Ann Thorac Surg 2007;83:47-54
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Altered Myocardial Shear Strains Are Associated With Chronic Ischemic Mitral Regurgitation
Tom C. Nguyen, MDa,
Allen Cheng, MDa,
Frank Langer, MDa,
Filiberto Rodriguez, MDa,
Robert A. Oakes, MDa,
Akinobu Itoh, MDa,
Daniel B. Ennis, PhDb,
David Liang, MD, PhDc,
George T. Daughters, MSa,d,
Neil B. Ingels, Jr, PhDa,d,
D. Craig Miller, MDa,*
a Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford
b Department of Radiology, Stanford University School of Medicine, Stanford
c Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford
d Research Institute of Palo Alto Medical Foundation, Palo Alto, California
Accepted for publication August 22, 2006.
* Address correspondence to Dr Miller, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94305-5247 (Email: dcm{at}stanford.edu).
Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract
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BACKGROUND: Ischemic mitral regurgitation (IMR) limits life expectancy and can lead to postinfarction global left ventricular (LV) dilatation and remodeling, the pathogenesis of which is not completely known. We tested the hypothesis that IMR perturbs adjacent myocardial LV systolic strains.
METHODS: Thirteen sheep had three columns of miniature beads inserted across the lateral LV wall, with additional epicardial markers silhouetting the ventricle. One week later posterolateral infarction was created. Seven weeks thereafter, the animals were divided into two groups according to severity of IMR (
1+, n = 7, IMR[–] vs 
2+, n = 6, IMR[+]). Four dimensional marker coordinates and quantitative histology were used to calculate ventricular volumes, transmural myocardial systolic strains, and systolic fiber shortening.
RESULTS: Seven weeks after infarction, end-diastolic (ED) volume increased similarly in both groups, end-systolic (ES) E13 (circumferential-radial) shear increased in both groups, but more so in IMR(+) than IMR(–) (+0.12 vs 0.04, p < 0.005), and E12 (circumferential-longitudinal) shear increased in IMR(–) but not IMR(+) (+0.04 vs –0.01, p < 0.005). There were no significant differences in ED or ES remodeling strains or systolic fiber shortening between IMR(–) and IMR(+).
CONCLUSIONS: An equivalent increase in LV end-diastolic (ED) volume in both groups, coupled with unchanged ED and end-systolic remodeling strains as well as systolic circumferential, longitudinal, and radial strains, argue against a global LV or regional myocardial geometric basis for the cardiomyopathy associated with IMR. Further, similar systolic fiber shortening in both groups militates against an intracellular (cardiomyocyte) mechanism. The differences in subepicardial E12 and E13 shears, however, suggest a causal role of altered interfiber (cytoskeleton and extracellular-matrix) interactions.
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Introduction
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Ischemic mitral regurgitation (IMR) is a serious complication of ischemic heart disease and it portends a poor prognosis [1–3]. Irrespective of medical or surgical intervention, disease process may progress in a downward spiral of ventricular and myocardial dysfunction and premature death [4, 5]. In previous studies of mitral regurgitation (MR), abnormal myocardial contraction has been demonstrated; eg, blunted force-frequency relationship (FFR), impaired cross-bridge cycling, and disturbed excitation-contraction coupling [4, 6–8]. These studies, however, were conducted using in vitro preparations and isolated myocardial strips. The interactions between myocardial function and IMR in vivo have not been completely characterized, but the recent development of methods to measure transmural left ventricular (LV) strains, shear strains, and systolic fiber shortening make possible investigation of this relationship in an intact animal model throughout the cardiac cycle [9]. Using an ovine infarct model of IMR, the objective of this study was to characterize in vivo alterations in peri-infarct transmural myocardial strain and systolic fiber shortening that may explain why IMR can progress to global cardiomyopathy.
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Material and Methods
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All animals received humane care in compliance with guidelines set forth by the National Institutes of Health (US Department of Health and Human Services NIH Publ. 85-23, Revised 1985). This study was approved by the Stanford Medical Center Laboratory Research Animal Review Committee and conducted according to Stanford University policy.
