Pigs and dogs are commonly used as experimental models in cardiovascular research because of their anatomical and physiological resemblance to humans 1. Moreover, they can serve as spontaneous animal models for the development of naturally occurring cardiovascular disease.
Mitral regurgitation (MR) is defined as a leakage of blood backwards to the left atrium. This occurs with an overall prevalence of 1.7% in the general population and is thus the most common valvular disease in humans 2. After the age of 75 years, the prevalence increases considerably and approaches 10% 2. In most cases, MR is caused by intrinsic valvular disease and is thus known as primary, or organic, MR 3. Almost 40% of primary MR incidents are caused by myxomatous mitral valve disease (MMVD), a disease also known as primary mitral valve prolapse and characterized by myxomatous degeneration, prolapse, and eventually incomplete coaptation of the mitral valve leaflets 4,5.
Pigs, dogs, and horses also develop myxomatous changes of the mitral valve and can thus serve as spontaneous animal models of MMVD in humans 6–8. Cats rarely develop MMVD, whereas dogs are very commonly affected and experience a prevalence that is ∼10 times higher than that seen in humans 9. Moreover, many common features have been identified in humans and dogs, including a strong genetic background, slow disease progression, increased prevalence with age, a higher risk of symptomatic disease in males, and similar pathological changes and signaling pathways involved 9–13. Hence, the dog is considered a good spontaneous model of MMVD in humans 9,14,15.
Both in humans and in dogs, the regurgitation of blood is tolerated reasonably well; however, if left untreated, significant MR may eventually lead to left ventricular (LV) systolic dysfunction and heart failure 16–19. Intriguingly, irreversible myocardial damage, not evident before surgery, has been observed following mitral valve repair in human patients 20,21. Therefore, accurate assessment of LV function and, in particular, detection of incipient deterioration are crucial to determine the optimal time for corrective replacement and repair. Nonetheless, identification of the exact time at which the LV function begins to deteriorate remains challenging and the exact pathogenesis behind the irreversible myocardial damage is still not clear 22,23. The relatively short life-span of the dog, combined with the fact that medical treatment rather than surgical intervention is the treatment of choice, renders this species as an excellent candidate for studies of the natural history and progression of LV dysfunction in MMVD and its response to medical treatment 24. However, a prerequisite for such studies is that the progression of LV dysfunction is similar in humans and dogs, a subject that has not been evaluated in translational studies. Therefore, this review summarizes studies of LV function in humans and dogs with naturally occurring MMVD. Owing to the fact that echocardiography is the method of choice for the clinical evaluation of LV function in patients with MMVD 25, this review has focused on studies in which assessment of LV function has been performed using conventional and advanced echocardiography.
Left ventricular function and its quantification
In addition to the intrinsic contractile properties of the myocardium, the function of the left ventricle is affected by the hemodynamic load placed on it. Moreover, several compensatory mechanisms such as myocardial remodeling, geometric alterations, and neurohormonal activation all come into play when the LV function becomes inadequate. Besides supporting the failing ventricle in meeting the needs of the body, the compensatory mechanisms also tend to mask a decreasing intrinsic myocardial function.
Both invasive and noninvasive techniques exist for the evaluation of LV function. Invasively obtained estimates, such as LV pressure–volume relationships, are more accurate but because of factors such as safety and ease of use, noninvasive techniques are still preferred. Several noninvasive techniques, including nuclear testing, MRI, and PET, provide estimates of LV function, but echocardiography is still the most commonly used technique. Traditionally, systolic LV function is estimated by conventional echocardiographic indices such as LV end-systolic dimensions, for example, end-systolic internal diameter and end-systolic volume index, and the ejection phase indices, fractional shortening and ejection fraction (EF), representing the percent change in LV internal diameter and volume, respectively, from end-diastole to end-systole. These variables are, however, affected by changes in hemodynamic load, described by preload (the stretch that the sarcomeres are subjected to before contraction and thus related to the end-diastolic pressure or volume) and afterload (the load against which the sarcomeres contract and thus related to the end-systolic pressure or volume).
