- Email: [email protected]
Apex-to-Base Dispersion in Regional Timing of Left Ventricular Shortening and Lengthening
Journal of the American College of Cardiology © 2006 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 47, No. 1, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2005.08.073
EXPEDITED REVIEWS
Apex-to-Base Dispersion in Regional Timing of Left Ventricular Shortening and Lengthening Partho P. Sengupta, MBBS, MD, DM, Bijoy K. Khandheria, MD, FACC, Josef Korinek, MD, Jianwen Wang, MD, PHD, Arshad Jahangir, MD, James B. Seward, MD, FACC, Marek Belohlavek, MD, PHD, FACC Rochester, Minnesota We investigated whether the onset and progression of regional left ventricular (LV) shortening and lengthening parallel the apex-to-base differences in depolarization and repolarization. BACKGROUND Limited information exists regarding apex-to-base differences in longitudinal and circumferential deformation sequence of the LV. METHODS The apex-to-base differences in electric activation and the progression of longitudinal and circumferential shortening and lengthening sequences were determined in 8 porcine beating hearts in situ by implanting bipolar electrodes and an array of 14 sonomicrometry crystals in the LV free wall. RESULTS Electric activation started at the apical subendocardium and showed significant delay in reaching the LV base. The onsets of mechanical activation and subsequent 20%, 40%, and 80% peak longitudinal shortenings required longer time to occur at base compared to the apex. The repolarization sequence propagated in reverse, with the base repolarizing before the apex. Subendocardial longitudinal shortening at base and subepicardial circumferential shortening at apex continued beyond the period of LV ejection, resulting in an apex-to-base gradient in the onset of lengthening. This gradient correlated with the duration of isovolumic relaxation (r ⫽ 0.85, p ⫽ 0.004) and the time required for reaching the lowest LV diastolic pressure (r ⫽ 0.70, p ⫽ 0.04). CONCLUSIONS Apex-to-base delay in mechanical shortening of LV parallels the apex-to-base direction of the electric activation sequence. Basal subendocardial and apical subepicardial regions deform through a characteristic phase of postsystolic shortening. Short-lived apex-to-base and subendocardial-to-subepicardial relaxation gradients at the onset of diastole may have a physiologic significance in facilitating active restoration of the LV cavity in diastole. (J Am Coll Cardiol 2006;47:163–72) © 2006 by the American College of Cardiology Foundation OBJECTIVES
The mechanical activation sequence of the left ventricle (LV) is an important determinant of global LV systolic and diastolic performance and evolves from a close anatomic relationship between the electric and mechanical framework of the myocardial wall. The fascicles of the His-Purkinje See page 173 system are insulated from the surrounding muscle during their course from the crest of the septum toward the ventricular apex (1). This insulation breaks down within the peripheral networks of Purkinje fibers, enabling direct electromechanical coupling at Purkinje-myocyte junctions. The onset of cardiac muscle electric activation begins on the left side of the apical septum in adult mammalian hearts (2) and subsequently spreads from subendocardium to subepicardium and from the apex toward the base (3–5). Mechanical activation of the subendocardium precedes that of the From the Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota. This work was supported by grants HL 70363 and HL68555 from the National Institutes of Health. Manuscript received April 28, 2005; revised manuscript received August 16, 2005, accepted August 22, 2005.
subepicardium (6). Whether the mechanical events also parallel the apex-to-base direction of electric activation remains unclear. Previous experimental studies suggested that a contraction wave travels longitudinally on the LV epicardial surface from the apex toward the base (7–9). Whether a similar sequence of shortening exists in the subendocardial region also remains unknown. Some other investigators have speculated a reverse sequence in which the LV initially contracts circumferentially at the base during isovolumic contraction and then shortens progressively from the base toward the apex, causing longitudinal shortening during ejection (10,11). The basal region of the LV is known to repolarize before the apical region (3). Whether the apex-to-base differences in repolarization also produce apex-to-base variations in the onset of LV lengthening sequences remains uninvestigated. For relating the electrophysiologic sequences with the kinematics of regional LV deformation, a high-temporalresolution technique such as sonomicrometry is required because shortening and lengthening sequences originate rapidly during the isovolumic periods of the cardiac cycle (12). The utility of high-resolution (ⱕ4 ms) sonomicrometry in understanding transient time-related changes in
164
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72 Table 1. Hemodynamic Parameters
Abbreviations and Acronyms ECG ⫽ electrocardiogram IVR ⫽ isovolumic relaxation LV ⫽ left ventricle/ventricular PSS ⫽ postsystolic shortening
cardiac geometry in vivo has been highlighted in recent investigations (12–14). The purpose of this study was to: 1) clarify the apex-versus-base variations in depolarization and repolarization sequences and in the onset and progression of shortening and lengthening, and 2) link these electrophysiologic and mechanical sequences by their selective analysis within the subendocardial and subepicardial regions of LV anterior wall.
METHODS Eight pigs weighing 30 to 60 kg were anesthetized with an infusion of ketamine, fentanyl, and etomidate. After midline sternotomy, a pericardial cradle was constructed and the animals were fully anticoagulated (activated clot times ⬎240 s) with repeated bolus injections of heparin. Three manometer-tipped catheters (Millar Instruments Inc., Houston, Texas) were placed into the LV, aorta, and left atrium. All animals received humane care in accordance with the Principles of Laboratory Animal Care formulated by the Animal Welfare Act in the Guide for Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication #85-23, revised 1996). The protocol used in this investigation was reviewed and approved by the Institutional Animal Care and Use
Figure 1. Arrangement of 14 sonomicrometry crystals in the left ventricular (LV) free wall. The black and gray circles indicate the location of subepicardial and subendocardial crystals and the black lines indicate the pair of crystals used for measuring longitudinal and circumferential deformations. LMCA ⫽ left main coronary artery; RV ⫽ right ventricle.
Hemodynamic Variables Heart rate (beats/min) R-R interval (ms) Isovolumic contraction (ms) Ejection period (ms) Isovolumic relaxation (ms) R-to-lowest LV pressure (ms) Aortic systolic pressure (mm Hg) Aortic diastolic pressure (mm Hg)
Baseline Values 67 ⫾ 7 901 ⫾ 90 66 ⫾ 15 347 ⫾ 16 64 ⫾ 15 497 ⫾ 56 104 ⫾ 7 56 ⫾ 7
LV ⫽ left ventricle.