Surgical Preparation and Marker Placement
The experimental preparation was similar to that described previously and will only be outlined briefly [9, 10]. Thirteen adult Dorsett hybrid sheep (61 ± 2 kg) had radiopaque ventricular markers surgically implanted to silhouette the LV chamber along four equally spaced longitudinal meridians (Fig 1). Epicardial echocardiography was used to locate an equatorial segment of the lateral LV wall equally spaced between the papillary muscles for transmural bead set placement. To measure regional three-dimensional (3D) myocardial deformations, three transmural columns of beads (0.7 mm diameter, 1.7 mm on epicardium) were implanted normal to the epicardial tangent plane and evenly spaced from endocardium to epicardium using a depth-adjustable insertion trocar [11]. Polypropylene sutures were then encircled around one or two distal obtuse marginal branches of the left circumflex coronary artery located between the posterior LV vein and middle cardiac vein and loosely snared using the method of Llaneras and colleagues [12]. These sutures would later be tightened one week postoperatively to create a posterior LV infarction adjacent to the transmural bead set. The chest was then closed and the sheep recovered.
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Fig 1. Locations of left ventricular (LV) epicardial markers and the LV mid-lateral equatorial wall transmural bead set. At each time sampled, long axis ( ) orients local cardiac coordinate axes X1 (circumferential) and X2 (longitudinal) in the epicardial tangent plane defined by markers A, B, and C with origin, and O the center of these markers. X3 (radial), pointing away from the LV chamber completes the right-handed local cardiac coordinate system.
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Experimental Protocol
One week postoperatively, the animals were taken to the cardiac catheterization laboratory, intubated, and mechanically ventilated. Transesophageal echocardiography (TEE) and coronary angiography were performed, and simultaneous biplane marker videofluoroscopic and hemodynamic data were acquired (baseline). The MR was graded qualitatively (0 to 4+) by an expert echocardiographer (D.L.) on the basis of TEE color Doppler regurgitant jet extent and width [13]. After premedication with lidocaine (100 mg intravenously [iv]), bretylium (75 mg iv), and magnesium (3g iv), the coronary artery snares were tightened to occlude the arteries (verified by angiography) and create a posterolateral infarction. After 7 ± 1 weeks (chronic), the animals were returned to the catheterization laboratory for TEE and recording of hemodynamic and marker data. Subsequently, the animals were divided into two groups according to severity of MR: 1+ or less, n = 7, "IMR(–)" versus 2+ or greater, n = 6, "IMR(+)". The animals were then euthanized using sodium pentothal (1 gm iv) followed by an intravenous bolus of potassium chloride (80 mEq). After adjusting left ventricular pressure by exsanguination to match the previous in vivo LV end-diastolic pressure, buffered glutaraldehyde (5%, 300 mL) solution was infused simultaneously into both coronary arteries to fix the hearts in situ.
Cardiac Strains
Placement of the transmural bead set allowed assessment of transmural 3D myocardial deformations in the lateral equatorial LV region adjacent to the infarction. The three normal strain components measured local myocardial stretch or shortening along the circumferential (E11), longitudinal (E22), and radial (E33) cardiac axes. The three shear strains represent angle changes between pairs of the originally orthogonal coordinate axes: Circumferential-longitudinal (E12), circumferential-radial (E13), and longitudinal-radial (E23). Detailed strain analysis methodology was described previously [9, 14]. For each beat, bead positions at end-systole (ES) (deformed configuration) at 20% (subepicardium), 50%, and 80% wall depths were compared with their positions at end-diastole (ED, reference configuration). Tissue blocks were studied by light microscopy adjacent to the bead region to measure transmural myocardial fiber angles [15]. The methods of Costa and colleagues [16] were then used to transform cardiac strains into fiber strains (Eff) at the same depth; negative Eff indicates fiber shortening from ED to ES.
Remodeling Strains
Bead positions at ED, end-isovolumetric contraction (EndIVC), mid-ejection (MidEjec), ES, and end-recoil (EndRCL) during the one-week study (reference configuration) were compared with their positions at the same five times during the cardiac cycle measured during the seven-week study (deformed configuration) to compute remodeling strains for each heart.
Regional LV Systolic Function
Ventricular systolic fractional area shortening was used as an index of regional LV systolic function to assess the functional demarcation between infarcted and noninfarcted myocardium. Each LV region defined by four subepicardial markers was divided into two triangular planar areas except the apical regions, which were defined by triangular areas, each of which included the apical marker. Fractional change in systolic epicardial area (fractional area shrinkage [FAS]) was calculated as
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where rAreaED was the regional area at ED and rAreaES was the regional area at ES.
