Cardiac efficiency and Starling's Law of the Heart.

The formulation by Starling of The Law of the Heart states that 'the [mechanical] energy of contraction, however measured, is a function of the length of the muscle fibre'. Starling later also stated that 'the oxygen consumption of the isolated heart … is determined by its diastolic volume, and therefore by the initial length of its muscular fibres'. This phrasing has motivated us to extend Starling's Law of the Heart to include consideration of the efficiency of contraction. In this study, we assessed both mechanical efficiency and crossbridge efficiency by studying the heat output of isolated rat ventricular trabeculae performing force-length work-loops over ranges of preload and afterload. The combination of preload and afterload allowed us, using our modelling frameworks for the end-systolic zone and the heat-force zone, to simulate cases by recreating physiologically feasible loading conditions. We found that across all cases examined, both work output and change of enthalpy increased with initial muscle length; hence it can only be that the former increases more than the latter to yield increased mechanical efficiency. In contrast, crossbridge efficiency increased with initial muscle length in cases where the extent of muscle shortening varied greatly with preload. We conclude that the efficiency of cardiac contraction increases with increasing initial muscle length and preload. An implication of our conclusion is that the length-dependent activation mechanism underlying the cellular basis of Starling's Law of the Heart is an energetically favourable process that increases the efficiency of cardiac contraction. KEY POINTS: Ernest Starling in 1914 formulated the Law of the Heart to describe the mechanical property of cardiac muscle whereby force of contraction increases with muscle length. He subsequently, in 1927, showed that the oxygen consumption of the heart is also a function of the length of the muscle fibre, but left the field unclear as to whether cardiac efficiency follows the same dependence. A century later, the field has gained an improved understanding of the factors, including the distinct effects of preload and afterload, that affect cardiac efficiency. This understanding presents an opportunity for us to investigate the elusive length-dependence of cardiac efficiency. We found that, by simulating physiologically feasible loading conditions using a mechano-energetics framework, cardiac efficiency increased with initial muscle length. A broader physiological importance of our findings is that the underlying cellular basis of Starling's Law of the Heart is an energetically favourable process that yields increased efficiency.

Slower shortening kinetics of cardiac muscle performing Windkessel work-loops increase mechanical efficiency.

Conventional experimental methods for studying cardiac muscle in vitro often do not expose the tissue preparations to a mechanical impedance that resembles the in vivo hemodynamic impedance dictated by the arterial system. That is, the afterload in work-loop contraction is conventionally simplified to be constant throughout muscle shortening, and at a magnitude arbitrarily defined. This conventional afterload does not capture the time-varying interaction between the left ventricle and the arterial system. We have developed a contraction protocol for isolated tissue experiments that allows the afterload to be described within a Windkessel framework that captures the mechanics of the large arteries. We aim to compare the energy expenditure of cardiac muscle undergoing the two contraction protocols: conventional versus Windkessel loading. Isolated rat left-ventricular trabeculae were subjected to the two force-length work-loop contractions. Mechanical work and heat liberation were assessed, and mechanical efficiency quantified, over wide ranges of afterloads or peripheral resistances. Both extent of shortening and heat output were unchanged between protocols, but peak shortening velocity was 39.0% lower and peak work output was 21.8% greater when muscles contracted against the Windkessel afterload than against the conventional isotonic afterload. The greater work led to a 25.2% greater mechanical efficiency. Our findings demonstrate that the mechanoenergetic performance of cardiac muscles in vitro may have been previously constrained by the conventional, arbitrary, loading method. A Windkessel loading protocol, by contrast, unleashes more cardiac muscle mechanoenergetic potential, where the slower shortening increases efficiency in performing mechanical work.NEW & NOTEWORTHY Cardiac muscle samples were allowed to describe their natural shortening dynamics while performing force-length work and liberating heat. The muscle shortened more slowly and produced greater force and work output against a time-varying "Windkessel" load than during conventional constant-force shortening, thereby yielding greater mechanical efficiency. A key finding is that the slower shortening kinetics developed in the face of a time-varying load enhances the mechanical efficiency of cardiac muscle during work-loop contractions.