Committee of the Mayo Clinic College of Medicine, Rochester, Minnesota. Sonomicrometry. Sonomicrometry has been established as the reference method for direct measurement of instantaneous distance between any two miniature (⬃2 mm in diameter) ultrasound crystals implanted within myocardium (12–14). A total of 14 ultrasonic crystals (Sonometrics Corp., London, Ontario, Canada) were placed in the anterior free wall of the LV (Fig. 1). The LV anterior wall was divided into three functional segments—apex, mid, and base—and crystals were placed in the subendocardial and subepicardial regions of each segment along longitudinal and circumferential directions. The longitudinal direction was defined as a line joining the apex and the bifurcation of the left main coronary artery. Crystals implanted orthogonally to the long axis defined the circumferential direction of each segment. The epicardial crystals were secured with 4-0 polypropylene sutures. For placing the subendocardial crys-
Figure 2. Bipolar electrograms obtained from apical and basal segments of the left ventricular free wall. Vertical dotted lines mark the time points of steepest portion of initial bipolar QRS waveforms and end of T-wave. Note the apex-to-base direction of depolarization. The direction is reversed (base to apex) during repolarization in both subendocardium (arrow 1) and subepicardium (arrow 2). ECG ⫽ electrocardiogram.
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
165
Figure 3. Distribution of bipolar electrical activation (A and B) and repolarization (C and D) intervals measured from eight pigs. Data are shown as mean ⫾ SD. Endo and Epi ⫽ subendocardium and subepicardium, respectively. *Apex versus base; †Endocardium versus epicardium (p ⫽ 0.01 and 0.04, respectively, for apex-endo vs. apex-epi and base-endo vs. base-epi electric activation intervals; p ⫽ 0.003 for apex-endo vs. apex-epi repolarization intervals).
tals, the end-diastolic thickness of the myocardium was measured at the site of implantation using a 13-MHz high-resolution linear array transducer (GE Healthcare, Horten, Norway). The epicardial surface was punctured using a needle; the crystals were inserted in the subendocardial region at a desired location using a plastic introducer with a depth marker to assure an appropriate implantation. For timing the differences in depolarization of the apical and basal regions of the LV, bipolar electric signals were recorded from 4 of the 15 implanted crystals, which had special bifilament stainless-steel electrodes sealed on their sides (Sonometrics Corp.). Two of these electrodes were located in crystals placed in the apical and basal segments of the subepicardium while the other two were positioned in the corresponding subendocardial region. Phases of the cardiac cycle. Each phase of the cardiac cycle was defined from aortic and LV pressure curves. The isovolumic contraction period was defined from the Q-wave of the surface electrocardiogram (ECG) to the beginning of ejection indicated by the crossing point of LV and aortic pressure curves. The dicrotic notch in the aortic pressure
curve defined the end-ejection time point. Isovolumic relaxation (IVR) was defined as the interval between the dicrotic notch and the crossover point of the LV and left atrial pressure curves in diastole. Data analysis. The temporal changes in sonomicrometry distances (250 to 300 measurements/s) along with the LV, aortic, left atrial, and surface ECG data were recorded simultaneously and imported into a Microsoft Excel file. Table 2. Peak Circumferential and Longitudinal Strains in Subendocardial and Subepicardial Region of Left Ventricular Anterior Wall Circumferential Apex Mid Base Longitudinal Apex Mid Base
Subendocardium
Subepicardium
p Value
39.2 ⫾ 16.2* 24.8 ⫾ 4.7* 16.1 ⫾ 7.4*
10.2 ⫾ 5.4† 10.4 ⫾ 2.7† 9.1 ⫾ 3.1†
⬍0.001 ⬍0.001 0.02
15.9 ⫾ 8.5 11.3 ⫾ 5.4 9.1 ⫾ 4.6
6.1 ⫾ 2.4 6.0 ⫾ 3.3 4.6 ⫾ 2.7
*p ⬍ 0.001 vs. longitudinal; †p ⬍ 0.01 vs. longitudinal.
0.02 0.04 0.005
166
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Figure 4. Distribution of time intervals for reaching 10%, 20%, 40%, and 80% of peak longitudinal and circumferential shortening in left ventricular subendocardium (A and B) and subepicardium (C and D). Data are shown as mean ⫾ SD. A ⫽ apex; B ⫽ base; M ⫽ mid. *Apex versus base (p ⫽ 0.004, 0.01, 0.02, and 0.06, respectively for 10% to 80% shortening time intervals in panel A; and 0.002, 0.0001, 0.001, and 0.005, respectively, for 10% to 80% shortening time intervals in panel C); †mid versus base (p ⫽ 0.008, 0.02, 0.01, and 0.005, respectively, for 10% to 80% shortening time intervals in panel A; and 0.006, 0.0004, and 0.0004, respectively, for 10% to 40% shortening time intervals in panel C); ‡apex versus mid (p ⬍ 0.0001 for 80% shortening time interval in panel C).
Mechanical activation time was defined on surface ECG as the time required from the onset of Q-wave to reach 10% of the maximum fiber shortening (6). The time required for subsequent 20%, 40%, and 80% peak shortening and the time interval from the dicrotic notch on the aortic pressure tracing to the onset and 20% of lengthening in early diastole were calculated for each pair of sonomicrometry crystal data. We did not choose to compare systolic shortening until the end of shortening (100%) because peak shortening in some segments flattened during peak ejection. The shorteninglengthening crossover point, however, could be accurately measured and indicated the onset of regional lengthening (15). Electric signals from the bipolar electrodes were digitized by an analog-to-digital converter (Sonometrics Corp.). The electric activation interval was defined as the time from the earliest QRS deflection seen on surface ECG lead to the first peak of the derivative of QRS in the regional bipolar deflection. The repolarization time was defined as the time
from the earliest QRS deflection on surface ECG and the steepest terminal phase of the T-wave of the bipolar electrocardiogram (16). A strong correlation exists between the activation-recovery intervals measured from the firstorder derivatives of QRS and T waves on the bipolar electrograms and the refractory periods and transmembrane action potential durations measured directly in cardiac tissues (17,18). Statistical analysis. All data are expressed as mean ⫾ SD. After the data were assessed for possible outliers, the subendocardial and subepicardial electric activation and deformations were compared among the three locations using repeated-measures analysis of variance. If a statistically significant result was obtained, then individual locations were compared by a two-tailed paired t test. Linear regression was used for comparing deformation variables obtained by sonomicrometry with intracardiac pressure tracings obtained simultaneously with Millar catheters and expressed with their correlation coefficient
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Sengupta et al. Timing of LV Deformation
167
Figure 5. Distribution of time intervals for the onset and 20% longitudinal and circumferential lengthening of left ventricular subendocardium (A and B) and subepicardium (C and D). Data are shown as mean ⫾ SD. A ⫽ apex; B ⫽ base; M ⫽ mid. *Apex versus base (p ⫽ 0.002 and ⬍0.0001, respectively, for onsets and 20% lengthening time intervals in panel A and 0.0004 and 0.008, respectively, for onsets and 20% lengthening time intervals in panel D); †mid versus base (p ⫽ 0.0005 and 0.01, respectively, for the onsets and 20% lengthening time intervals in panel A); ‡apex versus mid (p ⫽ 0.006 and 0.001, respectively, for onset and 20% lengthening time intervals in panel D).
(r) and p value. A value of p ⬍ 0.05 was considered statistically significant.