Hemodynamics and Cardiac Cycle Timing
Three consecutive steady-state beats in sinus rhythm were selected for analysis. Instantaneous left ventricular volume (LVV) was calculated from the 3D coordinates of the epicardial LV markers. For each cardiac cycle, ED was defined as the maximal second derivative of LV pressure, corresponding with the frame immediately before the upstroke of LV pressure. End-systole was defined as the videofluoroscopic frame before the time of peak negative LV rate of pressure decrease (–dP/dtmax).
Statistical Analysis
Data are reported as mean ±1 SD unless otherwise specified. Three consecutive steady-state beats in sinus rhythm were time-aligned at ED, averaged, and analyzed for each animal. Data were compared using two-way repeated measure analysis of variance with the Bonferroni post hoc test for multiple comparisons (Sigmastat 3.11.0; SPSS, Inc, Chicago, IL). A p value of 0.01 or less was considered statistically significant.
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Results
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Hemodynamic Variables
Table 1
summarizes the changes in hemodynamic variables in both groups at baseline and seven weeks later. At baseline, there was no significant difference between the IMR(+) and IMR(–) groups in IMR grade, LV dP/dt, LVED volume index (VI), LVESVI, LVED pressure (P), LVESP, or maximum LVP (LVPmax) (all p > 0.05). Heart rate was lower in the IMR(+) group both at baseline and after infarction (all p < 0.01) for inexplicable reasons. Eight weeks after infarction, EDVI increased significantly and to a comparable degree in both the IMR(–) and IMR(+) groups compared with baseline.
Systolic Fractional Area Shrinkage (FAS)
At baseline, there was no significant difference in systolic FAS between the IMR(–) and IMR(+) groups. In both the IMR(–) and IMR(+) groups, infarction decreased systolic FAS in the posterolateral equatorial region (12.5 ± 4.2% to 5.7 ± 3.3% and 12.0 ± 2.3% to 4.0 ± 3.1%, respectively, all p < 0.005 (Fig 2), indicating that the infarction was adjacent to the bead set in both groups. There also was no statistical difference in posterolateral systolic FAS at seven weeks between the IMR(–) and IMR(+) groups, suggesting that both groups had a similarly sized infarction.
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Fig 2. Systolic fractional area shrinkage (FAS) depicted with the three-dimensional (3D) left ventricular (LV) marker array unrolled and projected onto a 2D surface. Twelve contiguous LV epicardial regions (4 basal, 4 equatorial, and 4 apical) were defined and divided into anteroseptal, anterolateral, posterolateral, and posteroseptal walls. Calculated values for systolic FAS are shown at baseline and eight weeks for IMR(–) and IMR(+), respectively. The grey area indicates regions with significantly decreased FAS compared with baseline. The three column bead set used to measure transmural strain is shown in light grey circles. Note that this lateral equatorial bead set was adjacent to the infarct. Data are shown as mean ± 1 SD. (*p = 0.005 vs baseline.  p = 0.003 vs baseline;. IMR = ischemic mitral regurgitation.)
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Systolic Strains
Table 2
lists the transmural myocardial systolic strains from ED to ES for both groups. There was no significant difference in systolic cardiac strains at baseline between the IMR(–) and IMR(+) groups. For the shear strains, E12 increased in the subepicardium (0.01 ± 0.02 to 0.05 ± 0.05), E23 increased in the subepicardium (0.00 ± 0.02 to 0.08 ± 0.05) and midwall (0.05 ± 0.07 to 0.13 ± 0.06), and E13 increased in the subepicardium (0.02 ± 0.01 to 0.06 ± 0.03) (all p < 0.007) seven weeks after infarction in the IMR(–) group. Some shear strains changed in the IMR(+) group: E23 increased in the subepicardium (0.03 ± 0.02 to 0.12 ± 0.07) and midwall (0.03 ± 0.02 to 0.13 ± 0.05) and E13 in the subepicardium (0.03 ± 0.03 to 0.15 ± 0.07, all p < 0.007). Increased E13 shear strain was more pronounced in the IMR(+) group at seven weeks compared wih the IMR(–) group (0.15 ± 0.07 vs 0.06 ± 0.03, respectively, p = 0.005). Additionally, the increase in E12 in the IMR(–) group was different than in the IMR(+) group (0.05 ± 0.05 vs –0.01 ± 0.02, respectively, p = 0.007). Figures 3A and 3B depict the E13 and E12 strains throughout the cardiac cycle. There was no statistical difference in normal strains between baseline and chronic and the IMR(–) and IMR(+) groups, respectively, all p 0.10.
