Elsevier

International Journal of Cardiology

Volume 371, 15 January 2023, Pages 345-353
International Journal of Cardiology

Left ventricular contractance: A new measure of contractile function

https://doi.org/10.1016/j.ijcard.2022.09.001Get rights and content

Highlights

  • An accurate measure of contractile function is essential in understanding most cardiac disorders.

  • Current methods for assessing contractile function are not transferable across in vitro, ex vivo and in vivo studies.

  • Contractance defined by the myocardial active strain energy density (MASED), combines information from two crucial aspects of contractile function, namely stress and strain, and quantifies the mechanical work done (energy produced) by the muscle indexed to myocardial volume (kJ/m3).

  • This new method can be applied to experiments involving muscle tissue from single cell, trabecular, papillary muscle, Langendorff preparations and whole ventricle including global and regional myocardium, Importantly, contractance quantifies contractile function in all types of heart disease.

Abstract

Aims

Myocardial contractility is poorly defined and difficult to compare between studies. Contractance or myocardial active strain energy density (MASED) measures the mechanical work done per unit volume (with units of kJ/m3) by any cardiac tissue during contraction. Contractance is an ideal candidate for measuring contractile function as it combines information from both stress and strain.

Methods and results

Data obtained from three previously published experimental studies using trabecular tissue was used to provide contemporaneous nominal stress and strain data in 18 different scenarios with different loading conditions. Contractance varied in the differing loading conditions with values of 1.16 (low preload), 2.02 (high afterload) and 3.76 kJ/m3 (normal). Contractance varied between 0 with isometric loading and 2.14 kJ/m3 with an isotonic and moderate afterload. Increasing inotropy increased contractance to 4.7 kJ/m3.

Conclusion

We showed that calculating MASED was feasible and provided a measure of energy production (work done) per unit volume of myocardium during contraction. The new term for contractile function, contractance, can be defined and quantified by MASED. Contractance measures contractile function in differing preload, afterload and inotropic settings. The method of measuring contractance is transferable to the assessment of global and regional systolic function.

Introduction

The term “myocardial contractility” is used frequently in experimental studies and clinical practice. Despite this widespread use, contractility remains poorly characterised more than 125 years after first being introduced. [1] There are misunderstandings and misconceptions amongst experimentalists and clinicians because of the lack of a consistently accepted definition of contractility. Most descriptions of the term contractility suggest that it measures a characteristic that is independent of loading conditions. [1] This seems odd as loading conditions have a major impact on contractile properties. [2] Some authorities have even suggested the term contractility should no longer be employed. [1,3]

Myocardial contractility has been measured using the change in developed force at a given resting cardiomyocyte length or can be assessed with a static length (isometric), fixed tension (isotonic), unchanging velocity (isovelocity), variable (auxotonic) or ‘physiological’ where the loading is adjusted to mimic reality. [2,4,5] Contractility has been evaluated by a variety of other methods ex vivo, for example by either measuring peak isometric force, fractional shortening, time to peak shortening or maximal shortening velocity at ‘given’ initial length. [1,2,6] How the ‘given’ resting length is decided varies between studies and tissues.

Contractility, as measured by the force of contraction of cardiac muscle tissue ex vivo, is dependent on the duration of the active state (the period of contraction and relaxation) and its velocity of contraction. There is also a non-linear relationship between maximal isometric force and contraction frequency (Bowditch effect or Treppe phenomenon) as there is a frequency at which maximal isometric tension reaches a peak after which the forces decline. [2] In addition, higher afterloads may increase the force of contraction (Anrep effect). [2,7] Importantly, any force developed is dependent on the quantity of myocardial tissue present making comparison between tissues (c.f. isolated single cell, muscle strip, trabeculae, and papillary muscle) and species impractical.

Measurement of contractility in vivo is even more problematic and indirect. Often the left ventricular ejection fraction is used as a surrogate for ventricular contractility partly because it changes with preload and other physiological perturbations in a similar way to ex vivo studies. [2] However, it has been increasingly realised that the ejection fraction is also altered by geometric factors such as wall thickness [8,9] and internal dimensions. [10,11] An increase in wall thickness alone increases ejection fraction whereas an increase in internal diameter decreases ejection fraction. Furthermore, ejection fraction increases with greater myocardial shortening. [12] Surprisingly, midwall fractional shortening has a greater impact on ejection fraction than longitudinal shortening. [12] The effects of changes in geometry and strain on ejection fraction can be expressed mathematically either using analytic or numerical methods from modelling data [13] or statistically using regression equations in clinical data. [14] Stokke and colleagues [15] validated both the clinical and modelling findings. [[11], [12], [13],16,17] The geometric effects of changes in wall thickness and internal dimensions on ejection fraction can be accounted for and adjusted by using the corrected ejection fraction. [14]