RESULTS All eight pigs were in normal sinus rhythm with normal hemodynamic parameters at the completion of sonomicrometry crystal placement (Table 1). Bipolar electric recordings. The earliest electric activation occurred in the apical subendocardial region (Fig. 2). Activation of apical subepicardium showed a significant delay compared to the subendocardial region. For both layers of the LV wall, depolarization occurred earlier in the apical segment compared to the base, and the basal subepicardial region was last to depolarize (Figs. 3A and 3B). The repolarization time intervals also showed significant regional heterogeneity (Figs. 3C and 3D). No significant differences were seen in timing of repolarization of the basal subendo-
cardial and subepicardial region. Compared to the base, repolarization of the apex was significantly delayed for both subendocardial and subepicardial regions. The longest time for repolarization was seen in the apical subepicardial region. Longitudinal and circumferential shortening. Strains recorded from the endocardium were higher than the corresponding subepicardial region for their absolute values (Table 2). The time intervals required for 10%, 20%, 40%, and 80% shortening of subendocardial longitudinal segments were significantly shorter in the apical and mid segment compared to the base (Fig. 4). Compared to longitudinal shortening, the onset of circumferential shortening was significantly delayed in the apical subendocardial region (47 ⫾ 15 ms vs. 77 ⫾ 34 ms, p ⬍ 0.05). However, the apex-to-base time periods for onset, 20%, 40%, and 80% circumferential subendocardial shortening were not significantly different. For the subepicardium, 10%, 20%, 40%, and 80% longi-
168
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Figure 6. Example of the apex-to-base longitudinal deformation sequence of the subendocardial region of the left ventricular (LV) free wall. Onset of lengthening (arrows) occurs earlier in the apical segment and is delayed in the basal segments into the phase of isovolumic relaxation. Phase 1 ⫽ isovolumic contraction; 2 ⫽ ejection; 3 ⫽ isovolumic relaxation; 4 ⫽ early diastole; 5 ⫽ late diastole. Ao ⫽ aorta; ECG ⫽ electrocardiogram. LA ⫽ left atrium.
tudinal subepicardial shortening occurred at significantly shorter time intervals at the apex compared to the basal segment (Fig. 4). The mid segment showed intermediate features. The initial 10%, 20%, and 40% longitudinal shortening of the mid segment occurred significantly earlier than the base, whereas 80% shortening occurred at time intervals similar to that of the base. The apex-to-base time intervals for the 10%, 20%, 40%, and 80% circumferential subepicardial shortening were not significantly different. Longitudinal and circumferential lengthening. The onset of longitudinal lengthening and subsequent time to reach 20% longitudinal lengthening occurred earlier in the apical subendocardial region and showed a significant delay in the basal subendocardial region (Figs. 5 and 6). The segmental time intervals for onset and initial 20% subendocardial lengthening were similar in the circumferential direction. Relaxation in the subepicardium showed a reverse pattern (Figs. 5 and 7). The circumferential direction showed a base-to-apex gradient at onset and in the initial 20% epicardial lengthening. The time of onset of circumferential lengthening was longest in the apical subepicardial region and was delayed beyond aortic valve closure into IVR and the brief initial period of early diastolic filling (Fig. 8). The proportion of the diastolic period during which postsystolic circumferential contraction persisted in the subepicardium correlated with the time required for reaching the lowest LV pressure in diastole (Fig. 9). Similar correlations
were not seen for postsystolic longitudinal shortening (PSS) of the basal subendocardial region. The apex-to-base delay in the onset of subepicardial circumferential lengthening correlated with the duration of IVR and the time required for reaching the lowest LV diastolic pressure (Fig. 9).
DISCUSSION The present study elucidates the shortening and lengthening sequence of the subendocardial and subepicardial regions of the LV anterior wall in systole and diastole, which parallel the apex-to-base and base-to-apex directions of depolarization and repolarization, respectively. Specifically, we demonstrate that the subepicardial region of the LV apex is last to repolarize and shows circumferential shortening that continues beyond the period of aortic valve closure, that is, persisting into the IVR and an initial portion of early diastole. Figure 10 integrates the subendocardial and subepicardial differences in timing of contraction and relaxation sequences with previous available knowledge about cardiac muscle geometry and the twisting motion of the LV observed in the surgically opened chest (19 –22). Electric sequence. The apex-to-base sequence of depolarization and base-to-apex sequence of repolarization described in our study are consistent with earlier observations in mammalian hearts (1,3–5). The presence of a repolarization gradient between the “epicardium” and the “mid-
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Sengupta et al. Timing of LV Deformation
169
Figure 7. Example of the apex-to-base circumferential deformation sequence of the subepicardial region of the left ventricular (LV) free wall. Onset of lengthening (arrows) occurs earlier in the basal segment and is delayed in the apical segments beyond the phase of isovolumic relaxation into the early diastolic period. Phases 1 to 5 are described in Figure 6.
myocardial region” (M-cells) has been proposed to play a role in the genesis of upright T waves on surface ECG (23). The transmural sequence of repolarization, however, varies in different animal species. Although a repolarization gradient has been described between the subepicardium and subendocardium in mice (3), both regions repolarize at nearly similar time intervals in canine hearts (23). Transmural differences in repolarization of basal regions of LV are not seen using bipolar electrodes in beating canine hearts in situ (16). Thus, our findings regarding the bipolar recordings from the basal region of the LV are consistent with previous observations. The repolarization intervals recorded from the subepicardial region for the LV apex, however, are significantly longer than those of the corresponding subendocardial region. This new finding suggests that the process of repolarization in a beating heart may have further transmural heterogeneity in different regions of the LV. Electromechanical coupling. Following electric activation, the time of onset of cardiac mechanical activity varies for different regions of LV (8) and also transmurally for a given region of LV (24). The heterogeneity in the process of electromechanical coupling has been recently shown to exceed the differences in duration of action potential of different layers of myocardial wall (24). A “well-organized” heterogeneity in electromechanical coupling is thus a char-
acteristic feature and may be a prerequisite for normal performance of the cardiac muscle (25). Our observations suggest that this electromechanical heterogeneity is more evident at the onset of diastole. Because cardiac muscle lengthening is regulated by Ca2⫹ reuptake and extrusion, heterogeneity in calcium homeostasis and intrinsic differences in calcium handling proteins, myosin isoforms and distribution of T-tubules may explain the marked heterogeneity in onset of LV relaxation seen at different regions of LV wall (24 –27). Early diastolic relaxation. In an embryonic trabeculated heart, ventricular filling occurs predominantly in late diastole, primarily because of atrial contraction, and shifts into early diastole after the addition of compacted outer subepicardial layers of myocardial wall (28). A mutant mouse model with underdeveloped outer compact layers of myocardium shows diastolic dysfunction with diminished sucking pressure and reduced force development during ejection (28). Thus, maturation and contributions from different layers of myocardial wall improve diastolic performance of the heart. However, the fundamental interactions between different layers of the myocardial wall remain inadequately characterized. Ashikaga et al. (29) used cineangiographic analysis of implanted transmural markers in the LV wall and reported that the onset of diastole was characterized by a significant stretch along myofibers in the
170
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Figure 8. Comparison of circumferential post-systolic shortening (PSS) in the apical subepicardium with hemodynamic pressure tracings. The repolarization wave in epicardial bipolar tracing (arrow) extends well beyond the aortic valve closure and beyond the T-wave on the surface electrocardiogram. The right panel shows linear regression analysis and correlation between the period of diastole occupied by post-systolic subepicardial contraction (Tpeak, X-axis) in the eight pigs and the diastole time period required for reaching minimum left ventricular (LV) diastolic pressures (TLVmin, Y-axis). Values on both axes are expressed as percentage of the entire diastolic relaxation period. Ao ⫽ aortic; AVO ⫽ aortic valve opening; EMG ⫽ electromyogram; LA ⫽ left atrial; MVO ⫽ mitral valve opening; Tpeak ⫽ time to peak strain; TVLVmin ⫽ time-to-minimum LV pressure.
