Alterations in Lateral Left Ventricular Wall Transmural Strains During Acute Circumflex and Anterior Descending Coronary Occlusion

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1 Alterations in Lateral Left Ventricular Wall Transmural Strains During Acute Circumflex and Anterior Descending Coronary Occlusion CARDIOVASCULAR Frank Langer, MD, Filiberto Rodriguez, MD, Allen Cheng, MD, Saskia Ortiz, MD, Katherine B. Harrington, Mary K. Zasio, George T. Daughters, MS, John C. Criscione, MD, PhD, Neil B. Ingels, PhD, and D. Craig Miller, MD Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, Laboratory of Cardiovascular Physiology and Biophysics, Palo Alto Medical Foundation Research Institute, Palo Alto, California; and Department of Biomedical Engineering, Texas A&M University, College Station, Texas Background. Increased circumferential-radial shear in the midlateral left ventricle adjacent to ischemic myocardium has been observed during acute midcircumflex ischemia in open-chest animals. Extending this work, we studied transmural strains in closed-chest animals during acute proximal circumflex (pcx) and proximal left anterior descending (plad) occlusions. Methods. Six sheep had radiopaque markers implanted to silhouette the left ventricle and measure regional systolic fractional area shortening; three transmural bead columns were inserted into the midlateral wall for transmural myocardial strain analysis. After 8 weeks, threedimensional marker coordinates were obtained using biplane videofluoroscopy, both before and during separate 1-minute plad and pcx balloon occlusions. Systolic strains were assessed along circumferential, longitudinal, and radial axes, and then transformed into fiber strains using quantitative microstructural measurements. Results. Acute plad occlusion and pcx occlusion caused similar hemodynamic insults. Systolic fractional area shortening revealed that the beads were in the ischemic territory during pcx occlusion, but adjacent to the ischemic myocardium during plad occlusion. Transmural circumferential strain and fiber shortening fell in the ischemic region during pcx occlusion, but remained normal when adjacent to the ischemic myocardium during plad occlusion. Circumferential-radial shear strain increased in the lateral left ventricle during pcx occlusion, but reversed in this same region during plad occlusion. Longitudinal-radial shear also decreased during plad occlusion. Conclusions. Reversal of lateral wall circumferentialradial shear and decreased longitudinal-radial shear during acute plad occlusion reflects altered mechanical interaction between ischemic and nonischemic myocardium. Increased circumferential-radial shear during pcx occlusion also reflects mechanical interaction. The direction of circumferential-radial shear deformation depends on the location of the adjacent ischemic territory. (Ann Thorac Surg 2007;84:51 60) 2007 by The Society of Thoracic Surgeons Accepted for publication March 8, Presented at the Poster Session of the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24 26, Address correspondence to Dr Miller, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA ; dcm@stanford.edu. Ischemic heart disease is the most common cause of heart failure [1]. In addition to the irreversibly damaged infarcted myocardium, ongoing ischemia with stunned/hibernating myocardium contributes to progression of ischemic cardiomyopathy and heart failure [1]. In a subset of patients, isolated infarction can lead to heart failure in the absence of ongoing ischemia or recurrent infarction. This process of postinfarction left ventricular (LV) remodeling is incompletely understood, but nonischemic infarct extension has been postulated [2, 3]. This hypothesis is based on the concept that despite normal blood flow, mechanical strain alterations in otherwise healthy regions adjacent to infarcted myocardium can trigger the production of reactive oxygen species [4, 5], which induce myocyte apoptosis [6, 7] and activate matrix metalloproteinases [8, 9], causing subsequent collagen degradation and fibrosis. Hence, better insight regarding these strain alterations is important to prevent and treat ischemic cardiomyopathy. In a previous acute open-chest experiment, increased circumferential-radial shear strain was observed in the lateral wall adjacent to ischemic myocardium during a brief episode of acute mid circumflex artery occlusion before any molecular processes could be