Right-sided heart failure is also associated with transverse tubule remodeling in the left ventricle.

Right-sided heart failure is a common consequence of pulmonary arterial hypertension. Overloading the right ventricle results in right ventricular hypertrophy, which progresses to failure in a process characterized by impaired Ca2+ dynamics and force production that is linked with transverse (t)-tubule remodeling. This also unloads the left ventricle, which consequently atrophies. Experimental left-ventricular unloading can result in t-tubule remodeling, but it is currently unclear if this occurs in right-sided heart failure. In this work, we used a model of monocrotaline (MCT)-induced right heart failure in male rats, using confocal microscopy to investigate cellular remodeling of t-tubules, junctophilin-2 (JPH2), and ryanodine receptor-2 (RyR2). We examined remodeling across tissue anatomical regions of both ventricles: in trabeculae, papillary muscles, and free walls. Our analyses revealed that MCT hearts demonstrated a significant loss of t-tubule periodicity, disruption of the normal sarcomere striated pattern with JPH2 labeling, and also a disorganized striated pattern of RyR2, a feature not previously reported in right heart failure. Remodeling of JPH2 and RyR2 in the MCT heart was more pronounced in papillary muscles and trabeculae compared with free walls, particularly in the left ventricle. We find that these structures, commonly used as ex vivo muscle preparations, are more sensitive to the disease process.NEW & NOTEWORTHY In this work, we demonstrate that t-tubule remodeling occurs in the atrophied left ventricle as well as the overloaded right ventricle after right-side heart failure. Moreover, we identify that t-tubule remodeling in both ventricles is linked to sarcoplasmic reticulum remodeling as indicated by decreased labeling periodicity of both the Ca2+ release channel, RyR2, and the cardiac junction-forming protein, JPH2, that forms a link between the sarcoplasmic reticulum and sarcolemma. Studies developing treatments for right-sided heart failure should consider effects on both the right and left ventricle.

Heat production in quiescent cardiac muscle is length, velocity and muscle dependent: Implications for active heat measurement.

NEW FINDINGS: What is the central question of this study? Intracellular energetic processes in quiescent cardiac muscle release 'basal' heat; during contraction, a much larger amount of 'active' heat is also produced. Previously, measurement challenges have constrained researchers to assume that basal heat rate remains constant during contraction and shortening. Is this assumption correct? What is the main finding and its importance? We show that basal heat rate is modulated by the extent and velocity of muscle shortening. Their relative contributions are muscle specific. We apply a method with which researchers can now disentangle, for each experiment, changes in basal heat from active heat production, providing more precise measures of the individual energetic processes underlying cardiac muscle contraction. ABSTRACT: Separating the variations in cardiac basal heat rate from variations in active heat rate is necessary to determine cardiac muscle energy consumption accurately during the performance of active work. By developing a model of cardiac muscle basal heat rate, we aimed to investigate changes in basal heat rate when cardiac muscle performs work. Experiments were conducted on 10 isolated rat cardiac trabeculae subjected to both active (work-loops) and quiescent (length-change and velocity) interventions. Muscle force, length and heat output rate were measured simultaneously in a flow-through work-loop calorimeter. Quiescent muscle characteristics were used to parameterize muscle-specific models of change in basal heat rate, thereby to predict dynamic changes in basal heat rate during active work-loop contraction. Our data showed that the quiescent heat characteristics of cardiac muscle varied between samples, displaying dependence on both the extent and the rate of change in muscle length. We found a moderate correlation between muscle dimensions (cross-sectional area and volume) and the length-dependent basal heat parameter (P = 0.0330 and P = 0.0242, respectively), but no correlation with the velocity-dependent parameter. These findings lead us to conclude that the heat output of cardiac muscle at quiescence varies with both the extent and the velocity of shortening, to an extent that is muscle specific, and that this variation must be measured and accounted for in each specimen when assessing active energetics.