epicardial layers, whereas the endocardial layers sheared and showed sheet shortening. These observations agree with our findings in the basal LV segments, where we observed early relaxation of the subepicardium in the circumferential direction and shortening of the subendocardium in the longitudinal direction. However, these observations cannot be generalized for the entire length of the LV wall because deformation of the apex proceeds along a reverse sequence, with relaxation of the subendocardium preceding that of the subepicardium. PSS. The occurrence of PSS in healthy subjects was reported by Voigt et al. (30). The role of PSS as a normal physiologic event is further clarified in this investigation. The PSS of the apical subepicardium and basal subendocardium results in the development of an apex-to-base and subendocardial-tosubepicardial gradient of relaxation that probably facilitates rapid expansion of the LV cavity near the apex causing a rapid decrease of LV pressure during IVR. Further shortening of the apical subepicardial fibers is seen during the early diastolic period of LV filling and correlates with the time required by the LV in reaching the lowest diastolic pressure. We speculate that this prolonged mechanical activity of the apical subepicardium represents an active component of LV relaxation that promotes suction in early diastole. The PSS of the apical subepicardium can be considered active because the time required for repolarization is prolonged in the apical subepi-
cardium. The reason for longitudinal PSS of the basal subendocardium, however, remains unclear and may reflect a heterogeneity in the process of electromechanical coupling because a delay in the onset of relaxation here does not match the repolarization sequence. Clinical implications. Meta-analyses of earlier studies suggest that 40% to 50% of patients with heart failure syndrome have diastolic dysfunction, with current estimates ranging up to 74% (31). Our findings highlight that diastolic restoration of the LV is not passive recoil, but involves synergistic utilization of active shorteninglengthening sequences for facilitating expansion of LV cavity near the apex. Loss of active mechanical coordination could contribute to the severity of diastolic dysfunction. For example, the specific role of the LV apex during isovolumic relaxation could explain why diastolic function is impaired markedly after sacrificing the LV apex in a volume reduction surgery, but not during an apex-sparing surgery (14). Another clinical situation that supports the important role of the LV apex in diastolic function is the clinical condition called transient LV apical ballooning syndrome (32). Patients with this recently recognized condition develop transient dysfunction of the LV apex, and 3% to 46% of patients develop pulmonary edema or severe left-sided heart failure; some even require an aortic balloon counterpulsation (32).
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Sengupta et al. Timing of LV Deformation
171
Figure 9. Linear regression analysis and correlation of the apex-to-base difference in the onset of circumferential lengthening (X-axis) with the isovolumic relaxation (IVR) duration (Y-axis, A) and the time interval required for reaching minimum left ventricular (TLVmin) diastolic pressures (Y-axis, B).
These clinical features, however, revert with restoration of normal LV apex function. Methodologic considerations and limitations. Despite the open-chest and -pericardium model being a nonphysiologic condition, the observed apex-to-base sequences of deformation were consistent among all animals. We measured the apex-to-base differences in regional shortening and lengthening in the anterior free wall of the LV. Regional differences from other walls were not addressed in this study. Similarly, temporal differences in rotational motion of the LV (33) were not within the focus of the study and would require further investigations.
CONCLUSIONS During a cardiac cycle, the longitudinal shortening of subendocardial and subepicardial regions of the LV demonstrates apex-to-base temporal gradients that parallel apex-to-base differences in LV depolarization. Repolarization proceeds in a reversed sequence, with the apical subepicardium being last to repolarize. The corresponding subepicardial region shows persisting circumferential shortening beyond the period of aortic valve closure into IVR and the brief initial portion of early diastole. Short-lived apicalto-basal and subendocardial-to-subepicardial relaxation gradients at the onset of diastole may have a physiologic
Figure 10. Integrated overview of the left ventricular mechanical sequence during a cardiac cycle. Electric and mechanical activation are initiated in the apical subendocardial region. The subendocardial myofibers (righthanded helix) shorten, producing a brief twist along the right-handed helix direction during the isovolumic contraction period (phase 1) (33). During ejection (phase 2), the subendocardial and subepicardial layers shorten sequentially from the apex toward the base. The direction of apical twist is along the left-handed helix direction owing to dominating intrinsic twist imparting features of subepicardial myocytes (21), while the basal region torques briefly along the right-handed helical direction. Shortening of the subepicardium near the apex and the subendocardium near the base continues beyond aortic valve closure during the isovolumic relaxation (phase 3). This is accompanied with untwisting of the relaxed subendocardial layer with lengthening and enlargement of the left ventricular (LV) cavity at the apex. Shortening of the subepicardium near the apex continues briefly beyond the isovolumic relaxation period and is accompanied with further opening of the left ventricular cavity during early diastole (phase 4). The subsequent period of diastole is characterized by relaxation in both layers. The relaxation is further facilitated in the later phase of diastole by atrial contraction (phase 5). Phases 1 to 5 are described in Figure 6.