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Fig 3. Comparison of data at 20% wall depth (subepicardium) at one and seven weeks postinfarction between the IMR(–) and IMR(+) groups (mean ± 1 standard error of the mean, normalized cardiac cycle lengths) adjusted with cubic Hermite interpolation in time. The left ventricular pressure (LVP, mm Hg) is on the right ordinate (average LVP at eight weeks). Systolic myocardial shear strain is indicated on the left ordinate, with circumferential-radial strain (E13) illustrated in (A) and circumferential-longitudinal strain (E12) in (B), respectively. Baseline E13 (A) and E12 (B) strains at one week are represented by closed black circles. Open circles represent IMR(–) and open squares indicate IMR(+) at seven weeks, respectively. The shaded right glyphs graphically represent the direction and magnitude of systolic E13 (A) and E12 (B) shear deformation during for each condition. (IMR = ischemic mitral regurgitation.)
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Remodeling and Fiber Strains
There was no significant difference in transmural fiber angles between the IMR(–) and IMR(+) groups at either 20% wall depth (–40° ± 7° vs –39° ± 5°, p = 0.75), 50% wall depth (–12° ± 6° vs –10° ± 7°, p = 0.67), or 80% wall depth (20° ± 7° vs 18° ± 5°, p = 0.55). Table 3
displays remodeling strains at ED, EndIVC, MidEjec, ES, and EndRCL at one week (reference configuration) and seven weeks (deformed configuration) for both IMR(–) and IMR(+) groups; there was no significant change in remodeling strains (all p 0.10). Finally, Figures 4A,
4B, and 4C display transmural fiber strains throughout the cardiac cycle for both groups at both times. There was no significant difference in fiber shortening (Eff) between the IMR(–) and IMR(+) groups at baseline or at seven weeks.
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Fig 4. Comparison of transmural systolic fiber shortening (Eff, left ordinate) in the subepicardium (A), midwall (B), and subendocardium (C) at one and seven weeks post-infarction between IMR(–) and IMR(+) groups (mean ± 1 SEM, normalized cardiac cycle lengths) adjusted with cubic Hermite interpolation in time. Left ventricular pressure (LVP, mm Hg) is on the right ordinate and represents average LVP at eight weeks. Baseline Eff at one week is depicted by closed circles. Open circles represent Eff for IMR(–) at eight weeks, and open squares IMR(+) at eight weeks, respectively. (IMR = ischemic mitral regurgitation.)
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Comment
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Ischemic mitral regurgitation is classically defined as mitral regurgitation, which occurs as a consequence of myocardial infarction or ischemia. The mechanistic pathophysiology of how IMR can evolve to global ischemic cardiomyopathy remains incompletely understood. Here, we characterized in vivo alterations in transmural myocardial strain and systolic fiber shortening adjacent to an infarct in an ovine model, which may be related to the progression from a regional infarct to global cardiomyopathy.
Studies by Mulieri, Hasenfuss, Alpert, and colleagues [4, 6, 17, 18] provided mechanistic insight into IMR and heart failure by demonstrating impaired FFR in diseased myocardium from recipients undergoing cardiac transplantation and patients undergoing coronary artery surgery [17, 18] or treatment of mitral regurgitation [4]. Although these findings enhanced our understanding of heart failure and IMR at the level of the cardiomyocyte, these experiments were conducted in vitro using isolated strip preparations of myocardium. Investigation of myocardial function and IMR in vivo, however, has not been accomplished in intact animals.
Our finding that regional fiber shortening at various times during the cardiac cycle did not differ significantly between the IMR(+) and IMR(–) groups is discordant with the human findings reported by Mulieri and colleagues [4, 18], Hasenfuss and colleagues [6], and Alpert and colleagues [17], which showed that impaired fiber function was an important component of the heart failure cascade. We conjecture that in this early IMR (< 7 weeks) preparation, the cardiomyocytes per se in the adjacent myocardium may not be injured severely; instead, the mechanical impairment may be in extracellular matrix (ECM) between the fibers and the microtubules in the cytoskeleton that couple cardiomyocyte shortening to LV wall thickening. This notion is supported by our findings that shear strains were perturbed differently between IMR(–) and IMR(+) groups at seven weeks because shear strain represents the relative motion of fibers with respect to one another. In both IMR(–) and IMR(+) groups, E12 increased in the subepicardium, E23 increased in the subepicardium and midwall, and E13 increased in the subepicardium compared with baseline (Table 2). These shear strain perturbations were significantly more pronounced in the IMR(+) group than the IMR(–) group (Table 2; Figs 3A, 3B). These differences in shear strains between the two groups support our hypothesis that seven weeks after the infarct the main problem may reside in the ECM.
