cycling is reduced to 16.7 +/- 1.72 nmoles.g-1.-beat-1. In pressure-overloaded hypertrophied, as compared with control rabbit hearts, the calcium cycled per beat is reduced from 43.0 +/- 7.3 to 17.6 +/- 3.4 nmoles.g-1. It is suggested that the alterations in cross-bridge cycling are more likely to be related to isoenzyme shifts in light chains or troponin T than to myosin isoforms. The calcium cycling changes are well correlated with changes in the sarcoplasmic reticular and sarcolemmal calcium transport proteins. The alterations in the contractile and excitation contractions coupling systems contribute to the functional changes observed in the failing human and pressure-overload rabbit hearts.

Animals↗

PubMed1992

Cellular basis of negative inotropic effect of 2,3-butanedione monoxime in human myocardium.

2,3-Butanedione monoxime (BDM) exerts a marked negative inotropic effect and has been shown to have protective actions on human myocardial force production that may be of clinical use. To determine the underlying mechanisms, we studied the effects of BDM on chemically skinned and aequorin-loaded myopathic human myocardium from transplant recipients. Eighteen muscles were chemically skinned with saponin (250 micrograms/ml) and then subjected to activation-relaxation cycles, with and without 5 mM BDM. Contracture force vs. Ca2+ data were fitted to a modified Hill equation, and values for 50% maximal activation (pCa50) and maximal Ca(2+)-activated force (Fmax) were obtained. pCa50 was decreased by 0.2 pCa units, indicating myofilament Ca2+ desensitization, and Fmax was reduced by 48% in 5 mM BDM. A second group of intact muscles (n = 8) was loaded with aequorin to monitor intracellular calcium (Cai2+) transients (peak light) and twitch force in the presence of BDM (1-30 mM). Over a range of 1-20 mM, BDM depressed peak light by 3-49% while force was depressed by 10-82%. This was accompanied by an abbreviation of the duration of the twitch but not of the Cai2+ transient. At a concentration of 30 mM, BDM completely inhibited force generation, but an Cai2+ transient was still present. We conclude that in human myocardium, 5 mM BDM predominantly affects cross-bridge force production and Ca2+ sensitivity and has a less pronounced effect on Cai2+.

Aequorin↗

PubMed1992

Altered myocardial force-frequency relation in human heart failure.

BACKGROUND: In congestive heart failure (idiopathic dilated cardiomyopathy), exercise is accompanied by a smaller-than-normal decrease in end-diastolic left ventricular volume, depressed peak rates of left ventricular pressure rise and fall, and depressed heart-rate-dependent potentiation of contractility (bowditch treppe). We studied contractile function of isolated left ventricular myocardium from New York Heart Association class IV-failing and nonfailing hearts at physiological temperature and heart rates in order to identify and quantitate abnormalities in myocardial function that underlie abnormal ventricular function. METHODS AND RESULTS: The isometric tension-generating ability of isolated left ventricular strips from nonfailing and failing human hearts was investigated at 37 degrees C and contraction frequencies ranging from 12 to 240 per minute (min-1). Strips were dissected using a new method of protection against cutting injury with 2,3-butanedione monoxime (BDM) as a cardioplegic agent. In nonfailing myocardium the twitch tension-frequency relation is bell-shaped developing 25 +/- 2 mN/mm2 at a contraction frequency of 72 min-1 and peaking at 44 +/- 3.7 mN/mm2 at a contraction frequency of 174 +/- 4 min-1. In failing myocardium the peak of the curve occurs at lower frequencies between 6 and 120 min-1 averaging 81 +/- 22 min-1, and it develops 48% (p less than 0.001) and 80% (p less than 0.001) less tension than in nonfailing myocardium at 72 and 174 min-1, respectively. Between 60 and 150 min-1 tension increases by 107% in nonfailing myocardium, but it does not change significantly in failing myocardium. Peak rates of rise and fall of isometric twitch tension vary in parallel with twitch tension as stimulation frequency rises in nonfailing myocardium but not in failing myocardium. CONCLUSIONS: The quantitative agreement between these results from isolated myocardium and those from catheterization laboratory measurements on intact humans suggest that alterations of myocardial origin, independent of systemic factors, may contribute to the above mentioned abnormalities in left ventricular function seen in dilated cardiomyopathy.

Adult↗

PubMed1992

Alteration of contractile function and excitation-contraction coupling in dilated cardiomyopathy.

