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Transmural mechanics at left ventricular epicardial pacing site

Departments of ¹Medicine and ²Bioengineering, University of California, San Diego, La Jolla 92093; and ³Laboratory of Cardiovascular Physiology and Biophysics, Palo Alto Medical Foundation, Research Institute, Palo Alto 94301; and ⁴Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California 94305

Submitted 27 October 2003 ; accepted in final form 22 January 2004

	ABSTRACT

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Left ventricular (LV) epicardial pacing acutely reduces wall thickening at the pacing site. Because LV epicardial pacing also reduces transverse shear deformation, which is related to myocardial sheet shear, we hypothesized that impaired end-systolic wall thickening at the pacing site is due to reduction in myocardial sheet shear deformation, resulting in a reduced contribution of sheet shear to wall thickening. We also hypothesized that epicardial pacing would reverse the transmural mechanical activation sequence and thereby mitigate normal transmural deformation. To test these hypotheses, we investigated the effects of LV epicardial pacing on transmural fiber-sheet mechanics by determining three-dimensional finite deformation during normal atrioventricular conduction and LV epicardial pacing in the anterior wall of normal dog hearts in vivo. Our measurements indicate that impaired end-systolic wall thickening at the pacing site was not due to selective reduction of sheet shear, but rather resulted from overall depression of fiber-sheet deformation, and relative contributions of sheet strains to wall thickening were maintained. These findings suggest lack of effective end-systolic myocardial deformation at the pacing site, most likely because the pacing site initiates contraction significantly earlier than the rest of the ventricle. Epicardial pacing also induced reversal of the transmural mechanical activation sequence, which depressed sheet extension and wall thickening early in the cardiac cycle, whereas transverse shear and sheet shear deformation were not affected. These findings suggest that normal sheet extension and wall thickening immediately after activation may require normal transmural activation sequence, whereas sheet shear deformation may be determined by local anatomy.

epicardial pacing; transmural deformation; fiber; sheet

Several lines of evidence support the concept that transverse shear deformation is required for normal systolic wall thickening (17, 18, 30). Because the LV myocardium consists of helically woven myofibers (25, 31) that are arranged in transversely oriented myocardial sheets (17), transverse shear deformation is anatomically related to myocardial sheet shear, and sheet shear deformation contributes significantly to normal systolic wall thickening (8). Because LV epicardial pacing significantly reduces transverse shear deformation (33), we hypothesized that impaired end-systolic wall thickening at the epicardial pacing site is due to reduction in myocardial sheet shear deformation, resulting in a reduced contribution of sheet shear to wall thickening. We also hypothesized that LV epicardial pacing would reverse transmural mechanical activation sequence and thereby mitigate normal transmural deformation. To test these hypotheses, we investigated the effects of LV epicardial pacing on transmural fiber-sheet mechanics by determining three-dimensional (3-D) finite deformation during normal atrioventricular (AV) conduction and LV epicardial pacing in the anterior wall of normal dog hearts in vivo. Our measurements indicate that impaired end-systolic wall thickening at the epicardial pacing site was not due to selective reduction of sheet shear, but rather resulted from overall depression of fiber-sheet deformation, and relative contributions of sheet strains to wall thickening were maintained. Epicardial pacing also induced reversal of the transmural mechanical activation sequence, which significantly depressed sheet extension and wall thickening early in the cardiac cycle, whereas transverse shear and sheet shear deformation were not affected.

	MATERIALS AND METHODS

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All animal studies were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All protocols were approved by the Animal Subjects Committee of the University of California, San Diego, which is accredited by the American Association for Accreditation of Laboratory Animal Care. A subset of data from the five animals included in this study has been presented previously in our report (2), which described local ventricular deformation during early relaxation under normal AV conduction.