In MR, the favorable hemodynamic loading conditions characterized by an increased preload, because of the compensatory mechanisms, and a decreased afterload, because of the low-impedance retrograde ejection of blood into the left atrium, act in concert to preserve the ejection phase indices 26,27. Even though LV end-systolic volume indices are less dependent on preload, and thus better estimates of LV function in MR 28, intrinsic myocardial dysfunction may still be masked 28,29. This is the motivation behind the continuous search for newer conventional echocardiographic variables for determination of LV function. One proposed variable is the rate of increase of LV pressure, dp/dt, calculated from the continuous Doppler MR signal 30,31.
Newer advanced echocardiographic techniques have emerged recently and are reported to be less load dependent and thus more sensitive for the detection of altered LV function 32–34. Instead of quantifying LV dimensions and volumes, these modalities quantify LV motion, defined as a change in position and described by displacement and velocity, and LV deformation, which is the change in shape and described by strain and strain rate 35. Because of the fact that the different parts of the incompressible myocardium move at different velocities, the ventricle changes shape, that is, it deforms during the cardiac cycle. In systole, a deformational pattern consisting of an overall shortening along the longitudinal axis, an increase in wall thickness, and a decrease in cavity size is observed. Moreover, this deformation is accompanied by a ‘twisting’ motion, which is because of the fact that a majority of the myofibers are obliquely oriented, resulting in counter-directional rotations of the base and the apex (Fig. 1). Using advanced echocardiographic techniques, it is possible to quantify all three components of the LV deformation as well as the twisting motion, known as twist or torsion (reviewed by Mondillo et al. 36 and Sengupta et al. 37). When validated against measurements obtained by invasive techniques, systolic myocardial velocities, systolic myocardial deformation rates in the radial, the circumferential and the longitudinal directions, and systolic twist all correlate well with LV systolic function 33,36,38,39.
Left ventricular function in humans and dogs with naturally occurring mitral regurgitation
As stated, incipient LV dysfunction is masked because of the favorable loading conditions and the compensatory mechanisms in both humans and dogs with MR. Accordingly, conventional echocardiographic variables such as fractional shortening and EF are preserved until advanced symptomatic disease in humans and dogs 21,28,40. End-systolic dimensions and volumes are not consistently increased in asymptomatic humans or dogs, and even at heart failure stages, not all dogs have increased end-systolic LV dimensions when compared with reference values 17,21,40. Accordingly, neither end-systolic dimensions nor ejection phase indices can distinguish normal from depressed contractile LV reserve in humans 29. The Doppler-derived rate of increase of LV pressure is independent of afterload and predicts postoperative EF following mitral valve replacement in patients with symptomatic primary MR 31,41. This index has been largely disregarded in dogs with naturally occurring MR, but a preliminary study reported preserved Doppler-derived dp/dt even at advanced heart failure stages 42.
Advanced echocardiographic techniques have also been used in humans and dogs with primary MR. An overview of the results is presented in Table 1. Using such advanced techniques, a reduced longitudinal systolic myocardial velocity has already been reported before the onset of symptomatic disease in human patients with primary MR 29,43. Accordingly, the longitudinal myocardial velocity was lower in patients with reduced contractile reserve compared with patients with preserved contractile reserve 29,39,56. The same findings apply for longitudinal and radial deformations, as all except one study on the subject reported reduced deformational magnitudes and rates in human patients with severe asymptomatic primary MR 38,43,46–48. With respect to circumferential deformation, the results are more ambiguous: one study reported a lower rate of deformation in patients with severe primary MR when compared with control participants, whereas another study reported an increased magnitude of deformation in patients with moderate asymptomatic MR, but a preservation in patients with severe MR when compared with control participants 38,47.
