1. Introduction
Out of the many cardiovascular diseases plaguing millions of people throughout the world, disorders in the heart’s valves make up a significant proportion. These disorders frequently lead to death or morbidity, particularly in the ageing population [
1]. Disorders in the left ventricle valves are more numerous than those in the right ventricle, with disease in the aortic valve making up the largest proportion of valvular deaths [
2]. The three main disorders affecting the heart valves are prolapse, stenosis and regurgitation. Further, these pathologies can increase susceptibility to arrhythmia in the atrium and whole heart. It is known, for example that mitral valve prolapse may excite the electrical dynamics of the heart leading to cardiac arrhythmia [
3]. This is thought to be caused by the increased stretching of the valve leaflets during systole, which in turn excites the electrical messaging in the ventricle via a mechanism called the mechano-electric feedback (MEF) [
4]. Additional to the resulting arrhythmia, sudden cardiac death may also occur [
3]. Valve prolapse may also cause regurgitation, which increases myocardial load and hence, stretching of the cardiac muscles [
5]. Studies of valve patients that have recovered from arrhythmia as a complication frequently find fibrosis in the left-ventricular wall; evidence of excessive stretch [
6]. Mitral valve stenosis is often associated with arrhythmia and is due to the excessive stretching of the left atrium [
7].
Despite the heart’s apparent complexity, it remains a well-regulated organ and this is aided by many feedback mechanisms at work over multiple scales and domains; from the micro cellular scale of the myocytes to the macro organ level scale. The MEF is one of the main feedback mechanisms. Along with the electro-excitation coupling (ECC), these two mechanisms help maintain cardiac stability and synchronicity. As their names suggest, the MEF is the feedback of local mechanical cell stretch on the electrical dynamics, while the ECC operates in the opposite direction. For comprehensive reviews of the MEF see [
8,
9]. Whilst the MEF helps maintain synchronicity, it can have some peculiar consequences, particularly in the generation and termination of arrhythmia. Commitio-cordis, which is the mortal induction of fibrillation by an innocent impact to the chest is perhaps the most peculiar. Link et al. [
10,
11] conducted an illustrative set of clinical experiments studying how ventricular mechanical stretch can excite the cardiac electrical activity and induce arrhythmia. This is found to be highly dependent on the ECG timing, with only those cases in which stretching occurred during a certain window of the ECG initiating arrhythmia. A review of the recent clinical studies into mechanically induced electrophysiological behaviour is provided in [
5]. Stretch-activated-channels (SACs) are the leading mechanism thought to be responsible for the MEF [
9,
12], though other mechanisms may also be involved. SACs are cells which open or close cellular ion channels in response to mechanical stretch and for the left ventricle, their response depends on the timing during the cardiac cycle [
10,
13,
14]. Stimulating these channels can thereby change the character of the action potential: the electrical wave that causes cell contraction and relaxation. The action potential changes depend on the period in the cardiac cycle at which stretch is induced.
Computer and mathematical modelling is a powerful way to investigate complex systems as it allows for system visualisation, hypotheses and predictions to be examined at relatively low cost compared to experimental methods [
15]. Computer models of the cardiovascular system vary in complexity, from simple zero dimensional (0D) and one dimensional (1D) models to full three dimensional (3D) models, some involving motion of structure. Numerical investigations of the heart valves likewise vary in complexity. 0D and 1D models involving the heart valves frequently use a ‘diode’ approach in which the dynamics of the valve are ignored and the direction of flow imposed similar to an electrical diode [
16,
17], while fully 3D examples most frequently use stiff geometry and studies using dynamic values [
18] are rare. The 3D structural models provide flow field information and include interaction between the tissue structure and flow [
18,
19,
20]. Complex numerical models involving cellular mechanics, electrophysiology, ion movements, and 3D models requiring detailed mathematical solution do not lend themselves to the demanding clinical environment due to their high cost in terms of computational load and time [
21]. Numerical models of MEF likewise vary in complexity, with plenty of examples of relatively simple low-order 0D and 1D studies [
12,
22,
23,
24] and full cardiovascular system and 3D models [
25,
26,
27].
In this study a 0D mathematical model of the left ventricle with valve stenoses and regurgitation is developed, by modifying the synergistic cardiovascular model by Kim and Capoccia [
28]. The model consistently simulates the coupling of the mechanical, chemical and electrical functions of the myofiber on the micro-scale as well as the macro-scale organ activity. The consideration of different domains and scales gives it a synergistic quality, which is similar to Roy et al. [
16] who control organ dynamics through the electrophysiology. Their haemodynamic activity is controlled using the time-varying-elastance (TVE) method however, in which the ventricular pressure–volume relationship is imposed using a periodic function [
29,
30] instead of calculating it consistently. The TVE paradigm has frequently been questioned [
17,
31] when used for cardiovascular modelling due to its empirical foundations and neglect of haemodynamic-regulating feedback mechanisms. Use of the adopted model [
28] bypasses the need to use the TVE method due to its synergistic approach. The model has been validated as an alternative to the TVE method [
28] and previously used for the study of dilated cardiomyopathy, left ventricular assist devices (LVADs) and MEF [
32,
33]. In [
32], the model proved capable at reproducing known MEF effects consistent with previous findings by others, for example a prolonged action potential duration consistent with [
34], and ectopic peaks in electrical patterns along with rapid oscillation consistent with the effect of SACs seen in [
9,
27,
35]. The rest of the paper is organised as follows: the cardiovascular system model is described in
Section 2; in
Section 3, the results of using the model to simulate valve and MEF pathologies are described; in
Section 4, these results are discussed; and in
Section 5 a conclusion to this study is provided.