172
Sengupta et al. Timing of LV Deformation
significance in facilitating active restoration of the LV cavity in early diastole. Acknowledgments The authors thank Randall R. Kinnick, Steve Krage, and Kay D. Parker for their technical and veterinary assistance and Jennifer L. Milliken for her secretarial assistance. Reprint requests and correspondence: Dr. Marek Belohlavek, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
REFERENCES 1. Reckova M, Rosengarten C, deAlmeida A, et al. Hemodynamics is a key epigenetic factor in development of the cardiac conduction system. Circ Res 2003;93:77– 85. 2. Scher AM. Studies of the electrical activity of the ventricles and the origin of the QRS complex. Acta Cardiol 1995;50:429 – 65. 3. Liu G, Iden JB, Kovithavongs K, Gulamhusein R, Duff HJ, Kavanagh KM. In vivo temporal and spatial distribution of depolarization and repolarization and the illusive murine T wave. J Physiol 2004;555:267– 79. 4. Sedmera D, Reckova M, Bigelow MR, et al. Developmental transitions in electrical activation patterns in chick embryonic heart. Anat Rec A Discov Mol Cell Evol Biol 2004;280:1001–9. 5. Rothenberg F, Nikolski VP, Watanabe M, Efimov IR. Electrophysiology and anatomy of embryonic rabbit hearts before and after septation. Am J Physiol Heart Circ Physiol 2005;288:H344 –51. 6. Ashikaga H, Omens JH, Ingels NB Jr., Covell JW. Transmural mechanics at left ventricular epicardial pacing site. Am J Physiol Heart Circ Physiol 2004;286:H2401–7. 7. Hotta S. The sequence of mechanical activation of the ventricle. Jpn Circ J 1967;31:1568 –72. 8. Prinzen FW, Augustijn CH, Allessie MA, Arts T, Delhaas T, Reneman RS. The time sequence of electrical and mechanical activation during spontaneous beating and ectopic stimulation. Eur Heart J 1992;13:535– 43. 9. Kirn B, Starc V. Contraction wave in axial direction in free wall of guinea pig left ventricle. Am J Physiol Heart Circ Physiol 2004;287: H755–9. 10. Buckberg GD, Coghlan HC, Torrent-Guasp F. The structure and function of the helical heart and its buttress wrapping. V. Anatomic and physiologic considerations in the healthy and failing heart. Semin Thorac Cardiovasc Surg 2001;13:358 – 85. 11. Torrent-Guasp F, Buckberg GD, Clemente C, Cox JL, Coghlan HC, Gharib M. The structure and function of the helical heart and its buttress wrapping. I. The normal macroscopic structure of the heart. Semin Thorac Cardiovasc Surg 2001;13:301–19. 12. Goetz WA, Lansac E, Lim HS, Weber PA, Duran CM. Left ventricular endocardial longitudinal and transverse changes during isovolumic contraction and relaxation: a challenge. Am J Physiol Heart Circ Physiol 2005;289:H196 –201. 13. Urheim S, Edvardsen T, Steine K, et al. Postsystolic shortening of ischemic myocardium: A mechanism of abnormal intraventricular filling. Am J Physiol Heart Circ Physiol 2003;284:H2343–50. 14. Koyama T, Nishimura K, Soga Y, Unimonh O, Ueyama K, Komeda M. Importance of preserving the apex and plication of the base in left ventricular volume reduction surgery. J Thorac Cardiovasc Surg 2003;125:669 –77.
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72 15. Belohlavek M, Pislaru C, Bae RY, Greenleaf JF, Seward JB. Real-time strain rate echocardiographic imaging: temporal and spatial analysis of postsystolic compression in acutely ischemic myocardium. J Am Soc Echocardiogr 2001;14:360 –9. 16. Anyukhovsky EP, Sosunov EA, Rosen MR. Regional differences in electrophysiological properties of epicardium, midmyocardium, and endocardium. In vitro and in vivo correlations. Circulation 1996;94: 1981– 8. 17. Millar CK, Kralios FA, Lux RL. Correlation between refractory periods and activation-recovery intervals from electrograms: effects of rate and adrenergic interventions. Circulation 1985;72:1372–9. 18. Haws CW, Lux RL. Correlation between in vivo transmembrane action potential durations and activation-recovery intervals from electrograms. Effects of interventions that alter repolarization time. Circulation 1990;81:281– 8. 19. Greenbaum RA, Ho SY, Gibson DG, Becker AE, Anderson RH. Left ventricular fibre architecture in man. Br Heart J 1981;45:248 – 63. 20. Streeter DD Jr., Spotnitz HM, Patel DP, Ross J, Jr., Sonnenblick EH. Fiber orientation in the canine left ventricle during diastole and systole. Circ Res 1969;24:339 – 47. 21. Davis JS, Hassanzadeh S, Winitsky S, et al. The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation. Cell 2001;107:631– 41. 22. Notomi Y, Setser RM, Shiota T, et al. Assessment of left ventricular torsional deformation by Doppler tissue imaging. Validation study with tagged magnetic resonance imaging. Circulation 2005;111: 1141–7. 23. Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998;98:1928 –36. 24. Cordeiro JM, Greene L, Heilmann C, Antzelevitch D, Antzelevitch C. Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle. Am J Physiol Heart Circ Physiol 2004;286:H1471–9. 25. Markhasin VS, Solovyova O, Katsnelson LB, Protsenko Y, Kohl P, Noble D. Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models. Prog Biophys Mol Biol 2003;82:207–20. 26. Laurita KR, Katra R, Wible B, Wan X, Koo MH. Transmural heterogeneity of calcium handling in canine. Circ Res 2003;92:668 –75. 27. Heinzel FR, Bito V, Volders PG, Antoons G, Mubagwa K, Sipido KR. Spatial and temporal inhomogeneities during Ca2⫹ release from the sarcoplasmic reticulum in pig ventricular myocytes. Circ Res 2002;91:1023–30. 28. Ishiwata T, Nakazawa M, Pu WT, Tevosian SG, Izumo S. Developmental changes in ventricular diastolic function correlate with changes in ventricular myoarchitecture in normal mouse embryos. Circ Res 2003;93:857– 65. 29. Ashikaga H, Criscione JC, Omens JH, Covell JW, Ingels NB Jr. Transmural left ventricular mechanics underlying torsional recoil during relaxation. Am J Physiol Heart Circ Physiol 2004;286:H640 –7. 30. Voigt JU, Lindenmeier G, Exner B, et al. Incidence and characteristics of segmental postsystolic longitudinal shortening in normal, acutely ischemic, and scarred myocardium. J Am Soc Echocardiogr 2003;16: 415–23. 31. Burlew BS. Diastolic dysfunction in the elderly—the interstitial issue. Am J Geriatr Cardiol 2004;13:29 –38. 32. Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:858 – 65. 33. Gibbons Kroeker CA, Ter Keurs HE, Knudtson ML, Tyberg JV, Beyar R. An optical device to measure the dynamics of apex rotation of the left ventricle. Am J Physiol 1993;265:H1444 –9.