The peak systolic pressure-time derivative (dP/dt) during the isovolumic phase of the cardiac cycle (isometric contraction) or the velocity of blood flow in the aorta are often used as proxies for contractile function. [2] More recently, myocardial strain or strain rate have been employed as alternatives to measuring contractility although it is widely acknowledged that both are load dependent and may, therefore, be misleading. [18] For example, in severe aortic stenosis where pressure generation can be very high, strain and strain rate may be reduced but myocardial performance could be normal.

Methods have been developed that incorporate pressure generation into the assessment of contractile function by calculating the stroke work [19] or using pressure-strain loops (with units of mmHg%). [20] The end-systolic elastance (Ees), calculated in either mmHg/ml or Pa/m3, has similarly been promoted as a useful measure of myocardial contractility. [21] Ees is increased by either a higher end-systolic pressure or a lower end-systolic volume. Inotropic stimulation increases end-systolic pressure and decreases end-systolic volume leading to the view that measuring Ees assesses contractile function. However, factors such as systemic vascular resistance and ventricular remodelling can modify Ees independent of a change in contractile function as they alter pressure generation and ventricular volumes. [22,23] Methods using ventricular luminal pressure and/or volume information alone, such as ejection fraction, Ees or pressure-volume loops, certainly miss important myocardial physiological processes and are unable to account for geometric changes such as concentric ventricular remodelling.

Contractile properties not only change with the health of the muscle but also its milieu. For example, an increase in cardiomyocyte length above its normal ‘resting value’ increases the force of contraction (Frank–Starling mechanism). [2] Similarly changes in extracellular calcium concentration alters contraction by increasing the availability of calcium around the sarcolemma required for excitation-contraction coupling. [2,24] Neurohumoral changes such as adrenergic or vagal stimulation, hormones (angiotensin II) and heart rate all adjust cardiomyocyte contraction. [2] Phosphorylation of phospholamban [2] and environmental temperature in fish likewise modify myocardial function. [25]

In contrast to contractility, inotropy is often described as a change in the force of contraction arising from external factors such as drugs. One expert group defined contractility as “the tension developed and velocity of shortening (i.e., the "strength" of contraction) of myocardial fibers at a given preload and afterload. It represents a unique and intrinsic ability of cardiac muscle (contracting at a fixed heart rate) to generate a force that is independent of any load or stretch applied”. [26] Such definitions are unhelpful as they do not provide a clear testable and quantifiable (measurable) description. For example, how does ‘tension’ or ‘strength’ relate to velocity? The term strength is undefined in this review. [26] The word ‘tension’ has been used in the literature to variously mean a force (e.g. N), weight (g), force per unit length (N/m) or force per cross sectional area (N/m2). [2,6] Does a high velocity with low tension mean a greater contractility than high tension with low velocity? Furthermore, how should one compare ‘contractility’ with differing, heart rates and preload an afterload conditions?

Contractility has been assessed in several diverse ways and are often only comparable within the given experimental study. [27] It would be advantageous to have a method for assessing contractile function which has more widespread applicability and could be used across all types of studies.

Force of contraction is dependent on cross sectional area of the myocardial tissue under investigation. For example, the force generated by a thin trabecula is less than a thick papillary muscle. In contrast, myocardial active stress, i.e. the contractile force per unit area, allows comparison between tissues of differing thickness and so permits scalability. [4]

Contractile properties may also be measured using myocardial strain or relative shortening (percent shortening per original length). Given the same loading conditions, it is expected that a lower peak strain may indicate reduced contractile function. [18] However, myocardial strain is heavily dependent on loading conditions.

Mechanical work performed by the myocardial tissue can be calculated from the force of contraction and displacement distance or similar derivations such as the pressure-volume loop areas (stroke work - Appendix) in vivo (Fig. 1). [19] The three main weaknesses of stroke work are that a) it is most accurately measured invasively, b) is not applicable to regional differences, and c) fails to consider the quantity of myocardium generating the mechanical work. For example, a thick walled and a normal thickness left ventricle could produce the same stroke work, but the work done per unit volume (or mass) of myocardium is less in the former. Stroke work can be indexed to myocardial mass or volume but doing so would introduce potential further errors and is rarely performed in clinical practice. This maybe because left ventricular mass and volume are difficult to accurately measure or deemed too time consuming.

