The principal findings of this study were: (1) Twelve weeks of moderate to severe “pure” MR in this ovine model caused LV remodeling; (2) Early alterations in transmural myocardial deformation, particularly longitudinal diastolic filling strains in the lateral LV subendocardium, occurred; and (3) No demonstrable changes in BNP, PRSW, or tau were detected.
The present closed-chest model allowed us to study the effect of moderate to severe pure MR on LV morphology and function. We observed that the LV mass index was greater in EXP versus CTRL at 12 weeks, and that EDV index increased in EXP over time without change in CTRL, implying that the LV myocardium underwent global remodeling. This experimental model enabled analysis and comparison of 3-D transmural LV strain with BNP and global indices of LV contractility (PRSW) and relaxation (tau) during development of LV remodeling, induced by MR of known duration. In addition, the MR was not created by disruption of the mitral subvalvular apparatus, which can directly affect LV function.19
As discussed below, our 12-week data in general represent an early phase of the disease in a potential transition from compensated to decompensated LV function, a strength of the model in relation to the purpose of the study.
Previous studies have proposed that strain imaging can detect early LV systolic dysfunction in a variety of disease states before abnormalities can be observed using traditional measures of LV function.20
This is consistent with our data. In the setting of asymptomatic severe MR, Lee et al21
demonstrated that tissue Doppler strain (total deformation) and strain rate (instantaneous deformation) was a feasible technique for detecting subclinical LV dysfunction. Moreover, Marciniak et al22
proposed that, if corrected for LV geometry, tissue Doppler based strain rate could be a sensitive tool to detect subclinical LV dysfunction in asymptomatic patients with severe MR. In a porcine chronic MR model, Neilan et al23
recently showed that tissue Doppler-derived strain and strain rate indices, which initially increased post-MR, decreased to baseline before any detected changes in global LVEF.
Derangements in myocardial strain are linked to myocyte apoptosis24 and also affect collagen turnover by activating matrix metalloproteinases.8
Thus, alterations in strain may be detected before the onset of global LV dysfunction, as perturbations in strain may trigger progressive LV remodeling. 7
Furthermore, recent findings suggest that alterations in strain adjacent to infarcted myocardium (the normally per-fused “border zone”) trigger further LV remodeling.9
After approximately 1 minute of ischemia, presumably before extracellular matrix remodeling occurred, Rodriguez et al9
observed increased shear strain adjacent to ischemic myocardium. Whether a similar time sequence between alterations in myocardial strain and LV remodeling exists in chronic isolated MR (low pressure LV volume overload) remains to be proven.
In agreement with our observations, the study of Lee et al,21
and also several other studies,25
emphasize the importance of LV longitudinal motion in the evaluation of LV function in chronic volume overload. One simple reason for this could be that tissue Doppler imaging in particular allows measurements of longitudinal LV function, and that this technique has been widely used in recent studies. But there are most likely other more complex reasons as well. A considerable proportion of longitudinally directed myocardial fibers can be found in the LV subendocardium.26,27
It is also known that chronic volume-overload induces increased LV end-diastolic wall stress, which in turn causes compensatory remodeling (eccentric hypertrophy).28
Furthermore, the sub-endocardium is probably more sensitive to abnormal physiology (eg, increased wall stress) than layers with better perfusion.26,27
Our ovine findings most likely represent a very early phase of the remodeling process, and the increase in (negative) longitudinal strain observed in the subendocardium in EXP at 12 weeks may be an earlier marker of LV dysfunction than reduced LV longitudinal motion observed in long-standing chronic MR.21
The transmural beadset method used in this study allows accurate transmural measurements of myocardial 3-D strain, and the present findings suggest possible targets for further noninvasive evaluation. An increased longitudinal diastolic filling strain, with a similar magnitude as circumferential strain, in the lateral LV subendocardium, may prove to be a useful measurement of early changes in LV function in patients with chronic isolated MR. The current findings suggest including analysis of myocardial strain also during diastole (versus systole) as a potential indicator of deranged LV function. The alterations in LV strain that we report may be considered subtle and difficult to assess clinically. With the clinical scenario of long-standing isolated MR in human hearts, however, it is likely that the disease related changes would be more extensive. Furthermore, the requirement of the spatial resolution for noninvasive imaging in human hearts may actually be lower than for the current ovine model. In humans, the LV myocardial wall is thicker, and more importantly, the magnitude of the myocardial strain is much larger than in anesthetized sheep. Among noninvasive techniques, cardiac MRI will probably be the first modality to provide these measurements clinically. Displacement encoding with stimulated echoes (DENSE)29,30
appears to be the most promising and robust technique with the potential to provide these accurate transmural measurements in the immediate future.
The cardiac neurohormone B-type natriuretic peptide (BNP) is secreted from the ventricular myocardium mainly in response to myocardial stretch and increased wall stress, in humans as well as animals.16
BNP activation aids in the diagnosis and prognosis of LV dysfunction and heart failure of various etiologies.31,32
In terms of MR, it was recently demonstrated that BNP level was higher in patients with functional than those with organic MR.32
Furthermore, it has been suggested that BNP activation in chronic organic MR reflects primarily ventricular and atrial consequences rather than degree of MR.31
In this ovine model, however, we did not observe elevated BNP levels in EXP relative to CTRL at 12 weeks. This might result from the early phase of the LV remodeling process, as well as interspecies differences in BNP activation in response to low pressure LV volume overload.
No intergroup difference in traditional indices of LV function such as PRSW, EF, or Tau were observed. Under these experimental conditions these indices do not allow detection of changes in LV function during the very early stage of the disease, and this is consistent with recent findings.23
Accordingly, a correlation analysis between changes in strain and changes in PRSW, EF or Tau, did not show any closer association between the parameters.
Considerable caution is warranted in extrapolating these experimental findings in sheep hearts to the clinical scenario of long-standing isolated MR in human hearts. The sequela of MR in patients is a chronic and insidious phenomenon that can be tolerated clinically for years, and the 12-week follow-up in this study is insufficient to capture the complete pathophysiology of chronic MR. In this study we sought to detect very early changes in LV function, and for this purpose the actual “chronicity” of the model appears appropriate.
Insertion of myocardial markers and beads is invasive and associated with local LV wall trauma, however; this would affect the LV wall mechanics at all myocardial depths because the tunneling and placement of the beads are trans-mural in both groups of animals.
All animals underwent CPB surgery which is known to depress myocardial function. This is most likely the reason for the elevated BNP, and reduced PRSW and strain levels at 1 week relative to 12 weeks. This procedure, however, should affect both study groups equally.
Twelve weeks of “pure” MR in this ovine model caused signs of LV remodeling. Early changes in LV function were detected by alterations in transmural myocardial deformation, particularly in longitudinal diastolic filling strain in the subendocardium, but not by changes in BNP, PRSW, or tau. These alterations in transmural strains may prove useful in the clinical evaluation of latent LV dysfunction in asymptomatic patients with severe MR.