As opposed to the findings in humans, neither decreased longitudinal myocardial velocities nor decreased radial, circumferential, nor longitudinal deformations have been reported at asymptomatic stages of severe MR caused by MMVD in dogs 44,45,49–52. In contrast, several studies have reported increased myocardial velocities and deformations at this stage of canine disease 45,49,51. At overt heart failure stages, preserved, and even increased, myocardial velocities and deformations have been reported in dogs 44,45,49,55, albeit decreased longitudinal deformation in dogs with advanced heart failure has been reported in one preliminary study 57.
Results on systolic twist have been discordant in both human and canine studies. In human MMVD, one study reported a preserved magnitude of systolic twist in asymptomatic patients with moderate to severe MR when compared with healthy control participants 53. Another study subdivided asymptomatic to minimally symptomatic patients according to the severity of MR and could show a biphasic change characterized by hyperdynamic systolic twist in patients with moderate MR, followed by a hypodynamic twist in patients with severe MR 54. The presence of a hyperdynamic twist at moderate stages of MMVD progression in humans is further supported by a third study 47.
A similar discrepancy has been found among studies that evaluate systolic twist in dogs with MMVD. Suzuki and colleagues reported a decreased twist already at asymptomatic stages of moderate–severe MMVD, whereas this finding was not reproduced in another study 52,55. At symptomatic stages, the first study on the subject reported preserved magnitude of systolic twist in dogs with heart failure because of MMVD 52. Upon subdivision of dogs in heart failure, Suzuki and colleagues later reported a biphasic change, namely, a hyperdynamic twist in mild-to-moderate heart failure, followed by an apparent hypodynamic twist in advanced heart failure 55.
The dog as a model of left ventricular dysfunction in myxomatous mitral valve disease in humans
Spontaneous animal models are considered highly valuable for the study of equivalent diseases in humans as disease progression is often more precisely mimicked than in experimentally induced models. Moreover, useful spontaneous animal models may reduce the need to induce experimental animal disease. Because of many common pathological, clinical, and epidemiological features, the dog is considered a useful spontaneous model for MMVD in humans 9. Ideally, each aspect of the human disease should be reproduced by naturally occurring canine MMVD.
Comparison of the respective studies carried out within the field of LV function in naturally occurring MMVD in humans and dogs is challenged by the fact that study designs and classification of study participants into the respective study groups differ. This may result in disease severities among the various studies being less comparable, thus resulting in a lack of agreement among studies. This circumstance is further aggravated by the dynamic change observed in deformation and twist variables. In humans, circumferential deformation and twist behaves in a biphasic manner, characterized by hyperdynamic function, followed by hypodynamic function in severe, yet asymptomatic stages of MR 47,54. In the dog, twist shows a dynamic change and, at symptomatic stages, a biphasic behavior was found upon subdivision according to the severity of heart failure 55. Although increased deformation was reported at both asymptomatic and symptomatic stages of canine disease, curvilinear and not linear relationships were observed with radial and longitudinal deformation when disease severity was assessed as a continuous variable 49. This indicates the presence of a dynamic change of these variables in dogs as well. The significance of such dynamic changes encountered during MMVD progression is two-fold. First, the presence of hyperdynamic deformation and twist at disease stages, when the ventricle begins to experience a significantly altered hemodynamic load, indicates that the variables in question do, in fact, depend on preload and afterload. Second, detection of a dynamic change in deformation and twist variables may be obscured according to the classification criteria used.
Despite MMVD being the cause of primary MR in the majority of the included human patients, patients with primary MR of other etiologies such as rheumatic disease were also included in many studies 29,38,43,46,48. All of these factors limit an exact comparison of the results between the two species and may also be the cause of the divergent results encountered within species. With these limitations in mind, comparison of the results obtained in humans and dogs with primary MR, nonetheless, indicates certain differences between the two species. The body of evidence indicates that LV dysfunction is evident already at asymptomatic stages of primary MR in human patients. This is reflected by decreased longitudinal myocardial velocity and reduced longitudinal and radial deformations in patients with severe asymptomatic MR 29,38,43,46,48. In contrast, the longitudinal and radial myocardial velocities are preserved and the longitudinal and radial deformations (and deformation rates) are preserved, or even increased, in dogs with asymptomatic MMVD 49–51. In terms of the magnitude and rate of circumferential deformation, preservation or an increase was reported in canine asymptomatic severe MMVD, whereas corresponding human studies reported preservation or a decrease 38,48,50–52.