established [10]. Ultimately, such strain alterations reflect the mechanical interaction between ischemic and nonischemic myocardium. Based on these findings, we hypothesized that the direction and nature of ventricular shear-strain alterations adjacent to the ischemic zone may vary in relation to the location of the ischemic insult. We sought to characterize strain alterations in the lateral LV wall in a closed-chest ovine model during brief episodes of revers by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 CARDIOVASCULAR 52 LANGER ET AL Ann Thorac Surg ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS 2007;84:51 60 Surgical Preparation Eight Dorsett-hybrid sheep (71 3 [mean 1SD] kg) underwent left thoracotomy. Epicardial echocardiography was used to identify a region of the midlateral LV wall between the papillary muscles at the equatorial level (systolic wall thickness 10 1 mm). Three transmural columns of three gold beads each (0.7 mm diameter) were inserted using a needle trochar, spaced evenly from subendocardium to subepicardium. Three 1.7-mm beads were sutured to the epicardial surface at the entry hole of each column (Fig 1A) [11]. Thirteen radiopaque miniature helical tantalum markers were inserted in the subepicardium along four equally spaced longitudinal meridians defining the anterior, lateral, posterior, and septal LV walls at the basal, equatorial, and apical levels; with a single marker at the apex (nos. 1 to 13, Fig 1A). Care was taken to ensure that the equatorial lateral marker (no. 12, Figs 1A, 2) was immediately basal to the beads and that an imaginary line connecting markers no. 12 and no. 11 (apical lateral marker) bisected the transmural beadset (Figs 1A, 2). The chest was closed, and the animals were recovered. Fig 1. Schematic depicting the global marker array (nos. 1 to 13) and the three transmural columns of radiopaque beads in the midlateral left ventricle (LV) wall (APM anterior papillary muscle; PPM posterior papillary muscle). A. Fractional area shortening (FAS) analysis: FAS analysis was determined to characterize regional systolic function. B. Strain analysis: the bead columns were used for calculation of local strains along circumferential, longitudinal, and radial axes. C. Ultrastructural measurement: a transmural tissue block was excised (with edges cut parallel to the local circumferential, longitudinal, and radial axes). Fiber angles ( ) were measured transmurally from serial sections cut parallel to the epicardium. D. Transformation: cardiac strains were transformed into fiber strains using fiber angles ( ) at each wall depth. ible acute ischemia in three distinct vascular territories (proximal anterior descending [plad] artery, proximal circumflex [pcx] artery, and distal circumflex [dcx] artery). Material and Methods All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 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. Data Acquisition Eight weeks later, the animals were taken to the catheterization laboratory. After premedication with ketamine (25 mg/kg intramuscularly), anesthesia was induced with sodium thiopental (6.8 mg/kg intramuscularly) and maintained with inhalational isoflurane (1.5% to 2.2%). Data runs were acquired with the animal in the right lateral decubitus position with ventilation briefly arrested at end expiration. Animals received intravenous magnesium sulfate (3 g), lidocaine (100 mg), and bretylium (50 mg) before data acquisition. Five minutes after acquisition of baseline data, the distal CX was occluded by inflation of an intracoronary balloon catheter (distal to the second obtuse marginal branch) for 1 minute, and data were then acquired during ongoing ischemia. Coronary occlusion was released, and after a 10-minute recovery, a second set of baseline data was acquired. The proximal LAD was occluded for 1 minute, and data were then acquired during ongoing ischemia. After similar recovery, a third dataset was acquired before and during proximal CX occlusion (proximal to the first obtuse marginal). Two animals died of refractory ventricular fibrillation during the first ischemic episode (dcx occlusion) and were excluded from the study. The final study group consisted of 6 animals. A Philips Optimus 2000 biplane Lateral ARC 2/poly DIAGNOST C2 system (Philips Medical Systems, Pleasanton, California) was used to record videofluoroscopic images at 60Hz. Two-dimensional images from the two x-ray views were digitized using custom