Solving a century-old conundrum underlying cardiac force-length relations.

In the late 19th century, Otto Frank presented a diagram (Frank O. Z Biol 37: 483-526, 1899) showing that cardiac end-systolic pressure-volume relations are dependent on the mode of contraction: one for isovolumic contractions that locate above that for afterloaded ejecting contractions. Conflicting results to Frank's have been subsequently demonstrated in various species, both within and among preparations, ranging from the whole hearts to single myocytes, showing a single pressure-volume or force-length relation that is independent of the mode of contraction. Numerous explanations for these conflicting results have been proposed but are mutually contradictory and hence unsatisfying. The present study aimed to explore how these conflicting findings can be reconciled. We thus explored the cardiac force-length relation across a wide spectrum of both preloads and afterloads, encompassing the physiological working range. Experiments were performed using isolated ventricular trabeculae at physiological temperature and stimulus frequency. The force-length relation obtained from isometric contractions was indeed located above a family of those obtained from shortening contractions. Low preload conditions rendered the relation contraction mode independent. High afterload conditions also showed a comparable effect. Our exploration allowed us to reveal the loading conditions that can explain the apparent single, contraction mode-independent, force-length relation that is in contrast with that presented by Frank. Resolving this century-old cardiac conundrum highlights the caution that must be taken when using the end-systolic force-length relation to illustrate as well as to understand the concepts of the Frank-Starling law of the heart, "potential energy," and cardiac contractility. NEW & NOTEWORTHY Our exploration of the cardiac force-length relation under wide ranges of preload and afterload has allowed us to reconcile conflicting results in the literature regarding its length dependency. We show that the relation is dependent on the mode of contraction but can appear to be otherwise under certain conditions. This finding highlights the need for caution when using the force-length relation to understand key concepts in cardiac physiology.

Calcium mishandling impairs contraction in right ventricular hypertrophy prior to overt heart failure.

Currently, there are no tailored therapies available for the treatment of right ventricular (RV) hypertrophy, and the cellular mechanisms that underlie the disease are poorly understood. We investigated the cellular changes that occur early in the progression of the disease, when RV hypertrophy is evident, but prior to the onset of heart failure. Intracellular Ca2+ ([Ca2+]i) handling was examined in a rat model of monocrotaline (MCT)-induced pulmonary hypertension and subsequent RV hypertrophy. [Ca2+]i and stress production were measured in isolated RV trabeculae under baseline conditions (1-Hz stimulation, 1.5 mM [Ca2+]o, 37 °C), and in response to inotropic interventions (5-Hz stimulation or 1-µM isoproterenol). Under baseline conditions, MCT trabeculae had impaired Ca2+ release in response to stimulation with a 45% delay in the time-to-peak Ca2+, but there was no difference in the amplitude and decay of the Ca2+ transient, or active stress relative to RV trabeculae from normotensive hearts (CON). Increasing stimulation frequency from 1 to 5 Hz increased stress in CON, but not MCT trabeculae. Similarly, ß-adrenergic stimulation with isoproterenol increased Ca2+ transient amplitude and active stress in CON, but not in MCT trabeculae, despite accelerating Ca2+ transient decay in trabeculae from both groups. During isoproterenol treatment, MCT trabeculae showed increased diastolic Ca2+ leak, which may explain the blunted inotropic response to ß-adrenergic stimulation. Confocal imaging of trabeculae fixed following functional measurements showed that myocytes were on average wider, and transverse-tubule organisation was disrupted in MCT which provides a mechanism to explain the observed slower release of Ca2+.

The ineluctable constraints of thermodynamics in the aetiology of obesity.

