In vivo left ventricular functional capacity is compromised in cMyBP-C null mice

Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated protein that binds tightly to myosin and has a potential role for modulating myocardial contraction. We tested the hypothesis that cMyBP-C 1) contributes to the enhanced in vivo contractile state following beta-adrenergic stimulation and 2) is necessary for myocardial adaptation to chronic increases in afterload. In vivo pressure-volume relations demonstrated that left ventricular (LV) systolic and diastolic function were compromised under basal conditions in cMyBP-C(-/-) compared with WT mice. Moreover, whereas beta-adrenergic treatment significantly improved ejection fraction, peak elastance, and the time to peak elastance in WT mice, these functional indexes remained unchanged in cMyBP-C(-/-) mice. Morphological and functional changes were measured through echocardiography in anesthetized mice following 5 wk of aortic banding. Adaptation to pressure overload was diminished in cMyBP-C(-/-) mice as characterized by a lack of an increase in posterior wall thickness, increased LV diameter, deterioration of fractional shortening, and prolonged isovolumic relaxation time. These results suggest that the absence of cMyBP-C significantly diminishes in vivo LV function and markedly attenuates the increase in LV contractility following beta-adrenergic stimulation or adaptation to pressure overload.     

Source parameters of the left ventricle related to the physiological characteristics of the cardiac muscle.

An attempt is made here to correlate the physiological muscle parameters with the dynamic source parameters of the left ventricle (LV), i.e. the source (isovolumic) pressure Po and the source (internal) resistance, Rs. The internal resistance is described here as a time-dependent parameter, corresponding to the pressure drop (from the theoretical instantaneous isovolumic pressure) associated with the instantaneous ejection flow rate. The source pressure, which relates to the muscle stress and the ventricular volume, is represented by the time-varying elastance concept and a spheroidal model relating the average wall stress to LV pressure. Linear and exponential force-velocity relationships (FVR), expressed in stress-strain rate terms, are compared. Two possible characteristics of the dynamic FVR in the partially active state, based on either a parallel or a fanlike shift of the stress-strain rate curve, are studied by utilizing simple analytical models as well as a computer simulation model. Comparing the calculated results with experimental data indicates that the dynamic FVR shift occurs in a fanlike pattern in which the maximum strain rate remains constant throughout the cycle. This pattern of the FVR shift is consistent with experimental data that show that the internal resistance is linearly related to the instantaneous isovolumic pressure. The analysis also indicates that the difference between the hyperbolic and linear FVR is rather minor, and in spite of some effects on the ejection pattern and the value of Rs, the functional shape has no effect on the global LV characteristics, such as the ejection fraction and stroke volume.     

Continuum rheology of muscle contraction and its application to cardiac contractility.

A set of constitutive equations is proposed to describe the mechanics of contraction of skeletal and heart muscle. Fiber tension is assumed to depend on the degree of chemical activation, the stretch ratio, and the rate of stretching of the fibers. The time rate of change of activation is governed by a differential equation. The proposed constitutive equations are used to model the time courses of isotonic and isometric twitches during contraction and relaxation phases of the muscle response to stimulation. Various contractility indices of the left ventricle are considered next by using the proposed constitutive equations. The present analysis introduces a new interpretation of the index of contractility (dP/dt)/P used in cardiac literature. It is shown that this index may not be related at all to the maximum speed of shortening and that it may be dependent on both preload and afterload. The development of pressure during isovolumetric contraction of the left ventricle is shown to be governed by a differential equation describing the time rate of change of tension during isometric contraction of myocardium fibers.     