software and later merged to yield three-dimensional coordinates of each radiopaque marker every 16.7 ms (accuracy of mm compared with known marker-to-marker threedimensional lengths). Analog left ventricular pressure (LVP) and electrocardiographic signals were digitized simultaneously. QUANTITATIVE TRANSMURAL MICROSTRUCTURAL MEASUREMENTS. At the end of the experiment, animals received an intravenous bolus of sodium pentothal (1 g). The hearts were then depolarized and arrested at end diastole with an intravenous bolus of potassium (80 meq), LV pressure was adjusted to match in vivo baseline LV end-diastolic pressure through central venous exsanguination, and direct coronary perfusion with buffered glutaraldehyde (5%) allowed rapid in-situ fixation [10, 11]. Fiber angle ( ) was measured from sections cut parallel to the epicardium [10] and was defined as the angle subtended by X f

3 Ann Thorac Surg LANGER ET AL 2007;84:51 60 ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS and the circumferential axis (Fig 1C), being negative for a left-handed helix [12]. Data Analysis HEMODYNAMICS AND CARDIAC CYCLE TIMING. End diastole (ED) was defined as the maximum of the second derivative of LVP, corresponding with the frame immediately before the upstroke of the LVP curve. End systole (ES) was defined as the videofluoroscopic frame before the time of peak negative LV rate of pressure fall ( dp/dt max ). Instantaneous LV volume was calculated from LV markers using multiple tetrahedra and corrected for LV convexity. Although epicardial LV volume overestimates true LV chamber volume (because it incorporates an unknown amount of LV muscle mass), changes in this epicardial LV volume are an accurate measurement of relative changes in LV chamber volume, because LV muscle mass remains constant throughout the cardiac cycle. REGIONAL LV SYSTOLIC FUNCTION. As previously described [10], systolic fractional area shortening (FAS) was used to determine the functional demarcation between ischemic and nonischemic myocardium (Figs 1B and 2). For the region surrounding the transmural beadset, detailed local FAS was performed to more clearly determine the location of the beads in relation to the ischemic zones. TRANSMURAL DEFORMATIONS CARDIAC AND FIBER STRAIN ANALYSES. A local LV long-axis was defined using the centroid of the three 1.7-mm epicardial surface beads and the apical marker (no. 1), with origin at this centroid and local cardiac coordinates aligned with circumferential (X 1 ), longitudinal (X 2 ), and radial (X 3 ) axes of the LV lateral wall. Transmural strains were then calculated (Fig 1B) [10, 11]. In local cardiac coordinates [X 1, X 2, X 3 ], the three normal strain components measure myocardial stretch/ shortening along the circumferential (E 11 ), longitudinal (E 22 ), and radial (E 33 ) cardiac axes. The three shear strains (E 12, E 13, and E 23 ) represent angle changes between pairs of originally orthogonal coordinate axes. Transmural strains at 20% (subepicardial), 50% (mid), and 80% (subendocardial) wall depth were selected for analysis. Changes in bead positions at ED during ischemia (deformed configuration) were compared with ED at baseline (preischemia, reference configuration) to assess changes in local transmural myocardial geometry at ED (ie, end-diastolic strain) associated with acute alterations in material properties and loading conditions. Systolic strains were calculated by comparing bead positions at ES (deformed configuration) with ED (reference configuration) for each beat in each data run (3 beats per run) before and during ischemia. 53 CARDIOVASCULAR 4 Fig 2. Systolic fractional area shortening (FAS): three-dimensional global marker array was unrolled and projected onto a two-dimensional surface. Twelve contiguous epicardial regions (four basal, equatorial, and apical regions) were divided into anteroseptal, anterolateral, posterolateral, and posteroseptal walls, as shown in top part. Detailed local FAS analyses around the transmural beadset are depicted in each bottom part. The FAS analysis was depicted at baseline and during coronary occlusion: (A) proximal circumflex (prox. CX) occlusion; (B) proximal left anterior descending (prox. LAD) occlusion; and (C) distal-cx (dist. CX) occlusion. Bright red areas indicate decreased FAS, bright green areas indicate increased FAS (mean 1SD, *p 0.05). Lightly shaded areas denote regions where changes approached statistical significance (p 0.10).