Vol. 47, No. 1, 2006 ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2005.08.073
EXPEDITED REVIEWS
Apex-to-Base Dispersion in Regional Timing of Left Ventricular Shortening and Lengthening Partho P. Sengupta, MBBS, MD, DM, Bijoy K. Khandheria, MD, FACC, Josef Korinek, MD, Jianwen Wang, MD, PHD, Arshad Jahangir, MD, James B. Seward, MD, FACC, Marek Belohlavek, MD, PHD, FACC Rochester, Minnesota We investigated whether the onset and progression of regional left ventricular (LV) shortening and lengthening parallel the apex-to-base differences in depolarization and repolarization. BACKGROUND Limited information exists regarding apex-to-base differences in longitudinal and circumferential deformation sequence of the LV. METHODS The apex-to-base differences in electric activation and the progression of longitudinal and circumferential shortening and lengthening sequences were determined in 8 porcine beating hearts in situ by implanting bipolar electrodes and an array of 14 sonomicrometry crystals in the LV free wall. RESULTS Electric activation started at the apical subendocardium and showed significant delay in reaching the LV base. The onsets of mechanical activation and subsequent 20%, 40%, and 80% peak longitudinal shortenings required longer time to occur at base compared to the apex. The repolarization sequence propagated in reverse, with the base repolarizing before the apex. Subendocardial longitudinal shortening at base and subepicardial circumferential shortening at apex continued beyond the period of LV ejection, resulting in an apex-to-base gradient in the onset of lengthening. This gradient correlated with the duration of isovolumic relaxation (r ⫽ 0.85, p ⫽ 0.004) and the time required for reaching the lowest LV diastolic pressure (r ⫽ 0.70, p ⫽ 0.04). CONCLUSIONS Apex-to-base delay in mechanical shortening of LV parallels the apex-to-base direction of the electric activation sequence. Basal subendocardial and apical subepicardial regions deform through a characteristic phase of postsystolic shortening. Short-lived apex-to-base and subendocardial-to-subepicardial relaxation gradients at the onset of diastole may have a physiologic significance in facilitating active restoration of the LV cavity in diastole. (J Am Coll Cardiol 2006;47:163–72) © 2006 by the American College of Cardiology Foundation OBJECTIVES
The mechanical activation sequence of the left ventricle (LV) is an important determinant of global LV systolic and diastolic performance and evolves from a close anatomic relationship between the electric and mechanical framework of the myocardial wall. The fascicles of the His-Purkinje See page 173 system are insulated from the surrounding muscle during their course from the crest of the septum toward the ventricular apex (1). This insulation breaks down within the peripheral networks of Purkinje fibers, enabling direct electromechanical coupling at Purkinje-myocyte junctions. The onset of cardiac muscle electric activation begins on the left side of the apical septum in adult mammalian hearts (2) and subsequently spreads from subendocardium to subepicardium and from the apex toward the base (3–5). Mechanical activation of the subendocardium precedes that of the From the Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota. This work was supported by grants HL 70363 and HL68555 from the National Institutes of Health. Manuscript received April 28, 2005; revised manuscript received August 16, 2005, accepted August 22, 2005.
subepicardium (6). Whether the mechanical events also parallel the apex-to-base direction of electric activation remains unclear. Previous experimental studies suggested that a contraction wave travels longitudinally on the LV epicardial surface from the apex toward the base (7–9). Whether a similar sequence of shortening exists in the subendocardial region also remains unknown. Some other investigators have speculated a reverse sequence in which the LV initially contracts circumferentially at the base during isovolumic contraction and then shortens progressively from the base toward the apex, causing longitudinal shortening during ejection (10,11). The basal region of the LV is known to repolarize before the apical region (3). Whether the apex-to-base differences in repolarization also produce apex-to-base variations in the onset of LV lengthening sequences remains uninvestigated. For relating the electrophysiologic sequences with the kinematics of regional LV deformation, a high-temporalresolution technique such as sonomicrometry is required because shortening and lengthening sequences originate rapidly during the isovolumic periods of the cardiac cycle (12). The utility of high-resolution (ⱕ4 ms) sonomicrometry in understanding transient time-related changes in
164
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72 Table 1. Hemodynamic Parameters
Abbreviations and Acronyms ECG ⫽ electrocardiogram IVR ⫽ isovolumic relaxation LV ⫽ left ventricle/ventricular PSS ⫽ postsystolic shortening
cardiac geometry in vivo has been highlighted in recent investigations (12–14). The purpose of this study was to: 1) clarify the apex-versus-base variations in depolarization and repolarization sequences and in the onset and progression of shortening and lengthening, and 2) link these electrophysiologic and mechanical sequences by their selective analysis within the subendocardial and subepicardial regions of LV anterior wall.
METHODS Eight pigs weighing 30 to 60 kg were anesthetized with an infusion of ketamine, fentanyl, and etomidate. After midline sternotomy, a pericardial cradle was constructed and the animals were fully anticoagulated (activated clot times ⬎240 s) with repeated bolus injections of heparin. Three manometer-tipped catheters (Millar Instruments Inc., Houston, Texas) were placed into the LV, aorta, and left atrium. All animals received humane care in accordance with the Principles of Laboratory Animal Care formulated by the Animal Welfare Act in the Guide for Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication #85-23, revised 1996). The protocol used in this investigation was reviewed and approved by the Institutional Animal Care and Use
Figure 1. Arrangement of 14 sonomicrometry crystals in the left ventricular (LV) free wall. The black and gray circles indicate the location of subepicardial and subendocardial crystals and the black lines indicate the pair of crystals used for measuring longitudinal and circumferential deformations. LMCA ⫽ left main coronary artery; RV ⫽ right ventricle.
Hemodynamic Variables Heart rate (beats/min) R-R interval (ms) Isovolumic contraction (ms) Ejection period (ms) Isovolumic relaxation (ms) R-to-lowest LV pressure (ms) Aortic systolic pressure (mm Hg) Aortic diastolic pressure (mm Hg)
Baseline Values 67 ⫾ 7 901 ⫾ 90 66 ⫾ 15 347 ⫾ 16 64 ⫾ 15 497 ⫾ 56 104 ⫾ 7 56 ⫾ 7
LV ⫽ left ventricle.
Committee of the Mayo Clinic College of Medicine, Rochester, Minnesota. Sonomicrometry. Sonomicrometry has been established as the reference method for direct measurement of instantaneous distance between any two miniature (⬃2 mm in diameter) ultrasound crystals implanted within myocardium (12–14). A total of 14 ultrasonic crystals (Sonometrics Corp., London, Ontario, Canada) were placed in the anterior free wall of the LV (Fig. 1). The LV anterior wall was divided into three functional segments—apex, mid, and base—and crystals were placed in the subendocardial and subepicardial regions of each segment along longitudinal and circumferential directions. The longitudinal direction was defined as a line joining the apex and the bifurcation of the left main coronary artery. Crystals implanted orthogonally to the long axis defined the circumferential direction of each segment. The epicardial crystals were secured with 4-0 polypropylene sutures. For placing the subendocardial crys-
Figure 2. Bipolar electrograms obtained from apical and basal segments of the left ventricular free wall. Vertical dotted lines mark the time points of steepest portion of initial bipolar QRS waveforms and end of T-wave. Note the apex-to-base direction of depolarization. The direction is reversed (base to apex) during repolarization in both subendocardium (arrow 1) and subepicardium (arrow 2). ECG ⫽ electrocardiogram.