Experimental protocol. The protocol for surgical preparation was described in detail previously (2). Briefly, five adult mongrel dogs (19–28 kg) underwent median sternotomy under general anesthesia, with the LV pressure, central aortic pressure, and the surface ECG monitored throughout the study. Low-dose dopamine (2.5–5.0 µg·kg^–1·min^–1) was administered intravenously to maintain blood pressure in two animals. To measure 3-D myocardial deformation, three transmural columns of four to six 0.8-mm-diameter gold beads and a 1.7-mm-diameter surface gold bead above each column were placed within the anterior wall between the first and the second diagonal branches of the left anterior descending coronary artery (LAD) (Fig. 1A). To provide end points for a LV long axis, 2-mm-diameter gold beads were sutured to the apical dimple (apex bead, Fig. 1A) and on the epicardium at the bifurcation of the LAD and left circumflex coronary arteries (base bead, Fig. 1A). Pacing wire pairs were sutured to the left atrium (LA) and the LV epicardial surface across the triangle of the surface gold beads (Fig. 1A). Atrial pacing was performed by stimulating LA electrodes, and LV epicardial pacing was performed by stimulating both LA and LV electrodes (LA-LV delay = 20–40 ms), via a square-wave, constant-voltage electronic stimulator at a frequency 20% above baseline heart rate to suppress native sinus rhythm. Stimulation parameters (voltage 10% above threshold, duration 8 ms, and frequency) were kept constant in each animal. Each animal was positioned in a biplane radiography system, and synchronous biplane cineradiographic images (125 frames/s) of the bead markers were digitally acquired with mechanical ventilation suspended at end expiration. Image acquisition for the two pacing modes (atrial pacing and LV epicardial pacing) was performed consecutively at the same heart rate to minimize variation in hemodynamic conditions. At the end of the study, the animals were euthanized with pentobarbital sodium and the heart perfusion fixed with 2.5% buffered glutaraldehyde at the end-diastolic pressure measured in the study (2, 39). Because the heart was fixed at end-diastolic pressure, fiber and sheet orientations in the fixed hearts were assumed to represent the fiber-sheet structure in the end-diastolic reference configuration in vivo (2, 8, 32). To avoid the distortional effects of dehydration and shrinkage associated with embedding, histological measurements were obtained using freshly fixed heart tissue. In the transmural block of tissue within the implanted bead set, the mean fiber () and sheet angles () were determined from epicardium to endocardium at every 1-mm-thick section sliced parallel to the epicardial tangent plane (Fig. 1B) (2, 8). The digital images from the biplane X-ray were spherically corrected (2) to reconstruct the 3-D coordinates (20) of the gold bead markers. Continuous, nonhomogeneous transmural distributions of 3-D finite strains were computed (2). Six independent finite strains [circumferential strain (E₁₁), longitudinal strain (E₂₂), radial strain (E₃₃), circumferential-longitudinal shear (E₁₂), longitudinal-radial shear (E₂₃), and circumferential-radial shear (E₁₃)] were computed in the local cardiac coordinate axis (circumferential, longitudinal, and radial, respectively) system (X₁, X₂, X₃) (23), which were subsequently used to compute another set of six finite strains [fiber strain (E_ff), sheet strain (E_ss), strain normal to the sheet plane (E_nn), shear within the sheet plane (E_fs), sheet shear (E_sn), and fiber-normal shear (E_fn)] in the local fiber-sheet coordinate system (X_f, X_s, X_n) (7) through an orthogonal transformation to convert the strain tensor using and at each depth. Finite strains were calculated for each frame (125 frames/s) as a deformed configuration with end diastole as the reference state at three wall depths: 25% (subepicardium), 50% (midwall), and 75% (subendocardium) wall depth from the epicardial surface. End diastole was defined as the time of the peak of the ECG R-wave for atrial pacing and the ventricular pacing artifact (V-spike) for LV epicardial pacing. We chose the V-spike rather than the peak of R-wave as the reference state for LV epicardial pacing because the former reflects the timing of the activation of the pacing site, as opposed to the latter, which represents the timing of activation of the whole ventricle. End systole was derived from the nadir of the dicrotic notch of the central aortic pressure.

View larger version (26K): [in this window] [in a new window]   Fig. 1. A: schematic representation of the left ventricle (LV). X1, circumferential axis; X2, longitudinal axis; X3, radial axis; LAD, left anterior descending; LCx, left circumflex; D1, D2, first and second diagonal branch of LAD, respectively. B: schematic representation of local fiber-sheet axes. Fiber angle () was measured in the X1-X2 plane at each wall depth with reference to positive X1. Sheet angle () was measured in the plane perpendicular to the fiber angle at each wall depth with reference to positive X3. Xf, fiber axis, Xs, sheet axis, Xn, axis oriented normal to the sheet plane. The Xf, Xs, and Xn axes present a Cartesian system (for details, see Ref. 2).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Three cardiac phases are shown. dP/dtmax, LV peak positive developed pressure over time; EC, early contraction phase; Ejection, ejection phase; ER, early relaxation phase; ED, end diastole; ES, end systole; LVPmin, minimum LV pressure.