Myocardial failure in dilated cardiomyopathy may result from subcellular alterations in contractile protein function, excitation-contraction coupling processes, or recovery metabolism. We used isometric force and heat measurements to quantitatively investigate these subcellular systems in intact left ventricular muscle strips from nonfailing human hearts (n = 14) and from hearts with end-stage failing dilated cardiomyopathy (n = 13). In the failing myocardium, peak isometric twitch tension, maximum rate of tension rise, and maximum rate of relaxation were reduced by 46% (p = 0.013), 51% (p = 0.003), and 46% (p = 0.018), respectively (37 degrees C, 60 beats per minute). Tension-dependent heat, reflecting the number of crossbridge interactions during the isometric twitch, was reduced by 61% in the failing myocardium (p = 0.006). In terms of the individual crossbridge cycle, the average crossbridge force-time integral was increased by 33% (p = 0.04) in the failing myocardium. In the nonfailing myocardium, the crossbridge force-time integral was positively correlated with the patient's age (r = 0.86, p less than 0.02), whereas there was no significant correlation with age in the failing group. The amount and rate of excitation-contraction coupling-related heat evolution (tension-independent heat) were reduced by 69% (p = 0.24) and 71% (p = 0.028), respectively, in the failing myocardium, reflecting a considerable decrease in the amount of calcium released and in the rate of calcium removal. The efficiency of the metabolic recovery process, as assessed by the ratio of initial heat to total activity-related heat, was similar in failing and nonfailing myocardium (0.54 +/- 0.03 versus 0.50 +/- 0.02, p = 0.23).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗

PubMed1991

Cloning and characterization of the gene encoding rabbit cardiac calsequestrin.

A cDNA encoding rabbit cardiac calsequestrin was isolated and characterized. The deduced nascent cardiac calsequestrin contains 409 amino acids of which 26% are acidic residues, and had 93% and 67% aa identity with canine cardiac calsequestrin and rabbit fast-twitch skeletal muscle calsequestrin, respectively. RNA blot analyses indicate that this mRNA is expressed in atrium, ventricle and to a lesser amount in slow-twitch skeletal muscle. This mRNA transcript is not expressed in adult fast-twitch skeletal muscle, smooth muscle, or nonmuscle tissues. Analysis of in vitro skeletal muscle myogenesis using a mouse myoblast cell line C2C12, demonstrates that both cardiac and skeletal calsequestrin isoforms are coproduced during muscle differentiation.

Actins↗

PubMed1991

Time course of mechanical efficiency during afterloaded contractions in isolated cardiac muscle.

The time course of mechanical efficiency during working contractions in rabbit papillary muscle is presented. Efficiency is found to remain relatively constant during the working portion of the twitch, when the muscle is contracting against a constant load. As afterload was decreased, efficiency increased to 65 +/- 11% (mean +/- SE, n = 3) at 10% developed force at maximum length. This is in contrast to muscle work, which reached a peak of 3.0 +/- 0.3 (n = 6) mJ/g at 50% developed force at maximum length.

Animals↗

PubMed1991

Energetics of isometric force development in control and volume-overload human myocardium. Comparison with animal species.

Alteration in crossbridge behavior and myocardial performance have been associated with myosin isoenzyme composition in animal models of myocardial hypertrophy or atrophy. In the hypertrophied human heart, myocardial performance is altered without significant changes in myosin isoenzymes. To better understand this discrepancy, isometric heat and force measurements were carried out in 1) control and volume-overload human myocardium, 2) control, pressure-overload, and hyperthyroid rabbit myocardium, and 3) control and hypothyroid rat myocardium. In control human myocardium, peak isometric twitch tension was 44.0 +/- 11.7 mN/mm2, and maximum rate of tension rise was 69.2 +/- 21.0 mN/sec.mm2. In volume-overload human myocardium, peak twitch tension and maximum rate of tension rise were reduced by 55% (p less than 0.05) and 65% (p less than 0.05), respectively. The average force-time integral of the individual crossbridge cycle, calculated by myothermal techniques, was increased by 85% (p less than 0.005) in volume-overload human myocardium. In control and hormonally altered myocardium, both across and within species (control human, control rat, control rabbit, hypothyroid rat, and hyperthyroid rabbit), there was a close relation between the crossbridge force-time integral and the percentage of V3-type myosin isoenzyme in the myocardium. However, hemodynamically altered (volume-overload human and pressure-overload rabbit) myocardium did not follow this relation. Across and within species, there were significant correlations between maximum rate of tension rise and average tension-dependent heat rate (r = 0.97, p less than 0.001) and between maximum rate of tension fall and average tension-independent heat rate (r = 0.82; p less than 0.025). Furthermore, there were close inverse relations between these heat rates and the crossbridge force-time integral. In addition, there was an inverse relation between tension-independent heat and the crossbridge force-time integral. Across and within species total myocardial energy turnover was significantly correlated with the crossbridge force-time integral (relative total heat, r = -0.84, p less than 0.02; relative total-activity related heat, r = -0.88, p less than 0.01). The present findings indicate that 1) factors separate from myosin isoenzymes account for the altered crossbridge cycle in volume-overload human and pressure-overload rabbit myocardium, 2) changes in excitation-contraction coupling processes accompany changes in the crossbridge cycle within and across species, and 3) the force-time integral of the crossbridge cycle is a major determinant of total myocardial energy turnover.

Animals↗