4 CARDIOVASCULAR 54 LANGER ET AL Ann Thorac Surg ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS 2007;84:51 60 Table 1. Hemodynamics During Proximal Circumflex (pcx) Artery Occlusion Hemodynamics Pre-pCX pcx p Value Table 3. Hemodynamics During Distal Circumflex (dcx) Artery Occlusion Hemodynamics Pre-dCX dcx p Value HR (min 1 ) ns dp/dt max (mm Hg/s) 1, , a EDV (ml) a 0.01 EDP (mm Hg) a LVP max (mm Hg) a a p 0.05, ischemia versus preischemia, t test for paired observation. dp/dt max maximum positive rate of change of left ventricular (LV) pressure; EDP end-diastolic pressure; EDV end-diastolic volume; HR heart rate; LVP max maximum left ventricular pressure; ns not significant. Transmural cardiac strains were transformed into fiber coordinates (X f; Fig 1D) using previously described techniques [13]. The resulting fiber strains reflect stretch or shortening along the fiber axis (E ff ). Statistical Analysis Hemodynamic and marker-derived data from three consecutive steady-state beats in sinus rhythm were time aligned at ED and averaged for each animal at baseline (preischemia) and during coronary occlusion (ischemia). All data are reported as mean 1SD unless otherwise specified. End-diastolic strains were compared with zero using a one-sample t test. Changes in hemodynamics, FAS, and systolic strains were compared using Student s t test for paired observations. A p value of 0.05 or less was considered statistically significant; p less than 0.10 was considered to be possibly significant. Results Transmural Microstructure The microstructural configuration of the midlateral ovine LV wall at ED was characterized by helical fibers progressing inward smoothly from a left-handed helix in the subepicardium (20% wall depth, degrees), to circumferential in the midwall (50% wall depth, Table 2. Hemodynamics During Proximal Left Anterior Descending (plad) Artery Occlusion Hemodynamics Pre-pLAD plad p Value HR (min 1 ) ns dp/dt max (mm Hg/s) 1, a EDV (ml) a EDP (mm Hg) a LVP max (mm Hg) a a p 0.05, ischemia versus preischemia, t test for paired observations. dp/dt max maximum positive rate of change of left ventricular (LV) pressure; EDP end-diastolic pressure; EDV end-diastolic volume; HR heart rate; LVP max maximum left ventricular pressure; ns not significant. HR (min 1 ) dp/dt max (mm Hg/s) 1, , ns EDV (ml) ns EDP (mm Hg) ns LVP max (mm Hg) dp/dt max maximum positive rate of change of left ventricular (LV) pressure; EDP end-diastolic pressure; EDV end-diastolic volume; HR heart rate; LVP max maximum left ventricular pressure; ns not significant degrees), to a right-handed helix in the subendocardium (80% wall depth, 17 8 degrees). Hemodynamics Tables 1, 2, and 3 list the hemodynamics during acute ischemia. Occlusion of pcx as well as plad resulted in a significant ischemic insult with decreased LVP max and dp/dt max, and increased end-diastolic pressure and enddiastolic volume. Occlusion of the dcx did not induce significant hemodynamic changes. Systolic Fractional Area Shortening Consistent with pcx occlusion, ischemia was associated with decreased systolic FAS in the posterolateral regions, as shown in Figure 2. Decreased FAS was also noted in the anterolateral basal region, with concomitant hypercontractile function in the nonischemic anteroseptal basal region (increased FAS), which approached statistical significance. In contrast, plad occlusion resulted in decreased FAS of the entire anteroseptal region, the equatorial and apical anterolateral regions as well as the posterolateral apical region, while FAS increased in the remote posterolateral basal and posteroseptal basal regions. Examination of local systolic FAS revealed that the lateral wall transmural beadset was in the lateral most aspect of the ischemic territory during pcx occlusion, but was located adjacent to the ischemic myocardium during plad occlusion. During dcx occlusion, the beadset was remote from the ischemic territory. End-Diastolic Strains During acute pcx occlusion, the lateral LV wall became thinner as reflected by negative radial (E 33 ) strain in the subepicardium ( , p 0.04) and midwall ( , p 0.04). Occlusion of the plad resulted in similar deformation with negative radial strain in subepicardium ( , p 0.03), midwall ( , p 0.02), and subendocardium ( , p 0.02). Such wall thinning is consistent with the larger EDV observed during both pcx and plad occlusions (Tables 1 and 2). In contrast, no end-diastolic deformations were detected during dcx ischemia, which did not alter EDV (Table 3).