(1)

It is evident from Eq. 1 that in terms of fiber-sheet coordinates, E₃₃ depends only on the sheet angle () and the fiber-sheet strain components in the (X_s, X_n) plane normal to the local fiber axis, namely E_sn, E_ss, and E_nn (8).

To assess transmural mechanical activation sequence with both pacing modes, mechanical activation time (t_m) was defined as the time to reach 10% of the maximum fiber shortening (E_ff) at each transmural depth. To evaluate the effect of reversed transmural mechanical activation sequence on transmural deformation, transmural mechanical activation strains (E') were defined in both the local cardiac and fiber-sheet coordinate system. With atrial pacing, the reference configuration was t_m at subendocardium and the deformed configuration was mechanical activation time at subepicardium. Conversely, with epicardial pacing, the reference configuration was t_m at subepicardium and the deformed configuration was t_m at the subendocardium. Because transmural mechanical activation sequence propagates from subendocardium to subepicardium with arial pacing, and from subepicardium to subendocardium with epicardial pacing (see RESULTS), E' strains describe mean transmural myocardial deformation when mechanical activation travels between subendocardium and subepicardium.

Statistical analysis. Values are means ± SE unless otherwise specified. A paired t-test was used to compare atrial pacing and LV epicardial pacing for global hemodynamic parameters, time intervals, and each strain component. Two-factor repeated-measures ANOVA was used for the time course analysis, with the effects of pacing mode (atrial vs. LV epicardial pacing) and time on each strain component determined at three depths (subepicardium, midwall, and subendocardium) individually. Statistics were performed using SigmaStat version 3.0 (SPSS; Chicago, IL). Statistical significance was accepted atP < 0.05.

	RESULTS

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Anatomic measurements for these five animals were described previously (2). Briefly, the mean fiber angle ranged approximately from –60° (epicardium) to +60° (endocardium). The mean sheet angle was predominantly negative with smaller variations across the wall (–36° to –2°). The centroid of the bead set was 65 ± 1% of the distance from base bead to apex bead, in the anterior LV free wall 11.5 cm lateral from the LAD. Mean wall thickness at the bead set location was 10 ± 1 mm, and the deepest bead was located at 91 ± 2% wall depth. Global parameters are summarized in Table 1.

View larger version (52K): [in this window] [in a new window]   Fig. 3. Temporal sequence of each strain component. Values are means ± SE (n = 5). Subepicardium, midwall, and subendocardium represents 25%, 50%, and 75% wall depth from the epicardial surface, respectively. The reference state for strain calculation was end diastole for both atrial pacing (peak of the ECG R-wave) and LV epicardial pacing (V-spike). Note different scales for shear and normal strains. A: Cardiac strains; B: fiber-sheet strains.

View larger version (14K): [in this window] [in a new window]   Fig. 4. Transmural delay in mechanical activation time (tm). Values are means ± SE (n = 5). Subepicardium and subendocardium refer to 25% and 75% wall depth, respectively. End diastole was used as the reference state (time 0) for both atrial pacing and LV epicardial pacing. Maximum fiber shortening in atrial pacing and LV epicardial pacing was found near end systole and dP/dtmax, respectively. *P < 0.05 vs. subepicardium of the same pacing mode; P < 0.05 vs. subepicardium of atrial pacing.

	DISCUSSION

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Although the effect of LV epicardial pacing on fiber strain has been described at single selected layers at the pacing site, including the subepicardium (9, 27) and midwall (21, 28, 35, 36), the present study is the first to examine the transmural gradient of fiber-sheet strains at the pacing site.