Combining information from both stress and strain would compensate for the effect of stress on strain as well as the impact of strain on stress. Strain energy density is calculated from the stress-strain relationship. Strain energy density has a long standing and well-established role in both physics and engineering sciences (see Appendix). Strain energy is defined as the potential energy stored in any material due to deformation arising from an external stress. In most circumstances, the stored potential energy, in the form of internal electrostatic forces between the molecules, can be converted back into the kinetic energy of movement.

Myocardial active strain energy density (MASED) can be defined as the work done per unit volume (energy density) of myocardium during contraction resulting in both deformation and stress generation. The myocardial stress generation produces the luminal ventricular systolic pressure. The energy arises from the internal electrostatic forces within the actin-myosin filaments – an active ATP requiring process (chemical energy).

MASED has the advantage of providing a quantifiable measure of the energy density produced irrespective of the structure and size (e.g. thickness, diameter) of the myocardial tissue and, vitally, without the need to know the myocardial muscle volume (see Appendix).

Here, we introduce a new term contractance calculated from the MASED. It is an overarching term that includes features overlapping with contractility but also includes any inotropic, rate related and loading effects on the myocardial function and, crucially, is quantifiable and transferable across in vitro, ex vivo and in vivo studies. Contractance potentially provides an improved method of measuring contractile function compared with other approaches.

We hypothesised that the measurement of contractance is feasible and that the results could be quantified in different loading conditions. We, therefore, compared contractance in different loading conditions and with changing inotropic effects using cardiac trabeculae.

Section snippets

Study design

We sought previously peer reviewed and published manuscripts investigating myocardial ventricular trabeculae that included both stress and shortening data under different physiological conditions. The papers published in 1997 by Guccione, [4] Han, [28] and Lee [29] fulfilled our criteria and consequently avoided the need for additional experimentation on animal tissue as per animal welfare ethics.

The first study used unbranching ventricular trabeculae obtained from twelve rats. The loading

Pressure-volume loops – Stroke work

Data was obtained for twelve pressure-volume loops consisting of two sites with six different loading conditions (Fig. 1) from Study 1. Normal loading conditions gave the highest stroke work of 0.38 J (Table 1). A high afterload resulted in stroke work of 0.34 J. Intermediate results were obtained with the combination of high afterload and moderately reduced preload (0.22 J and 0.24 J respectively). The lowest stroke work occurred in very high afterload and severely reduced preloads (0.19 J and

Discussion

To our knowledge this is the first study to assess the myocardial active strain energy density in ex vivo cardiac tissues. MASED is based on the principles of strain energy density that has a strong background in physics and engineering science. The main advantages of MASED are that it corrects for the effects of afterload (contractile stress) on strain and the effects of strain on contractile stress. MASED also produces an important physiological measurement, namely the work performed per unit

Limitations

We did not repeat the high-quality studies performed by Guccione, [4,30] Han [28] and Lee. [29] We believe it would not have been ethically appropriate to experiment and undertake euthenasia on additional animals. Given the limited resources available for research and necessity for efficient use of funding, we think that the novel analyses of previously published data should be encouraged. No statistical analyses were performed as the published data used individual scenarios. Guccione and

Conclusion

An improved measure of contractile function will aid understanding conditions such as heart failure. We showed that myocardial active strain energy density varied under differing loading and inotropic conditions. The term contractility, despite being widely used, has vague definitions often resulting in misunderstandings. We introduce a new term contractance that is quantified using MASED.

Contractance assesses myocardial work done (energy produced) per unit volume of myocardium and may be used

Contributions

DHM: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Validation; Visualization; Writing - original draft; Writing - review & editing. TS: Validation; Writing - review & editing; Formal analysis. HZ: Supervision; Funding acquisition; Writing - review & editing.

Data availability request

The corresponding author will share the data underlying this article on reasonable request.

Clinical and translational impact statement

An accurate measure of contractile function is essential to the understanding of most cardiac disorders. Current methods for assessing contractile function are not transferable across in vitro, ex vivo and in vivo studies. Contractance defined by the myocardial active strain energy density (MASED), combines information from two crucial aspects of contractile function, namely stress and strain, and quantifies the mechanical work done (energy produced) by the muscle indexed to myocardial volume

Funding

No specific funding was obtained for this project.

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The work was supported by Engineering and Physical Sciences Research Council Doctoral Training Partnership.

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