Recent reports suggest an important role for mechanical ECM alterations during the pathogenesis of postinfarction LV remodeling [19]. During postinfarct, early remodeling alterations in regional strains most likely follow matrix metalloproteinase activation and subsequent ECM degradation. In this ovine model, exaggerated shear strains in the peri-infarct region may possibly be secondary to ECM breakdown. Further evolution of ECM changes in the infarct area then become dominated by collagen synthesis and deposition.
Changes in myocardial normal strain and shear strain patterns may also mediate postinfarction LV remodeling [10, 20, 21]. Perturbations in normal strain stimulate myocyte apoptosis [22, 23] and activate matrix metalloproteinases [24, 25]. At the cellular level, changes in strain have important implications for development, differentiation, disease, and regeneration [26]. Previous observations from our laboratory suggest that increased E13 shear strain adjacent to the infarct may trigger further LV remodeling [10]. After only 70 seconds of ischemia, presumably before ECM remodeling can take place, Rodriguez and colleagues [10] demonstrated increased E13 shear together with increased fiber-sheet shear strain adjacent to acutely ischemic myocardium. Unpublished data from our laboratory reveals that subepicardial E13 shear strain remained increased one hour after posterolateral infarction, after the onset of presumably irreversible myocyte injury. These findings at various times after infarction demonstrate consistently increased E13 shear strains adjacent to posterolateral ischemic or infarcted LV myocardium in sheep after 70 seconds, one hour, and seven weeks.
Future insight into the pathologic development and consequences of abnormal myocardial shear strains may be gleaned from advances in magnetic resonance imaging (MRI). Noninvasive MRI motion encoding has been used to quantify myocardial deformation in chronic ischemia [27, 28], and displacement encoded MRI techniques (tagged or dense MRI) are capable of quantifying transmural gradients in cardiac strains [29]. Increasing interest in myocardial shear strains adds to the potential utility of this clinically relevant imaging modality. In the future such techniques may find clinical application to determine whether particular strain patterns in the patient with a chronic infarct portend the onset of more IMR over time or inexorable progression to global LV cardiomyopathy. Stratification of patients could affect treatment plans.
Data were obtained from a chronic ovine infarction model and direct extrapolation of these findings to patients is difficult and fraught with uncertainty. Histology in the glutaraldehyde-fixed myocardium adjacent to the bead set to measure transmural fiber angles was required in order to transform subsequently cardiac strains into fiber strains [16]. This destroys the tissue and precludes histologic perfusion analysis to determine the perfusion status of the myocardial sample (bead set) and whether it was located in the remote, border zone, or infarction zones. Because the bead set was placed in the midlateral wall adjacent to the posterolateral infarction, we do not believe that the bead set was located in normal remote myocardium, which was confirmed by postmortem examination and by functional assessment with FAS (Fig 2). We do not believe the bead set was located in the infarct based on FAS analysis (Fig 2), where one would expect impaired function; further, our analysis revealed that transmural circumferential shortening (E11 strain) was preserved (Table 2). Whether the beads were definitely located in the "border zone" is unanswerable; therefore, we elected to use instead the term "adjacent" to the infarct zone.
The majority of animals in the IMR(+) group had only moderate MR (2.0 ± 1.1), n = –6. Analysis of the one sheep with severe 4+ MR did not yield a significant difference in LV remodeling or transmural shear strain, but no conclusions can be supported based on data from one animal.
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Acknowledgments
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This work was supported by Grants HL-29589 and HL-67025 from the National Heart, Lung and Blood Institute. Doctors Nguyen, Langer, Cheng, Rodriguez, and Oakes were Carl and Leah McConnell Cardiovascular Surgical Research Fellows. Doctors Nguyen and Cheng were recipients of the Thoracic Society Foundation Research Education (TSFRE) Fellowship Awards. Doctor Langer was also supported by the Deutsche Akademie der Naturforscher Leopoldina, Halle, Germany. Doctor Itoh was a recipient of the Uehara Memorial Foundation Research Fellowship. We deeply appreciate the technical expertise provided by Mary K. Zasio, BA, Maggie Brophy, AS, and Katha Gazda, BA. We thank Drs. James W. Covell, Andrew D. McCulloch, and Jeffrey H. Omens at the University of California, San Diego, and Dr. John C. Criscione at the Texas A&M University for their generous help and advice.
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Abstract
Introduction