Mechanism of impaired endocardial wall thickening at the epicardial pacing site. On the basis of reduced transverse shear deformation at the epicardial pacing site, we hypothesized that impaired end-systolic wall thickening results from reduction in myocardial sheet shear. However, our results indicate that impaired end-systolic wall thickening at the epicardial pacing site was not due to selective reduction of sheet shear but rather resulted from overall depression of sheet deformation. In fact, all end-systolic fiber-sheet strains were significantly depressed by epicardial pacing (Table 2). Relative contributions of sheet shear, sheet extension or sheet thickening to wall thickening were consistent with the results of Costa et al. (8) and were not altered significantly by epicardial pacing. These findings imply that impaired wall thickening results from lack of effective myocardial deformation, most likely due to insufficient calcium levels at end systole at the pacing site. Intracellular calcium levels at the pacing site may be depleted by the time LV reaches end systole because the pacing site initiates contraction earlier than the rest of the ventricle, and the time interval from electrical activation to end systole is significantly increased (ED-ES duration, Table 1). Moreover, early myofiber shortening at a pacing site is unloaded (14, 28), and unloaded shortening is associated with increased rates of decay of intracellular calcium transient (38).

Reversal of transmural mechanical activation. Our measurements demonstrate that epicardial pacing reversed the transmural mechanical activation sequence, resulting in an earlier onset of myofiber shortening in the epicardium. Notably, this is the first study to show that the onset of fiber shortening in the subendocardium leads that of the subepicardium and that this mechanical sequence is reversed when the transmural sequence of activation is reversed with epicardial pacing. To assess the effect of reversed transmural mechanical activation sequence on transmural deformation, we defined E', which describe mean transmural myocardial deformation when mechanical activation travels between subendocardium and subepicardium. Because E₂₃ and E_sn were not affected by epicardial pacing, these shear deformations do not depend on the transmural sequence of mechanical activation but depend on the magnitudes of fiber shortening. This finding implies that the direction and the magnitude of sheet shear deformation may be determined by local anatomy and supports the concept that sheet shear deformation is required for normal systolic wall thickening (8, 17, 18, 30). In contrast, other E' strain components were significantly depressed by epicardial pacing. For example, E_ss and E₃₃ were significantly reduced when "afterload" was low. These results suggest that a normal transmural mechanical activation sequence may be required for normal sheet extension and therefore wall thickening. Normal endocardial-epicardial activation sequence may allow optimal coordination of sequential fiber shortening and sheet mechanics across the wall to maximize wall thickening.

Limitations. Our data describe transmural mechanics in the LV midanterior wall from the epicardium to 90% wall depth. Regional and transmural variations should be taken into consideration when these results are extrapolated to other regions of the LV, such as the lateral, posterior wall and the septum. In addition, the 3-D finite strains that we measured in open-chest, anesthetized dogs may not accurately reflect the transmural mechanics in closed-chest, conscious animals. Finally, the magnitude of baseline dP/dt_max and dP/dt_min was relatively high for open-chest dogs in this study, most likely due to dopamine use in two of five animals during surgical procedure, which may have affected the normal transmural mechanics. To minimize the confounding effects of surgery, anesthesia, and dopamine between normal AV conduction and epicardial pacing, two pacing modes were studied consecutively in a short period of time.

In conclusion, we demonstrate that impaired end-systolic wall thickening at the epicardial pacing site was not due to selective reduction of sheet shear but rather resulted from overall depression of fiber-sheet deformation, and relative contributions of sheet strains to wall thickening were maintained. These findings suggest lack of effective end-systolic myocardial deformation at the pacing site, most likely because the pacing site initiates contraction significantly earlier than the rest of the ventricle. Epicardial pacing also induced reversal of the transmural mechanical activation sequence, which significantly depressed sheet extension and wall thickening early in the cardiac cycle, whereas transverse shear and sheet shear deformation were not affected. These findings suggest that normal sheet extension and wall thickening immediately after activation may require normal transmural activation sequence, whereas sheet shear deformation may be determined by local anatomy.

	GRANTS

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This work was supported by National Heart, Lung, and Blood Institute Grants HL-29589 (to N. B. Ingels, Jr.) and HL-32583 (to J. W. Covell). H. Ashikaga is a recipient of the American Heart Association Postdoctoral Fellowship (Western States Affiliate).

	ACKNOWLEDGMENTS

 
We thank Rish Pavelec and Rachel Alexander for excellent managerial and surgical assistance. We also acknowledge outstanding technical assistance of Satoko Nagato for data analysis.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. W. Covell, Dept. of Medicine, Univ. of California, San Diego, 9500 Gilman Dr., 0613J, La Jolla, CA 92093 (E-mail: jcovell{at}ucsd.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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