5 Ann Thorac Surg LANGER ET AL 2007;84:51 60 ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS Table 4. Transmural Systolic Strains During Proximal Circumflex (pcx) Artery Occlusion Pre-pCX pcx 55 P Value CARDIOVASCULAR Cardiac strains Circumferential strain (E 11 ) a 0.03 Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) Longitudinal-radial shear (E 23 ) ns Circumferential-radial shear (E 13 ) a 0.04 Circumferential strain (E 11 ) a 0.05 Longitudinal strain (E 22 ) ns Radial strain (E 33 ) Circumferential-longitudinal shear (E 12 ) Longitudinal-radial shear (E 23 ) ns Circumferential-radial shear (E 13 ) ns Circumferential strain (E 11 ) a Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) Circumferential-radial shear (E 13 ) ns Fiber strains Fiber strain (E ff ) a Fiber strain (E ff ) a 0.04 Fiber strain (E ff ) a a p 0.05, versus pre, t test for paired observations. ns not significant. Systolic Strains Transmural circumferential strain (E 11 ) and fiber shortening (E ff ) fell in the ischemic region during pcx occlusion, but remained normal when adjacent to the ischemic myocardial region during plad occlusion (Tables 4 and 5, Fig 3). Subepicardial circumferential-radial shear strain (E 13 ) increased in the lateral LV during pcx occlusion; but during plad occlusion, subepicardial and midwall circumferential-radial shear reversed (Tables 4 and 5, Figs 3 and 4). During plad occlusion, subepicardial and midwall longitudinal-radial (E 23 ) shear also became abolished or reversed (Table 5, Fig 3). No strain alterations were observed in the midlateral wall during dcx ischemia (Table 6, Fig 4). Comment The principal findings of the present study are that (1) abrupt alterations in transmural cardiac and fiber systolic strains occur in acutely ischemic myocardium, with decreased circumferential strain and fiber shortening observed as would be expected; and (2) increased circumferential-radial shear deformation of the lateral LV occurs during pcx occlusion with ischemia in the posterolateral region; but (3) during plad occlusion inducing ischemia in the anterolateral and anteroseptal regions, circumferential-radial shear become reversed in the lateral LV. The experimental design, with the region of interest in the midlateral LV wall in sheep (left-dominant coronary system, no preformed coronary collaterals), allowed us to study the effects of three distinct experimental conditions: (1) pcx occlusion, with the beadset located in the ischemic zone; (2) plad occlusion, with the beadset located adjacent to the ischemic zone; and (3) dcx occlusion, with the beadset located away from ischemic zone. The transmural beads were implanted in the midlateral LV wall straddling the presumptive border between the vascular territories of LAD and CX. By determining regional systolic function, it was possible to

6 CARDIOVASCULAR 56 LANGER ET AL Ann Thorac Surg ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS 2007;84:51 60 Table 5. Transmural Systolic Strains During Proximal Left Anterior Descending (plad) Occlusion Pre-pLAD plad P Value Cardiac strains Circumferential strain (E 11 ) ns Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) a Circumferential-radial shear (E 13 ) a 0.02 Circumferential strain (E 11 ) ns Longitudinal strain (E 22 ) ns Radial strain (E 33 ) Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) a 0.02 Circumferential-radial shear (E 13 ) a 0.05 Circumferential strain (E 11 ) Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) Circumferential-radial shear (E 13 ) ns Fiber strains Fiber strain (E ff ) ns Fiber strain (E ff ) ns Fiber strain (E ff ) ns a p 0.05, ischemia versus preischemia, t test for paired observations. ns not significant. define the demarcation between acutely ischemic and nonischemic myocardium. Because sheep have no collaterals, a sharp functional demarcation was identified by FAS analysis (Fig 2). Such a functional analysis was critical for this experiment, because the need for immediate glutaraldehyde perfusion fixation at the end of the experiment for quantitative microstructural measurements of transmural fiber angles (necessary for transforming the measured cardiac strains into fiber strains) precluded assessment of tissue perfusion using dye or microsphere injection. It was fortunate to have the bead set located at the demarcation between the plad and pcx ischemic zones (Fig 2), probably because of a combination of serendipity and intent, as all of the bead sets were placed in the same location in relation to the global LV markers (as shown in Fig 2) by a single surgeon (F.L.) to eliminate variability. In our previous, acute open-chest experiment, increased circumferential-radial shear strain was observed in the lateral wall adjacent to the ischemic myocardium during a brief episode of acute mid-cx occlusion [10]. The