Effects of modulation of left ventricular contractile state and loading conditions on tissue Doppler myocardial performance index

The Tei index is clinically useful to quantify left ventricular (LV) function, but it requires sequential Doppler recordings from two different views. A related myocardial performance index (MPI) using tissue Doppler (TD) can be rapidly calculated from a single beat; however, its ability to quantify contractility and the effects of acute changes in loading have not been determined. Our aim was to test the hypothesis that TD MPI can quantify contractile state but is affected by acute alterations in loading, using LV pressure-volume relations in an animal model. Eight dogs were studied by using mitral annular TD, high-fidelity pressure, and conductance catheters. TD MPI was calculated as (a' - b')/b', where a' was the duration of mitral annular velocity during diastole and b' was the duration of the systolic wave. End-systolic elastance (Ees), the time constant of isovolumic relaxation (tau), and peak positive and negative first derivative of pressure (dP/dtmax and dP/dtmin, respectively) were used as measures of LV function. Data were obtained at baseline, at dobutamine and esmolol infusion to alter contractile state, and at inferior vena cava and aortic occlusion to alter preload and afterload. TD MPI decreased from 0.83 (SD 0.19) to 0.62 (SD 0.20) with dobutamine and increased to 1.19 (SD 0.26) with esmolol. TD MPI significantly correlated with dP/dtmax (r = -0.76), Ees (r = -0.68), dP/dtmin (r = 0.82), and tau (r = 0.78); however, it was affected by acute decreases in preload [from 0.83 (SD 0.19) to 1.09 (SD 0.36)] and acute increases in afterload [to 1.23 (SD 0.17)]. All the above increases and decreases and r values were significant (P < 0.05 vs. baseline). In conclusion, TD MPI can rapidly quantify alterations in LV contractile state but is affected by acute alterations in preload and afterload.     

Frequency-dependent left ventricular performance in women and men

We aimed to determine whether sex differences in humans extend to the dynamic response of the left ventricular (LV) chamber to changes in heart rate (HR). Several observations suggest sex influences LV structure and function in health; moreover, this physiology is also affected in a sex-specific manner by aging. Eight postmenopausal women and eight similarly aged men underwent a cardiac catheterization-based study for force-interval relationships of the LV. HR was controlled by right atrial (RA) pacing, and LV +dP/dt(max) and volume were assessed by micromanometer-tipped catheter and Doppler echocardiography, respectively. Analysis of approximated LV pressure-volume relationships was performed using a time-varying model of elastance. External stroke work was also calculated. The relationship between HR and LV +dP/dt(max) was expressed as LV +dP/dt(max) = b + mHR. The slope (m) of the relationship was steeper in women compared with men (11.8 ± 4.0 vs. 6.1 ± 4.1 mmHg·s(-1)·beats(-1)·min(-1), P = 0.01). The greater increase in contractility in women was reproducibly observed after normalizing LV +dP/dt(max) to LV end-diastolic volume (LVVed) or by measuring end-systolic elastance. LVVed and stroke volume decreased more in women. Thus, despite greater increases in contractility, HR was associated with a lesser rise in cardiac output and a steeper fall in external stroke work in women. Compared with men, women exhibit greater inotropic responses to incremental RA pacing, which occurs at the same time as a steeper decline in external stroke work. In older adults, we observed sexual dimorphism in determinants of LV mechanical performance.     

Physiological basis for mechanical time-variance in the heart: special consideration of non-linear function

A relationship between ventricular pressure and volume is developed starting from basic cardiac muscle mechanics. The known and measurable properties of myocardium, such as the Hill law, the periodic excitation-contraction mechanism, and non-linear elasticity of the surrounding elastin and collagen structure, are formulated into a myofibril unit. A cylindrical geometry is chosen to represent the structure of the ventricle, using the myofibril unit as the basic building block. Pressure-volume isochrones computed from this model illustrate non-linear function in the heart which arises from both geometric effects and muscle effects. The above theory and model is linearized to provide a special study case. The behavior that resulted is that of a time-varying elastance, E(t), and, hence, can help in the interpretation of its meaning. It is found that the minimum in E(t) is the consequence of the stiffness of the myocardial fibrous network, adjusted by a geometric factor. In addition, the magnitude of E(t) is governed by myocardial contractility, a geometric factor, and the excitation-contraction mechanism, where time-dependency is imparted by periodic excitation. Since the elastic fibers are the only true elastic elements, the quantity of elastance is determined by controlled volume feedback. A circuit model is provided to illustrate this concept. The non-linear active and passive heart function curves are specified independently. These curves are required to intersect below the resting volume and result in a negative pressure at the intersection. This is found to explain the phenomenon of ventricular suction. In addition, they lead to a time-varying dead volume by virtue of time-dependent isochronal slope. Non-linear function is introduced to the model and is found to explain the variation in curvature of the ventricular isochrones.     