We exploit the detail-independence feature of thermodynamics to examine issues related to the development of obesity. We adopt a 'global' approach consistent with focus on the first law of thermodynamics - namely that the metabolic energy provided by dietary foodstuffs has only three possible fates: the performance of work (be it microscopic or macroscopic), the generation of heat, or storage - primarily in the form of adipose tissue. Quantification of the energy expended, in the form of fat metabolised, during selected endurance events, reveals the inherent limitation of over-reliance on exercise as a primary agent of weight loss. This result prompts examination of various (non-exercise based) possibilities of increasing the rate of heat loss. Since these, too, give little cause for optimism, we are obliged to conclude that obesity can be prevented, or weight loss achieved, only if exercise is supplemented by reduction of food intake.

Myocardial energetics is not compromised during compensated hypertrophy in the Dahl salt-sensitive rat model of hypertension.

Salt-induced hypertension leads to development of left ventricular hypertrophy in the Dahl salt-sensitive (Dahl/SS) rat. Before progression to left ventricular failure, the heart initially undergoes a compensated hypertrophic response. We hypothesized that changes in myocardial energetics may be an early indicator of transition to failure. Dahl/SS rats and their salt-resistant consomic controls (SS-13(BN)) were placed on either a low- or high-salt diet to generate four cohorts: Dahl-SS rats on a low- (Dahl-LS) or high-salt diet (Dahl-HS), and SS-13(BN) rats on a low- (SSBN-LS) or high-salt diet (SSBN-HS). We isolated left ventricular trabeculae and characterized their mechanoenergetic performance. Our results show, at most, modest effects of salt-induced compensated hypertrophy on myocardial energetics. We found that the Dahl-HS cohort had a higher work-loop heat of activation (estimated from the intercept of the heat vs. relative afterload relationship generated from work-loop contractions) relative to the SSBN-HS cohort and a higher economy of contraction (inverse of the slope of the heat vs. active stress relation) relative to the Dahl-LS cohort. The maximum extent of shortening and maximum shortening velocity of the Dahl/SS groups were higher than those of the SS-13(BN) groups. Despite these differences, no significant effect of salt-induced hypertension was observed for either peak work output or peak mechanical efficiency during compensated hypertrophy.

Cardiac activation heat remains inversely dependent on temperature over the range 27-37°C.

The relation between heat output and stress production (force per cross-sectional area) of isolated cardiac tissue is a key metric that provides insight into muscle energetic performance. The heat intercept of the relation, termed "activation heat," reflects the metabolic cost of restoring transmembrane gradients of Na(+) and K(+) following electrical excitation, and myoplasmic Ca(2+) concentration following its release from the sarcoplasmic reticulum. At subphysiological temperatures, activation heat is inversely dependent on temperature. Thus one may presume that activation heat would decrease even further at body temperature. However, this assumption is prima facie inconsistent with a study, using intact hearts, which revealed no apparent change in the combination of activation and basal metabolism between 27 and 37°C. It is thus desired to directly determine the change in activation heat between 27 and 37°C. In this study, we use our recently constructed high-thermal resolution muscle calorimeter to determine the first heat-stress relation of isolated cardiac muscle at 37°C. We compare the relation at 37°C to that at 27°C to examine whether the inverse temperature dependence of activation heat, observed under hypothermic conditions, prevails at body temperature. Our results show that activation heat was reduced (from 3.5 ± 0.3 to 2.3 ± 0.3 kJ/m(3)) at the higher temperature. This leads us to conclude that activation metabolism continues to decline as temperature is increased from hypothermia to normothermia and allows us to comment on results obtained from the intact heart by previous investigators.

Impaired ADP channeling to mitochondria and elevated reactive oxygen species in hypertensive hearts.