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
165
Figure 3. Distribution of bipolar electrical activation (A and B) and repolarization (C and D) intervals measured from eight pigs. Data are shown as mean ⫾ SD. Endo and Epi ⫽ subendocardium and subepicardium, respectively. *Apex versus base; †Endocardium versus epicardium (p ⫽ 0.01 and 0.04, respectively, for apex-endo vs. apex-epi and base-endo vs. base-epi electric activation intervals; p ⫽ 0.003 for apex-endo vs. apex-epi repolarization intervals).
tals, the end-diastolic thickness of the myocardium was measured at the site of implantation using a 13-MHz high-resolution linear array transducer (GE Healthcare, Horten, Norway). The epicardial surface was punctured using a needle; the crystals were inserted in the subendocardial region at a desired location using a plastic introducer with a depth marker to assure an appropriate implantation. For timing the differences in depolarization of the apical and basal regions of the LV, bipolar electric signals were recorded from 4 of the 15 implanted crystals, which had special bifilament stainless-steel electrodes sealed on their sides (Sonometrics Corp.). Two of these electrodes were located in crystals placed in the apical and basal segments of the subepicardium while the other two were positioned in the corresponding subendocardial region. Phases of the cardiac cycle. Each phase of the cardiac cycle was defined from aortic and LV pressure curves. The isovolumic contraction period was defined from the Q-wave of the surface electrocardiogram (ECG) to the beginning of ejection indicated by the crossing point of LV and aortic pressure curves. The dicrotic notch in the aortic pressure
curve defined the end-ejection time point. Isovolumic relaxation (IVR) was defined as the interval between the dicrotic notch and the crossover point of the LV and left atrial pressure curves in diastole. Data analysis. The temporal changes in sonomicrometry distances (250 to 300 measurements/s) along with the LV, aortic, left atrial, and surface ECG data were recorded simultaneously and imported into a Microsoft Excel file. Table 2. Peak Circumferential and Longitudinal Strains in Subendocardial and Subepicardial Region of Left Ventricular Anterior Wall Circumferential Apex Mid Base Longitudinal Apex Mid Base
Subendocardium
Subepicardium
p Value
39.2 ⫾ 16.2* 24.8 ⫾ 4.7* 16.1 ⫾ 7.4*
10.2 ⫾ 5.4† 10.4 ⫾ 2.7† 9.1 ⫾ 3.1†
⬍0.001 ⬍0.001 0.02
15.9 ⫾ 8.5 11.3 ⫾ 5.4 9.1 ⫾ 4.6
6.1 ⫾ 2.4 6.0 ⫾ 3.3 4.6 ⫾ 2.7
*p ⬍ 0.001 vs. longitudinal; †p ⬍ 0.01 vs. longitudinal.
0.02 0.04 0.005
166
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Figure 4. Distribution of time intervals for reaching 10%, 20%, 40%, and 80% of peak longitudinal and circumferential shortening in left ventricular subendocardium (A and B) and subepicardium (C and D). Data are shown as mean ⫾ SD. A ⫽ apex; B ⫽ base; M ⫽ mid. *Apex versus base (p ⫽ 0.004, 0.01, 0.02, and 0.06, respectively for 10% to 80% shortening time intervals in panel A; and 0.002, 0.0001, 0.001, and 0.005, respectively, for 10% to 80% shortening time intervals in panel C); †mid versus base (p ⫽ 0.008, 0.02, 0.01, and 0.005, respectively, for 10% to 80% shortening time intervals in panel A; and 0.006, 0.0004, and 0.0004, respectively, for 10% to 40% shortening time intervals in panel C); ‡apex versus mid (p ⬍ 0.0001 for 80% shortening time interval in panel C).
Mechanical activation time was defined on surface ECG as the time required from the onset of Q-wave to reach 10% of the maximum fiber shortening (6). The time required for subsequent 20%, 40%, and 80% peak shortening and the time interval from the dicrotic notch on the aortic pressure tracing to the onset and 20% of lengthening in early diastole were calculated for each pair of sonomicrometry crystal data. We did not choose to compare systolic shortening until the end of shortening (100%) because peak shortening in some segments flattened during peak ejection. The shorteninglengthening crossover point, however, could be accurately measured and indicated the onset of regional lengthening (15). Electric signals from the bipolar electrodes were digitized by an analog-to-digital converter (Sonometrics Corp.). The electric activation interval was defined as the time from the earliest QRS deflection seen on surface ECG lead to the first peak of the derivative of QRS in the regional bipolar deflection. The repolarization time was defined as the time
from the earliest QRS deflection on surface ECG and the steepest terminal phase of the T-wave of the bipolar electrocardiogram (16). A strong correlation exists between the activation-recovery intervals measured from the firstorder derivatives of QRS and T waves on the bipolar electrograms and the refractory periods and transmembrane action potential durations measured directly in cardiac tissues (17,18). Statistical analysis. All data are expressed as mean ⫾ SD. After the data were assessed for possible outliers, the subendocardial and subepicardial electric activation and deformations were compared among the three locations using repeated-measures analysis of variance. If a statistically significant result was obtained, then individual locations were compared by a two-tailed paired t test. Linear regression was used for comparing deformation variables obtained by sonomicrometry with intracardiac pressure tracings obtained simultaneously with Millar catheters and expressed with their correlation coefficient
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Sengupta et al. Timing of LV Deformation
167
Figure 5. Distribution of time intervals for the onset and 20% longitudinal and circumferential lengthening of left ventricular subendocardium (A and B) and subepicardium (C and D). Data are shown as mean ⫾ SD. A ⫽ apex; B ⫽ base; M ⫽ mid. *Apex versus base (p ⫽ 0.002 and ⬍0.0001, respectively, for onsets and 20% lengthening time intervals in panel A and 0.0004 and 0.008, respectively, for onsets and 20% lengthening time intervals in panel D); †mid versus base (p ⫽ 0.0005 and 0.01, respectively, for the onsets and 20% lengthening time intervals in panel A); ‡apex versus mid (p ⫽ 0.006 and 0.001, respectively, for onset and 20% lengthening time intervals in panel D).
(r) and p value. A value of p ⬍ 0.05 was considered statistically significant.
RESULTS All eight pigs were in normal sinus rhythm with normal hemodynamic parameters at the completion of sonomicrometry crystal placement (Table 1). Bipolar electric recordings. The earliest electric activation occurred in the apical subendocardial region (Fig. 2). Activation of apical subepicardium showed a significant delay compared to the subendocardial region. For both layers of the LV wall, depolarization occurred earlier in the apical segment compared to the base, and the basal subepicardial region was last to depolarize (Figs. 3A and 3B). The repolarization time intervals also showed significant regional heterogeneity (Figs. 3C and 3D). No significant differences were seen in timing of repolarization of the basal subendo-
cardial and subepicardial region. Compared to the base, repolarization of the apex was significantly delayed for both subendocardial and subepicardial regions. The longest time for repolarization was seen in the apical subepicardial region. Longitudinal and circumferential shortening. Strains recorded from the endocardium were higher than the corresponding subepicardial region for their absolute values (Table 2). The time intervals required for 10%, 20%, 40%, and 80% shortening of subendocardial longitudinal segments were significantly shorter in the apical and mid segment compared to the base (Fig. 4). Compared to longitudinal shortening, the onset of circumferential shortening was significantly delayed in the apical subendocardial region (47 ⫾ 15 ms vs. 77 ⫾ 34 ms, p ⬍ 0.05). However, the apex-to-base time periods for onset, 20%, 40%, and 80% circumferential subendocardial shortening were not significantly different. For the subepicardium, 10%, 20%, 40%, and 80% longi-
168
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Figure 6. Example of the apex-to-base longitudinal deformation sequence of the subendocardial region of the left ventricular (LV) free wall. Onset of lengthening (arrows) occurs earlier in the apical segment and is delayed in the basal segments into the phase of isovolumic relaxation. Phase 1 ⫽ isovolumic contraction; 2 ⫽ ejection; 3 ⫽ isovolumic relaxation; 4 ⫽ early diastole; 5 ⫽ late diastole. Ao ⫽ aorta; ECG ⫽ electrocardiogram. LA ⫽ left atrium.