Single-beat estimation of right ventricular end-systolic pressure-volume relationship

Assessment of right ventricular (RV) contractility from end-systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR and contractility can be determined without measuring RV volume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (P(max)) was predicted from isovolumic portions of RV pressure during ejecting beats and compared with P(max) measured during the first beat after pulmonary artery clamping. In RV pressure-volume loops obtained from RV pressure and integrated pulmonary arterial flow, end-systolic elastance (E(es)) was assessed as the slope of P(max)-derived ESPVR, pulmonary artery effective elastance (E(a)) as the slope of end-diastolic to end-systolic relation, and coupling efficiency as the E(es)-to-E(a) ratio (E(es)/E(a)). Predicted P(max) correlated with observed P(max) (r = 0.98 +/- 0.02). Dobutamine increased E(es) from 1.07 to 2.00 mmHg/ml and E(es)/E(a) from 1.64 to 2.49, and propranolol decreased E(es)/E(a) from 1.64 to 0.91 (all P < 0.05). After adrenergic blockade, preload reduction did not affect E(es), whereas hypoxia and arterial constriction markedly increased E(a) and somewhat increased E(es) due to the Anrep effect. Low preload did not affect E(es)/E(a) and high afterload decreased E(es)/E(a). In conclusion, in the right ventricle 1) P(max) can be calculated from normal beats, 2) P(max) can be used to determine ESPVR without change in load, and 3) P(max)-derived ESPVR can be used to assess ventricular contractility and ventricular-arterial coupling efficiency.     

Impact of Acute Changes of Left Ventricular Contractility on the Transvalvular Impedance: Validation Study by Pressure-Volume Loop Analysis in Healthy Pigs

Background

The real-time and continuous assessment of left ventricular (LV) myocardial contractility through an implanted device is a clinically relevant goal. Transvalvular impedance (TVI) is an impedentiometric signal detected in the right cardiac chambers that changes during stroke volume fluctuations in patients. However, the relationship between TVI signals and LV contractility has not been proven. We investigated whether TVI signals predict changes of LV inotropic state during clinically relevant loading and inotropic conditions in swine normal heart.

Methods

The assessment of RVTVI signals was performed in anesthetized adult healthy anesthetized pigs (n = 6) instrumented for measurement of aortic and LV pressure, dP/dt_max and LV volumes. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea) and stroke work (SW) were determined from the LV pressure-volume loops. Pigs were studied at rest (baseline), after transient mechanical preload reduction and afterload increase, after 10-min of low dose dobutamine infusion (LDDS, 10 ug/kg/min, i.v), and esmolol administration (ESMO, bolus of 500 µg and continuous infusion of 100 µg·kg−1·min−1).

Results

We detected a significant relationship between ESTVI and dP/dtmax during LDDS and ESMO administration. In addition, the fluctuations of ESTVI were significantly related to changes of the Ees during afterload increase, LDDS and ESMO infusion.

Conclusions

ESTVI signal detected in right cardiac chamber is significantly affected by acute changes in cardiac mechanical activity and is able to predict acute changes of LV inotropic state in normal heart.     

Right ventricular adaptation to pulmonary hypertension: an interspecies comparison

Right ventricular (RV) adaptation is an important prognostic factor in acute and chronic pulmonary hypertension. Pulmonary vascular basal tone and hypoxic reactivity are known to vary widely between species. We investigated how RV adaptation to acute pulmonary hypertension is preserved in species with low, intermediate, and high pulmonary vascular resistance and reactivity. Acute pulmonary hypertension was induced by hypoxia, distal embolism, and proximal constriction in anesthetized dogs (n = 10), goats (n = 8), and pigs (n = 8). Pulmonary vessels were assessed by flow-pressure curves and by impedance to quantify distal resistance, proximal elastance, and wave reflections. RV function was assessed by pressure-volume curves to quantify afterload, contractility, and ventricular-arterial coupling efficiency. First, hypoxia was associated with a progressive increase of resistance, elastance, and wave reflection from dogs to goats and from goats to pigs. RV contractility increased proportionally to RV afterload, and optimal coupling was preserved in all species. Second, embolism increased resistance and wave reflection but not elastance. The increase in RV contractility matched the increase in RV afterload and optimal coupling was preserved. Finally, proximal pulmonary artery constriction increased resistance, increased and accelerated wave reflection, and markedly increased elastance. RV contractility increased markedly and coupling showed a nonsignificant trend to decrease. We conclude that optimal or near-optimal ventricular-arterial coupling is maintained in acute pulmonary hypertension, whether in absence or presence of chronic species-induced pulmonary hypertension.     