Systemic hypertension initially promotes a compensatory cardiac hypertrophy, yet it progresses to heart failure (HF), and energetic deficits appear to be central to this failure. However, the transfer of energy between the mitochondria and the myofibrils is not often considered as part of the energetic equation. We compared hearts from old spontaneously hypertensive rats (SHRs) and normotensive Wistar controls. SHR hearts showed a 35% depression in mitochondrial function, yet produced at least double the amount of reactive oxygen species (ROS) in all respiration states in left ventricular (LV) homogenates. To test the connectivity between mitochondria and myofibrils, respiration was further tested in situ with LV permeabilized fibers by addition of multiple substrates and ATP, which requires hydrolysis to mediate oxidative phosphorylation. By trapping ADP using a pyruvate kinase enzyme system, we tested ADP channeling towards mitochondria, and this suppressed respiration and elevated ROS production more in the SHR fibers. The ADP-trapped state was also less relieved on creatine addition, likely reflecting the 30% depression in total CK activity in the SHR heart fibers. Confocal imaging identified a 34% longer distance between the centers of myofibril to mitochondria in the SHR hearts, which increases transverse metabolite diffusion distances (e.g., for ATP, ADP, and creatine phosphate). We propose that impaired connectivity between mitochondria and myofibrils may contribute to elevated ROS production. Impaired energy exchange could be the result of ultrastructural changes that occur with hypertrophy in this model of hypertension.

Dietary pre-exposure of rats to fish oil does not enhance myocardial efficiency of isolated working hearts or their left ventricular trabeculae.

Numerous epidemiological studies, supported by clinical and experimental findings, have suggested beneficial effects of dietary fish or fish oil supplementation on cardiovascular health. One such experimental study showed a profound (100%) increase in myocardial efficiency (i.e. the ratio of work output to metabolic energy input) of the isolated whole heart, achieved by a corresponding decrease in the rate of myocardial oxygen consumption. However, a number of other investigations have returned null results on the latter energetic index. Such conflicting findings have motivated us to undertake a re-examination. To that effect, we investigated the effects of dietary fatty acid supplementation on myocardial mechano-energetics, with our primary focus on cardiac efficiency. We used both isolated hearts and isolated left ventricular trabeculae of rats fed with one of three distinct diets: reference (REF), fish oil-supplemented (FO) or saturated fat-supplemented (SFA). For all three groups, and at both spatial levels, we supplied 10 mm glucose as the exogenous metabolic substrate. In the working heart experiments, we found no difference in the average mechanical efficiency among the three dietary groups: 14.8 ± 1.1% (REF), 13.9 ± 0.6% (FO) and 13.6 ± 0.7% (SFA). Likewise, we observed no difference in peak mechanical efficiency of left ventricular trabeculae among the REF, FO and SFA groups: 13.3 ± 1.4, 11.2 ± 2.2 and 12.5 ± 1.5%, respectively. We conclude that there is no effect of a period of pre-exposure to a diet supplemented with either fish oil or saturated fatty acids on the efficiency of the myocardium at either spatial level: tissue or whole heart.

Streptozotocin-induced diabetes prolongs twitch duration without affecting the energetics of isolated ventricular trabeculae.

BACKGROUND: Diabetes induces numerous electrical, ionic and biochemical defects in the heart. A general feature of diabetic myocardium is its low rate of activity, commonly characterised by prolonged twitch duration. This diabetes-induced mechanical change, however, seems to have no effect on contractile performance (i.e., force production) at the tissue level. Hence, we hypothesise that diabetes has no effect on either myocardial work output or heat production and, consequently, the dependence of myocardial efficiency on afterload of diabetic tissue is the same as that of healthy tissue. METHODS: We used isolated left ventricular trabeculae (streptozotocin-induced diabetes versus control) as our experimental tissue preparations. We measured a number of indices of mechanical (stress production, twitch duration, extent of shortening, shortening velocity, shortening power, stiffness, and work output) and energetic (heat production, change of enthalpy, and efficiency) performance. We calculated efficiency as the ratio of work output to change of enthalpy (the sum of work and heat). RESULTS: Consistent with literature results, we showed that peak twitch stress of diabetic tissue was normal despite suffering prolonged duration. We report, for the first time, the effect of diabetes on mechanoenergetic performance. We found that the indices of performance listed above were unaffected by diabetes. Hence, since neither work output nor change of enthalpy was affected, the efficiency-afterload relation of diabetic tissue was unaffected, as hypothesised. CONCLUSIONS: Diabetes prolongs twitch duration without having an effect on work output or heat production, and hence efficiency, of isolated ventricular trabeculae. Collectively, our results, arising from isolated trabeculae, reconcile the discrepancy between the mechanical performance of the whole heart and its tissues.