findings from this present, closed-chest experiment corroborate and extend these findings. Although the beadset was located in the ischemic zone during proximal-cx occlusion (Fig 2), increased circumferentialradial shear was also observed in the lateral wall in this experiment (Fig 3.). This consistent pattern of increased lateral wall shear deformation may reflect the overwhelming distortion induced by proximal- or mid-cx ischemia on the lateral LV. In contrast, during dcx occlusion, with the beadset located away from the ischemic zone, no acute strain alterations occurred (Figs 2, 4). Moreover, increased lateral wall circumferential-radial strain deformation has been shown to persist 8 weeks after posterolateral infarction in the adjacent noninfarcted zone [14]. A noteworthy finding of the present study is that the direction of circumferential-radial shear-strain alterations adjacent to ischemic myocardium appears to depend on the location of the ischemic territory. During plad occlusion, with the ischemic region located adjacent anterior to the beadset, reversal of circumferential-radial shear strain was

7 Ann Thorac Surg LANGER ET AL 2007;84:51 60 ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS 57 Fig 3. Systolic normal strains and shear strains in the midlateral left ventricle (LV) subepicardium (20% wall depth) before and during proximal circumflex (prox. CX) ischemia (left) and before and during proximal left anterior descending (prox. LAD) ischemia (right). Left ventricle pressure (mm Hg) on the right ordinate (black control, red ischemia); circumferential strain (E 11 [A, top row]), fiber strain (E ff [A, bottom row]), longitudinal-radial shear strain (E 23 [B, top row]), and circumferential-radial shear strain (E 13 [B, bottom row]) on the left ordinate are shown as a function of percent cardiac cycle from end diastole (%) on the abscissa. Data are shown during control (black) and ischemia (red) as mean 1SD for 6 animals (three beats each) with cardiac cycle lengths normalized and adjusted with cubic Hermite interpolation in time using five equally spaced time nodes in the cardiac cycle (*p 0.05). CARDIOVASCULAR observed (Figs 2, 3, 4) reflecting the mechanical interaction between adjacent ischemic and nonischemic myocardium with the direction of the shear deformation depending on the location of the adjacent ischemic territory. Previous investigators have sought to characterize the mechanisms that underlie the altered function noted at the junction between ischemic and nonischemic myocardium ( borderzone ). Utilizing a dense epicardial marker array, Van Leuven and colleagues [15] observed strain gradients across the perfusion boundary during acute myocardial ischemia, and postulated a mechanical interaction between the ischemic myocardium and the adja-

8 CARDIOVASCULAR 58 LANGER ET AL Ann Thorac Surg ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS 2007;84:51 60 Fig 4. Circumferential-radial shear alterations in the lateral wall with three distinct coronary occlusions. Proximal circumflex (CX) occlusion increased circumferential radial (CIRC-RAD) shear from control values, while proximal anterior descending (LAD) occlusion reversed CIRC-RAD shear. Occlusion of the distal-cx did not result in altered shear-strain patterns in the midlateral ventricle. cent normally perfused myocardium. More recently, Mazhari and colleagues [16] investigated 3-minute LAD and CX occlusions in open-chest dogs and postulated that abnormal regional mechanics in the acute ischemic border arise from increased wall stress without a transitional zone of intermediate contractility. Other investigators have studied the nonischemic border zone adjacent to a myocardial infarction or LV aneurysm. Jackson and coworkers [17] report increased dynamic wall stress in the borderzone caused by geometric changes (endocardial curvature, wall thinning), with similar findings reported by Moustakidis and associates [18]. On the other hand, Guccione and associates [19] suggest that contractile dysfunction in the borderzone is due to intrinsic changes in the myocardium and not to increased stress; and Moulton and coworkers [20] postulated that increased myofiber stretch during isovolumic contraction contributes to the reduction of systolic fiber shortening in the borderzone. Our present experiment included only brief episodes of ischemia instead of an infarct/aneurysm, and intrinsic myocardial changes were unlikely. Since the strain alterations observed in the present study occurred abruptly, after short 1-minute balloon occlusions, it is difficult to extrapolate findings from chronic infarct studies onto these data. The transmural beads allow direct measurement of myocardial deformations in a specific region. This permits characterization of normal wall-thickening mechanics at baseline [11], and