Validation of a novel noninvasive cardiac index of left ventricular contractility in patients

Although there are several excellent indexes of myocardial contractility, they require accurate measurement of pressure via left ventricular (LV) catheterization. Here we validate a novel noninvasive contractility index that is dependent only on lumen and wall volume of the LV chamber in patients with normal and compromised LV ejection fraction (LVEF). By analysis of the myocardial chamber as a thick-walled sphere, LV contractility index can be expressed as maximum rate of change of pressure-normalized stress (d sigma*/dt(max), where sigma* = sigma/P and sigma and P are circumferential stress and pressure, respectively). To validate this parameter, d sigma*/dt(max) was determined from contrast cine-ventriculography-assessed LV cavity and myocardial volumes and compared with LVEF, dP/dt(max), maximum active elastance (E(a,max)), and single-beat end-systolic elastance [E(es(SB))] in 30 patients undergoing clinically indicated LV catheterization. Patients with different tertiles of LVEF exhibit statistically significant differences in d sigma*/dt(max). There was a significant correlation between d sigma*/dt(max) and dP/dt(max) (d sigma*/dt(max) = 0.0075 dP/dt(max) - 4.70, r=0.88, P<0.01), E(a,max) (d sigma*/dt(max) = 1.20E(a,max) + 1.40, r=0.89, P<0.01), and E(es(SB)) [d sigma*/dt(max)=1.60 E(es(SB)) + 1.20, r=0.88, P<0.01]. In 30 additional individuals, we determined sensitivity of the parameter to changes in preload (intravenous saline infusion, n = 10 subjects), afterload (sublingual glyceryl trinitrate, n = 10 subjects), and increased contractility (intravenous dobutamine, n=10 patients). We confirmed that the index is not dependent on load but is sensitive to changes in contractility. In conclusion, d sigma*/dt(max) is equivalent to dP/dt(max), E(a,max), and E(es(SB)) as an index of myocardial contractility and appears to be load independent. In contrast to other measures of contractility, d sigma*/dt(max) can be assessed with noninvasive cardiac imaging and, thereby, should have more routine clinical applicability.     

Systolic elastance and resistance in the regulation of cardiac pumping function in early streptozotocin-diabetic rats

We determined the roles of maximal systolic elastance (E(max)) and theoretical maximum flow ((max)) in the regulation of cardiac pumping function in early streptozotocin (STZ)-diabetic rats. Physically, E(max) can reflect the intrinsic contractility of the myocardium as an intact heart, and (max) has an inverse relation to the systolic resistance of the left ventricle. Rats given STZ 65 mg/kg i.v. (n = 17) were divided into two groups, 1 week and 4 weeks after induction of diabetes, and compared with untreated age-matched controls (n = 15). Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate E(max) and (max), using the elastance-resistance model. After 1 or 4 weeks, STZ-diabetic animals show an increase in effective LV end-diastolic volume (V(eed)), no significant change in peak isovolumic pressure (P(iso)(max)), and a decline in effective arterial volume elastance (E(a)). The maximal systolic elastance E(max) is reduced from 751.5 +/- 23.1 mmHg/ml in controls to 514.1 +/- 22.4 mmHg/ml in 1- and 538.4 +/- 33.8 mmHg/ml in 4-week diabetic rats. Since E(max) equals P(iso)(max)/V(eed), an increase in V(eed) with unaltered P(iso)(max) may primarily act to diminish E(max) so that the intrinsic contractility of the diabetic heart is impaired. By contrast, STZ-diabetic rats have higher theoretical maximum flow (max) (40.9 +/- 2.8 ml/s in 1- and 44.5 +/- 3.8 ml/s in 4-week diabetic rats) than do controls (30.7 +/- 1.7 ml/s). There exists an inverse relation between (max) and E(a) when a linear regression of (max) on E(a) is performed over all animals studied (r = 0.65, p < 0.01). The enhanced (max) is indicative of the decline in systolic resistance of the diabetic rat heart. The opposing effects of enhanced (max) and reduced E(max) may negate each other, and then the cardiac pumping function of the early STZ-diabetic rat heart could be preserved before cardiac failure occurs.     