The afterload-dependent peak efficiency of the isolated working rat heart is unaffected by streptozotocin-induced diabetes.

BACKGROUND: Diabetes is known to alter the energy metabolism of the heart. Thus, it may be expected to affect the efficiency of contraction (i.e., the ratio of mechanical work output to metabolic energy input). The literature on the subject is conflicting. The majority of studies have reported a reduction of myocardial efficiency of the diabetic heart, yet a number of studies have returned a null effect. We propose that these discrepant findings can be reconciled by examining the dependence of myocardial efficiency on afterload. METHODS: We performed experiments on streptozotocin (STZ)-induced diabetic rats (7-8 weeks post-induction), subjecting their (isolated) hearts to a wide range of afterloads (40 mmHg to maximal, where aortic flow approached zero). We measured work output and oxygen consumption, and their suitably scaled ratio (i.e., myocardial efficiency). RESULTS: We found that myocardial efficiency is a complex function of afterload: its value peaks in the mid-range and decreases on either side. Diabetes reduced the maximal afterload to which the hearts could pump (105 mmHg versus 150 mmHg). Thus, at high afterloads (for example, 90 mmHg), the efficiency of the STZ heart was lower than that of the healthy heart (10.4% versus 14.5%) due to its decreased work output. Diabetes also reduced the afterload at which peak efficiency occurred (optimal afterload: 63 mmHg versus 83 mmHg). Despite these negative effects, the peak value of myocardial efficiency (14.7%) was unaffected by diabetes. CONCLUSIONS: Diabetes reduces the ability of the heart to pump at high afterloads and, consequently, reduces the afterload at which peak efficiency occurs. However, the peak efficiency of the isolated working rat heart remains unaffected by STZ-induced diabetes.

Interventricular comparison of the energetics of contraction of trabeculae carneae isolated from the rat heart.

We compare the energetics of right ventricular and left ventricular trabeculae carneae isolated from rat hearts. Using our work-loop calorimeter, we subjected trabeculae to stress-length work (W), designed to mimic the pressure-volume work of the heart. Simultaneous measurement of heat production (Q) allowed calculation of the accompanying change of enthalpy (H = W + Q). From the mechanical measurements (i.e. stress and change of length), we calculated work, shortening velocity and power. In combination with heat measurements, we calculated activation heat (Q(A)), crossbridge heat (Q(xb)) and two measures of cardiac efficiency: 'mechanical efficiency' ((mech) = W/H) and 'crossbridge efficiency' ((xb) = W/(H - Q(A))). With respect to their left ventricular counterparts, right venticular trabeculae have higher peak shortening velocity, and higher peak mechanical efficiency, but with no difference of stress development, twitch duration, work performance, shortening power or crossbridge efficiency. That is, the 35% greater maximum mechanical efficiency of right venticular than left ventricular trabeculae (13.6 vs. 10.2%) is offset by the greater metabolic cost of activation (Q(A)) in the latter. When corrected for this difference, crossbridge efficiency does not differ between the ventricles.

Resolving an inconsistency in the estimation of the energy for excitation of cardiac muscle contraction.