4. Discussion
Our aim was to develop a new model by extending a synergistic reduced-order mathematical model of the cardiovascular system [
28] to include the effects of pathologies in the valves of the left-ventricle; the mitral valve and the aortic valve. A further aim was to see what effect if any, valve pathologies have on (disorders of) the mechano-electric physiology of the heart. In order to meet the latter aim, the popular time-varying elastance method of generating the pressure–volume relationship could not by applied. The TVE method uses a periodic function to generate the pressure–volume relationship rather than calculating it consistently, hence it cannot be used to simulate the feedback mechanisms which maintain cardiac stability, most notably the MEF. It has frequently been questioned both due to its empirical foundations and validity for cardiac modelling [
17,
31]. The synergistic model [
28] develops the organ scale dynamics of pressure and volume from the micro-scale activity of the myocytes. Since it encompasses the mechanical, electrical and chemical domains it can be used to simulate the MEF. The model is modified to include stenoses and regurgitation in the heart’s mitral and aortic valves, modelling different severities of different valve disorders.
Mitral valve stenosis without a dysfunction of the MEF is found to cause a reduction in ventricular and systemic pressures and reduction in the cardiac output and stroke volume. The atrial pressure increases slightly. The EDV and ESV both reduce, shifting the P-V loop to the right. The extent of this reduction and shift is of similar order to [
16] for a comparable range of severity. The results with mitral regurgitation show that the P-V loop widens, enlarging the ventricle, increasing the stroke volume, cardiac output, and myocardial load in agreement with medical reports [
40]. The degree of the changes in the ventricle agrees well with [
16,
41]. The atrial pressure rises whilst the systemic blood pressure falls. For aortic valve stenosis, the ventricular pressure rises but this rise is very minor, even with 90% flow restriction. The stroke volume and cardiac output reduce but again, this reduction is very minor. Aortic valve regurgitation has a greater effect and agrees with with published literature [
43]. Like the mitral valve, the stroke volume and cardiac output rise. This is due to an increase in the end-diastolic volume and slight decrease in end-systolic volume. The systemic blood pressure falls significantly during diastole, but the atrial pressure rises.
Dysfunction of the MEF is modelled by increasing the coupling between the mechanical part of the model and the electrical. Two parameters are used for this coupling;
and
. The former mimics the effect of mechanical ventricular stretch during systole and the latter mimics the effect stretch during diastole. By increasing these parameters, dysfunctions of the MEF can be simulated and the effects on the cardiovascular system investigated. See [
32,
33] for their effects without valve disorders. A dysfunction of the MEF is investigated here with the addition of severe disorders in the mitral and aortic valves. Disorders in the mitral and aortic valves do not qualitatively change the overall effects of the MEF parameters. The parameter
mimicking systolic stretch causes a reduction in the electrical activity, leading to missed heartbeats and a reduction in the pumping power of the heart, and is unaffected by disorders in the aortic and mitral valves. The parameter
mimicking systolic stretch causes an increase in the electrical activity leading to ectopic beats and complex pressure–volume behaviour. This too is unaffected by disorders in the valves of the left ventricle.
Valve disorders do however have quantitative effects. Specifically, they change the sensitivity of the heart to arrhythmia-stimulating stretch. Sensitivity to systolic stretch is compared between cases by looking at the value of at which period doubling occurs. The lower the value of when periodic behaviour appears, the greater the sensitivity to systolic stretch. Mitral valve stenosis slightly increases the sensitivity to systolic stretch while regurgitation reduces it to a greater extent. Neither stenosis nor regurgitation affect the number and frequency of ectopic beats and the heart rate remains the same as the control case. Aortic valve stenosis does not change the sensitivity to systolic stretch, and regurgitation decreases it, as the value of is larger than the control case. Similar to the mitral valve, pathologies in the aortic valve do not change the frequency of missed beats.
Sensitivity to diastolic stretch is compared between cases by finding the approximate value of
at which the results begin to bifurcate. Again, a lower value of
is indicative of increased sensitivity. Cases are also compared for similar values of
, such that the same level of diastolic stretch is applied. Mitral stenosis slightly reduces sensitivity to arrhythmia stimulating diastolic stretch while aortic stenosis has no effect. Stenosis in either valve does not change the heart rate rise resulting from the MEF. Mitral and aortic valve regurgitation do not affect the sensitivity to diastolic stretch. Furthermore, we find that valve regurgitation increases the heart rate and frequency of ectopic beats resulting from diastolic stretch. This applies whenever
and valve regurgitation is introduced. The mechanism behind this result is found to be the increase in myocardial load and diastolic stroke resulting from regurgitation. The diastolic stretch is therefore longer and larger. Arrhythmia (ectopic beats, irregular heart rate) resulting from MEF dysfunction will therefore be more severe. This result agrees very well with clinical results showing that the severity of regurgitation is an indicator for the complications experienced during arrhythmia [
47,
48,
49].
Limitations of the model: The model inherits the same limitations as the model by Kim and Capoccia [
28], namely that the 0-dimensional lumped-parameter nature does not allow for wave dynamics in the electrical and cellular behaviour to be modelled. This could limit the investigation of the MEF in which wave dynamics can have a significant effect. Another weakness is the simple electro-chemical model. This model cannot be used to identify the specific ion channels involved in the pattern of cellular excitation.