A new integrated method for analyzing heart mechanics using a cell-hemodynamics-autonomic nerve control coupled model of the cardiovascular system

A model of the cardiovascular system coupling cell, hemodynamics, and autonomic nerve control function is proposed for analyzing heart mechanics. We developed a comprehensive cardiovascular model with multi-physics and multi-scale characteristics that simulates the physiological events from membrane excitation of a cardiac cell to contraction of the human heart and systemic blood circulation and ultimately to autonomic nerve control. A lumped parameter model is used to compute the systemic and pulmonary circulations interacting with the cardiac cell mechanism. For autonomic control of the cardiovascular system, we used the approach suggested by Heldt et al. [2002. Computational modeling of cardiovascular response to orthostatic stress. J. Appl. Physiol. 92, 1239–1254] (Heldt model), including baroreflex and cardiopulmonary reflexes. We assumed sympathetic and parasympathetic pathways for the nerve control system. The cardiac muscle response to these reflex control systems was implemented using the activation-level changes in the L-type calcium channel and sarcoplasmic/endoplasmic reticulum calcium ATPase function based on experimental observations. Using this model, we delineated the cellular mechanism of heart contractility mediated by nerve control function. To verify the integrated method, we simulated a 10% hemorrhage, which involves cardiac cell mechanics, circulatory hemodynamics, and nerve control function. The computed and experimental results were compared. Using this methodology, the state of cardiac contractility, influenced by diverse properties such as the afterload and nerve control systems, is easily assessed in an integrated manner.     

Load dependence of ventricular performance explained by model of calcium-myofilament interactions

Although a simple concept of load-independent behavior of the intact heart evolved from early studies of isolated, intact blood-perfused hearts, more recent studies showed that, as in isolated muscle, the mode of contraction (isovolumic vs. ejection) impacts on end-systolic elastance. The purpose of the present study was to test whether a four-state model of myofilament interactions with length-dependent rate constants could explain the complex contractile behavior of the intact, ejecting heart. Studies were performed in isolated, blood-perfused canine hearts with intracellular calcium transients measured by macroinjected aequorin. Measured calcium transients were used as the driving function for the model, and length-dependent rate constants yielding the highest concordance between measured and model-predicted midwall stress at different isovolumic volumes were determined. These length-dependent rate constants successfully predicted contractile behavior on ejecting contractions. This, along with additional model analysis, suggests that length-dependent changes in calcium binding affinity may not be an important factor contributing to load-dependent contractile performance in the intact heart under physiological conditions.     

Acute effects of methoxamine on left ventricular-arterial coupling in streptozotocin-diabetic rats: a pressure-volume analysis

We determined the acute effects of methoxamine, a specific alpha1-selective adrenoceptor agonist, on the left ventricular-arterial coupling in streptozotocin (STZ)-diabetic rats, using the end-systolic pressure-stroke volume relationships. Rats given STZ 65 mg x kg(-1) iv (n = 8) were compared with untreated age-matched controls (n = 8). A high-fidelity pressure sensor and an electromagnetic flow probe measured left ventricular (LV) pressure and ascending aortic flow, respectively. Both LV end-systolic elastance E(LV,ES) and effective arterial elastance Ea were estimated from the pressure-ejected volume loop. The optimal afterload Q(load) determined by the ratio of Ea to E(LV,ES) was used to measure the optimality of energy transmission from the left ventricle to the arterial system. In comparison with controls, diabetic rats had decreased LV end-systolic elastance E(LV,ES), at 513 +/- 30 vs. 613 +/- 29 mmHg x mL(-1), decreased effective arterial elastance Ea, at 296 +/- 20 vs. 572 +/- 48 mmHg x mL(-1), and decreased optimal afterload Q(load), at 0.938 +/- 0.007 vs. 0.985 +/- 0.009. Methoxamine administration to STZ-diabetic rats significantly increased LV end-systolic elastance E(LV,ES), from 513 +/- 30 to 602 +/- 38 mmHg x mL(-1), and effective arterial elastance Ea, from 296 +/- 20 to 371 +/- 28 mmHg x mL(-1), but did not change optimal afterload Q(load). We conclude that diabetes worsens not only the contractile function of the left ventricle, but also the matching condition for the left ventricular-arterial coupling. In STZ-diabetic rats, administration of methoxamine improves the contractile status of the ventricle and arteries, but not the optimality of energy transmission from the left ventricle to the arterial system.     