In the excitation of muscle contraction, calcium ions interact with transmembrane transporters. This process is accompanied by energy consumption and heat liberation. To quantify this activation energy or heat in the heart or cardiac muscle, two non-pharmacological approaches can be used. In one approach using the "pressure-volume area" concept, the same estimate of activation energy is obtained regardless of the mode of contraction (either isovolumic/isometric or ejecting/shortening). In the other approach, an accurate estimate of activation energy is obtained only when the muscle contracts isometrically. If the contraction involves muscle shortening, then an additional component of heat associated with shortening is liberated, over and above that of activation. The present study thus examines the reconcilability of the two approaches by performing experiments on isolated muscles measuring contractile force and heat output. A framework was devised from the experimental data to allow us to replicate several mechanoenergetics results gleaned from the literature. From these replications, we conclude that the choice of initial muscle length (or ventricular volume) underlies the divergence of the two approaches in the estimation of activation energy when the mode of contraction involves shortening (ejection). At low initial muscle lengths, the heat of shortening is relatively small, which can lead to the misconception that activation energy is contraction mode independent. In fact, because cardiac muscle liberates heat of shortening when allowed to shorten, estimation of activation heat must be performed only under isometric (isovolumic) contractions. We thus recommend caution when estimating activation energy using the "pressure-volume area" concept.

Cross-bridge thermodynamics in pulmonary arterial hypertensive right-ventricular failure.

Right-ventricular (RV) failure is an event consequent to pathological RV hypertrophy commonly resulting from pulmonary arterial hypertension. This pathology is well characterized by RV diastolic dysfunction, impaired ejection, and reduced mechanical efficiency. However, whether the dynamic stiffness and cross-bridge thermodynamics in the failing RV muscles are compromised remains uncertain. Pulmonary arterial hypertension was induced in the rat by injection of monocrotaline, and RV trabeculae were isolated from RV failing rats. Cross-bridge mechano-energetics were characterized by subjecting the trabeculae to two interventions: 1) force-length work-loop contractions over a range of afterloads while measuring heat output, followed by careful partitioning of heat components into activation heat and cross-bridge heat to separately assess mechanical efficiency and cross-bridge efficiency, and 2) sinusoidal-perturbation of muscle length while trabeculae were actively contracting to interrogate cross-bridge dynamic stiffness. We found that reduced mechanical efficiency is correlated with increased passive stress, reduced shortening, and elevated activation heat. In contrast, the thermodynamics, specifically the efficiency of, and the stiffness characteristics of, cross bridges did not differ between the control and failing trabeculae and were not correlated with elevated passive stress or reduced shortening. We thus conclude that, despite diastolic dysfunction and mechanical inefficiency, cross-bridge stiffness and thermodynamics are unaffected in RV failure following pulmonary arterial hypertension.NEW & NOTEWORTHY This study characterizes cross-bridge mechano-energetics and dynamic stiffness of right-ventricular trabeculae isolated from a rat model of pulmonary hypertensive right-ventricular failure. Failing trabeculae showed increased passive force but normal active force. Their lower mechanical efficiency is found to be driven by an increase in the energy expenditure arising from contractile activation. This does not reflect a change in their cross-bridge stiffness and efficiency.

Uncovering cross-bridge properties that underlie the cardiac active complex modulus using model linearisation techniques.

The properties underlying cardiac cross-bridge kinetics can be characterised by a muscle's active complex modulus. While the complex modulus can be described by a series of linear transfer functions, the biophysical mechanisms underlying these components are represented inconsistently among existing cross-bridge models. To address this, we examined the properties commonly implemented in cross-bridge models using model linearisation techniques and assessed their contributions to the complex modulus. From this analysis, we developed a biophysical model of cross-bridge kinetics that captures the three components of the active complex modulus: (1) the elastic modulus at low frequencies that arises from allowing the proportion of cross-bridges in the post-power stroke state to increase with sarcomere length, (2) the increase in elastic modulus at high frequencies that arises from the dependence of cross-bridge strain on sarcomere velocity, and (3) the negative viscous modulus which signifies the production of work by cross-bridges arises from either a sarcomere length or strain dependence, or both, on the rate of change of cross-bridge proportion in the post-power stroke state. While a model that includes all these features can theoretically reproduce the cardiac complex modulus, analysis of their transfer functions reveals that the relative contributions of these components are often not taken into account. As a result, the negative viscous component that signifies work production is not visible because the complex modulus is dominated by the effects of sarcomere velocity on cross-bridge strain.