The results on the twisting motion of the ventricle have also been divergent and thus not so easily decipherable in both humans and dogs. Apparently, a dynamic change in systolic twist is found depending on the subgrouping of study participants in both species. In human patients, a biphasic change characterized by a hyperdynamic twist, followed by a hypodynamic twist was reported at asymptomatic-to-minimally symptomatic stages 54. In dogs, a corresponding biphasic change is observed, albeit at symptomatic stages 55. Further complicating the picture is the decreased systolic twist in asymptomatic dogs with a wide range of MMVD severities (ranging from no indications of volume overload to echocardiographic signs of compensatory cardiac enlargement) when compared with control dogs 55; these results were, however, not reproduced in another study, which reported a preserved systolic twist in dogs with moderate–severe asymptomatic MR because of MMVD 52.
The divergent results among studies of circumferential deformation and twist may be attributed to the fact that these parameters have been reported to be better preserved than long-axis function and, moreover, have been suggested to exert compensatory hyperdynamic functions in settings with depressed long-axis function 38,58. Differences in disease severity, and thus the degree of compensation, could therefore have had an impact on the reported results, and may also help to explain why some studies report preserved circumferential deformation and twist, whereas others, after subdivision of patient groups, show a biphasic change 52–55.
Focusing on longitudinal velocity and deformation, it appears as if the systolic long-axis function decreases before the onset of symptomatic disease in human patients but is preserved until – and maybe even after – the onset of overt heart failure in dogs with MMVD. All dogs with MMVD included in the respective studies are small-sized to medium-sized dogs, and, interestingly, a previous study has suggested that small-breed dogs tolerate a larger regurgitant volume than humans, considering that the majority of dogs with severe MR had a regurgitant volume above 75%, whereas the corresponding number in human studies was 50% 59. It is thus possible that not only do small-breed dogs tolerate larger regurgitant volumes but that they also preserve their myocardial function better than humans during the course of MMVD. Such a difference can be caused by the more common occurrence of atherosclerosis in humans and also the presence of anatomical differences such as the presence of a significant collateral circulation in the myocardium of the dog 60–62. These factors may be of importance with respect to perfusion, and thus function, of the myocardial tissue throughout the progression of MMVD.
The differences observed may also be caused by differences in body size and thus cardiac size. Intriguingly, a more severe LV dysfunction has been reported in large-breed dogs when compared with small-breed dogs presenting with similar severities of MMVD 63,64. Despite differences in cardiac size and geometrics, comparable cardiac wall stress has been reported across species 65. However, allometric studies have indicated that large mammals rely more on the long-axis contribution to systolic function than small mammals 66,67. In theory, human patients and large-breed dogs may develop systolic dysfunction because of a depressed long-axis deformation, whereas the overall systolic function in small-breed dogs relies more on the short-axis deformation, which was not depressed at any stage in the studies referred to here. The presence of a differential progression toward myocardial failure, and maybe also a differential compensation for this, dependent on body size can only remain speculation. If such differences do occur, they would be of great importance for the accurate translation of results obtained in both spontaneous and experimental animal models. Studies designed for exact comparisons are therefore needed to elucidate this subject.
The results from the present comparison of studies carried out in humans and dogs are not conclusive, but they do, nonetheless, indicate the existence of certain differences in the systolic LV function in the progression of MMVD. Apparently, small-sized to medium-sized dogs maintain their systolic function better than humans with comparable severity of disease. This may pose a limitation on the suitability of small-sized and medium-sized dogs as spontaneous models of LV dysfunction in human MMVD. Comparative studies specifically designed to study the influence of body size and myocardial perfusion are warranted.
L.H. Olsen and N.E. Zois have been supported by the Danish Council of Independent Research, Medical Sciences (project no. 271-08-0998).
Conflicts of interest
There are no conflicts of interest.
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