Torsion of the human left ventricle: experimental analysis and computational modeling

We set a twofold investigation: we assess left ventricular (LV) rotation and twist in the human heart through 3D-echocardiographic speckle tracking, and use representative experimental data as benchmark with respect to numerical results obtained by solving our mechanical model of the LV. We aim at new insight into the relationships between myocardial contraction patterns and the overall behavior at the scale of the whole organ. It is concluded that torsional rotation is sensitive to transmural gradients of contractility which is assumed linearly related to action potential duration (APD). Pressure-volume loops and other basic strain measures are not affected by these gradients. Therefore, realistic torsional behavior of human LV may indeed correspond to the electrophysiological and functional differences between endocardial and epicardial cells recently observed in non-failing hearts. Future investigations need now to integrate the mechanical model proposed here with minimal models of human ventricular APD to drive excitation-contraction coupling transmurally.     

Targeted gene transfer increases contractility and decreases oxygen cost of contractility in normal rat hearts

The aim of this study was to examine how global cardiac gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) can influence left ventricular (LV) mechanical and energetic function, especially in terms of O(2) cost of LV contractility, in normal rats. Normal rats were randomized to receive an adenovirus carrying the SERCA2a (SERCA) or beta-galactosidase (beta-Gal) gene or saline by a catheter-based technique. LV mechanical and energetic function was measured in cross-circulated heart preparations 2-3 days after the infection. The end-systolic pressure-volume relation was shifted upward, end-systolic pressure at 0.1 ml of intraballoon water volume was higher, and equivalent maximal elastance, i.e., enhanced LV contractility, was higher in the SERCA group than in the normal, beta-Gal, and saline groups. Moreover, the LV relaxation rate was faster in the SERCA group. There was no significant difference in myocardial O(2) consumption per beat-systolic pressure-volume area relation among the groups. Finally, O(2) cost of LV contractility was decreased to subnormal levels in the SERCA group but remained unchanged in the beta-Gal and saline groups. This lowered O(2) cost of LV contractility in SERCA hearts indicates energy saving in Ca(2+) handling during excitation-contraction coupling. Thus overexpression of SERCA2a transformed the normal energy utilization to a more efficient state in Ca(2+) handling and superinduced the supranormal contraction/relaxation due to enhanced Ca(2+) handling.     

Energetics of ventricular contraction as traced in the pressure-volume diagram

The pressure-volume (P-V) relationship of the canine left ventricle can reasonably be simulated by a time-varying elastance model. In this model the total mechanical energy generated by a contraction can be determined theoretically from the change in the elastance. Applying this theory to the actual left ventricle, we have found that the area in the P-V diagram circumscribed by the end-systolic P-V relation line, the end-diastolic P-V relation curve, and the systolic segment of the P-V trajectory is equivalent to the total mechanical energy generated by ventricular contraction. We call this area the systolic P-V area (PVA). We have studied experimentally the correlation between the PVA and myocardial oxygen consumption (VO2) in the canine left ventricle. VO2 was linearly correlated with PVA regardless of the contraction mode and loading conditions in a given left ventricle. The VO2-PVA relation parallel shifted upward with positive inotropic agents. This shift comprised a significant increase in VO2 component for the unloaded contraction. We therefore consider that further analyses of the VO2-PVA relationship will greatly promote our understanding of cardiac energetics.