Exacerbated potassium-induced paralysis of mouse soleus muscle at 37°C vis-à-vis 25°C: implications for fatigue. K+ -induced paralysis at 37°C.

The main aim was to investigate the effects of raised [K+](o) on contraction of isolated non-fatigued skeletal muscle at 37°C and 25°C to assess the physiological significance of K+ in fatigue. Mouse soleus muscles equilibrated at 25°C had good mechanical stability when temperature was elevated to 37°C. The main findings at 37°C vis-à-vis 25°C were as follows. When [K+](o) was raised from 4 to 7 mM, there was greater twitch potentiation, but no significant difference in peak tetanic force. At 10 mM [K+](o) there was (1) a faster time course for the decline of peak tetanic force, (2) a greater steady-state depression of twitches and tetani, (3) an increase of peak force over 50-200 Hz (whereas it decreased at 25°C), (4) significant tetanus restoration when stimulus pulse duration increased from 0.1 to 0.25 ms and (5) greater depolarisation of layer-2 fibres, with no repolarisation of surface fibres. These combined data strengthen the proposal that a large run-down of the K+ gradient contributes to severe fatigue at physiological temperatures via depolarisation and impaired sarcolemmal excitability. Moreover, terbutaline, a ß(2)-adrenergic agonist, induced a slightly greater and more rapid, but transient, restoration of peak tetanic force at 10 mM [K+](o) at 37°C vis-à-vis 25°C. A right shift of the twitch force-stimulation strength relationship at 10 mM [K+](o) was partially reversed with terbutaline to confer the protective effect. Thus, catecholamines are likely to stimulate the Na+ -K+ pump more powerfully at 37°C to restore excitability and attenuate, but not prevent, the detrimental effects of K+.

Radius-dependent decline of performance in isolated cardiac muscle does not reflect inadequacy of diffusive oxygen supply.

The study of cardiac energetics commonly involves the use of isolated muscle preparations (papillary muscles or trabeculae carneae). Their contractile performance has been observed to vary inversely with thickness. This inverse dependence has been attributed, almost without exception, to inadequate diffusion of oxygen into the centers of muscles of large diameter. It is thus commonly hypothesized that the radius-dependent diminution of performance reflects the development of an anoxic core. We tested this hypothesis theoretically by solving a modification of the diffusion equation, in which the rate of oxygen consumption is a sigmoidal function of the partial pressure of oxygen. The model demonstrates that sufficiently thick muscles, operating at sufficiently high rates of oxygen demand or sufficiently low ambient partial pressures of oxygen, will indeed show diminished energetic performance, whether indirectly indexed as stress (force per cross-sectional area) development or as the rate of heat production. However, such simulated behavior requires the adoption of extreme parameter values, often differing by an order of magnitude from their experimental equivalents. We thus conclude that the radius-dependent diminution of muscle performance in vitro cannot be attributed entirely to an insufficient supply of oxygen via diffusion.

Thermodynamic inconsistency disproves the Suga-Sagawa theory of cardiac energetics.

The theory proposed by Suga and Sagawa, encompassing the concepts of 'time-varying elastance', 'pressure-volume area' and 'isoefficiency', has been widely applied in cardiac research - albeit not without contention. In this Review, we commence with a brief history of striated muscle energetics as a prelude to re-visiting the Suga-Sagawa Theory. We conclude our discussion by including recent insights into the fundamental flaw underlying the metabolic component of the Theory.