also changes that can occur very rapidly during ischemia [10]. In the present study, contractile dysfunction in the region adjacent to the ischemic zone was not measured per se. Instead, reversal of lateral wall circumferential-radial shear and reduction of longitudinal-radial shear probably reflect the mechanical deformation of the myocardium adjacent to the ischemic zone during acute plad occlusion. These strain alterations reflect the abrupt change in the mechanical interaction between ischemic and nonischemic myocardium as suggested by Van Leuven and colleagues [15], and also possibly increased regional wall stress as suggested by Mazhari and coworkers [16]. Wall stress calculations were not part of our experimental design, and we cannot conjecture on this possibility. Mechanical stimuli have important implications for tissue development, differentiation, disease and regeneration [21]. In a ventricle with more than 60 mechanical deformations per minute, any alterations in the interactions between myocytes and extracellular matrix might have consequences. A fundamental component of the nonischemic infarct extension hypothesis is that mechanical strain alterations trigger molecular remodeling processes that promote global progression of ischemic cardiomyopathy [2, 3, 20]. Specifically, in-vitro studies have shown that altered fiber strains trigger the production of reactive oxygen species, apoptosis and extracellular matrix remodeling [4 9]. Although myocardial fiber architecture and integrity remain initially preserved adjacent to an infarct [2, 3, 20], altered strain patterns adjacent to the ischemic zone may thus represent the first steps in the remodeling process, which progressively evolves into global ischemic cardiomyopathy. The development of rational therapies should therefore be based on improved, integrated insight into remodeling, including both mechanics and bio-

9 Ann Thorac Surg LANGER ET AL 2007;84:51 60 ALTERATIONS IN MYOCARDIAL TRANSMURAL STRAINS Table 6. Transmural Systolic Strains During Distal Circumflex (dcx) Artery-Occlusion pre-dcx dcx 59 p Value CARDIOVASCULAR Cardiac strains Circumferential strain (E 11 ) ns Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) Circumferential-radial shear (E 13 ) ns Circumferential strain (E 11 ) ns Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) ns Circumferential-radial shear (E 13 ) ns Circumferential strain (E 11 ) ns Longitudinal strain (E 22 ) ns Radial strain (E 33 ) ns Circumferential-longitudinal shear (E 12 ) ns Longitudinal-radial shear (E 23 ) ns Circumferential-radial shear (E 13 ) ns Fiber strains Fiber strain (E ff ) ns Fiber strain (E ff ) ns Fiber strain (E ff ) ns ns not significant. chemical pathways of myofilaments, cytoskeleton, extracellular matrix, and myolaminar sheets [22]. Surgical attempts to restore normal LV geometry in patients with ischemic cardiomyopathy [23] may be ineffective because they are performed after the borderzone has undergone deleterious remodeling. Medical therapy (inhibition of matrix metalloproteinases) [8] and surgical approaches (passive LV constraint devices to limit myopathic stretching postinfarction) [24, 25] may be more effective to limit the remodeling process. Study Limitations These data were obtained in a closed-chest sheep model of acute coronary ischemia different from the clinical scenario of acute coronary syndrome. Measurements at baseline and 8 weeks after insertion of the transmural beadset showed that tissue fibrosis or postsurgical adhesions do not influence the results of our deformation measurements [11]. Although additional beadsets would have added more information, technical limitations related to bead implantation and data acquisition precluded such additional beadsets. We appreciate the superb technical support provided by Maggie Brophy, AS, and Katha Gazda, BA. We also appreciate the expertise, collaboration, and support of James W. Covell, MD. Supported by Grants HL-29589/HL from the National Heart, Lung and Blood Institute. Doctors Rodriguez, Langer, and Cheng were Carl and Leah McConnell Cardiovascular Surgical Research Fellows. Doctor Langer was supported by the Deutsche Akademie der Naturforscher Leopoldina, Germany. Doctor Rodriguez was supported by Grant HL S1 from the NHLBI and was a recipient of an American College of Surgeons Resident Research Scholarship Award. Doctor Criscione was supported by Grant Y from the American Heart Association. References 1. Gheorghiade M, Bonow RO. Chronic heart failure in the US: manifestation of coronary artery disease. Circulation 1998; 97: Jackson BM, Gorman JH, Moainie SL, et al. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. J Am Coll Cardiol 2002;40: Ratcliffe MB. Non-ischemic infarct extension. J Am Coll Cardiol 2002;40:

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