tudinal subepicardial shortening occurred at significantly shorter time intervals at the apex compared to the basal segment (Fig. 4). The mid segment showed intermediate features. The initial 10%, 20%, and 40% longitudinal shortening of the mid segment occurred significantly earlier than the base, whereas 80% shortening occurred at time intervals similar to that of the base. The apex-to-base time intervals for the 10%, 20%, 40%, and 80% circumferential subepicardial shortening were not significantly different. Longitudinal and circumferential lengthening. The onset of longitudinal lengthening and subsequent time to reach 20% longitudinal lengthening occurred earlier in the apical subendocardial region and showed a significant delay in the basal subendocardial region (Figs. 5 and 6). The segmental time intervals for onset and initial 20% subendocardial lengthening were similar in the circumferential direction. Relaxation in the subepicardium showed a reverse pattern (Figs. 5 and 7). The circumferential direction showed a base-to-apex gradient at onset and in the initial 20% epicardial lengthening. The time of onset of circumferential lengthening was longest in the apical subepicardial region and was delayed beyond aortic valve closure into IVR and the brief initial period of early diastolic filling (Fig. 8). The proportion of the diastolic period during which postsystolic circumferential contraction persisted in the subepicardium correlated with the time required for reaching the lowest LV pressure in diastole (Fig. 9). Similar correlations
were not seen for postsystolic longitudinal shortening (PSS) of the basal subendocardial region. The apex-to-base delay in the onset of subepicardial circumferential lengthening correlated with the duration of IVR and the time required for reaching the lowest LV diastolic pressure (Fig. 9).
DISCUSSION The present study elucidates the shortening and lengthening sequence of the subendocardial and subepicardial regions of the LV anterior wall in systole and diastole, which parallel the apex-to-base and base-to-apex directions of depolarization and repolarization, respectively. Specifically, we demonstrate that the subepicardial region of the LV apex is last to repolarize and shows circumferential shortening that continues beyond the period of aortic valve closure, that is, persisting into the IVR and an initial portion of early diastole. Figure 10 integrates the subendocardial and subepicardial differences in timing of contraction and relaxation sequences with previous available knowledge about cardiac muscle geometry and the twisting motion of the LV observed in the surgically opened chest (19 –22). Electric sequence. The apex-to-base sequence of depolarization and base-to-apex sequence of repolarization described in our study are consistent with earlier observations in mammalian hearts (1,3–5). The presence of a repolarization gradient between the “epicardium” and the “mid-
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Sengupta et al. Timing of LV Deformation
169
Figure 7. Example of the apex-to-base circumferential deformation sequence of the subepicardial region of the left ventricular (LV) free wall. Onset of lengthening (arrows) occurs earlier in the basal segment and is delayed in the apical segments beyond the phase of isovolumic relaxation into the early diastolic period. Phases 1 to 5 are described in Figure 6.
myocardial region” (M-cells) has been proposed to play a role in the genesis of upright T waves on surface ECG (23). The transmural sequence of repolarization, however, varies in different animal species. Although a repolarization gradient has been described between the subepicardium and subendocardium in mice (3), both regions repolarize at nearly similar time intervals in canine hearts (23). Transmural differences in repolarization of basal regions of LV are not seen using bipolar electrodes in beating canine hearts in situ (16). Thus, our findings regarding the bipolar recordings from the basal region of the LV are consistent with previous observations. The repolarization intervals recorded from the subepicardial region for the LV apex, however, are significantly longer than those of the corresponding subendocardial region. This new finding suggests that the process of repolarization in a beating heart may have further transmural heterogeneity in different regions of the LV. Electromechanical coupling. Following electric activation, the time of onset of cardiac mechanical activity varies for different regions of LV (8) and also transmurally for a given region of LV (24). The heterogeneity in the process of electromechanical coupling has been recently shown to exceed the differences in duration of action potential of different layers of myocardial wall (24). A “well-organized” heterogeneity in electromechanical coupling is thus a char-
acteristic feature and may be a prerequisite for normal performance of the cardiac muscle (25). Our observations suggest that this electromechanical heterogeneity is more evident at the onset of diastole. Because cardiac muscle lengthening is regulated by Ca2⫹ reuptake and extrusion, heterogeneity in calcium homeostasis and intrinsic differences in calcium handling proteins, myosin isoforms and distribution of T-tubules may explain the marked heterogeneity in onset of LV relaxation seen at different regions of LV wall (24 –27). Early diastolic relaxation. In an embryonic trabeculated heart, ventricular filling occurs predominantly in late diastole, primarily because of atrial contraction, and shifts into early diastole after the addition of compacted outer subepicardial layers of myocardial wall (28). A mutant mouse model with underdeveloped outer compact layers of myocardium shows diastolic dysfunction with diminished sucking pressure and reduced force development during ejection (28). Thus, maturation and contributions from different layers of myocardial wall improve diastolic performance of the heart. However, the fundamental interactions between different layers of the myocardial wall remain inadequately characterized. Ashikaga et al. (29) used cineangiographic analysis of implanted transmural markers in the LV wall and reported that the onset of diastole was characterized by a significant stretch along myofibers in the
170
Sengupta et al. Timing of LV Deformation
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Figure 8. Comparison of circumferential post-systolic shortening (PSS) in the apical subepicardium with hemodynamic pressure tracings. The repolarization wave in epicardial bipolar tracing (arrow) extends well beyond the aortic valve closure and beyond the T-wave on the surface electrocardiogram. The right panel shows linear regression analysis and correlation between the period of diastole occupied by post-systolic subepicardial contraction (Tpeak, X-axis) in the eight pigs and the diastole time period required for reaching minimum left ventricular (LV) diastolic pressures (TLVmin, Y-axis). Values on both axes are expressed as percentage of the entire diastolic relaxation period. Ao ⫽ aortic; AVO ⫽ aortic valve opening; EMG ⫽ electromyogram; LA ⫽ left atrial; MVO ⫽ mitral valve opening; Tpeak ⫽ time to peak strain; TVLVmin ⫽ time-to-minimum LV pressure.
epicardial layers, whereas the endocardial layers sheared and showed sheet shortening. These observations agree with our findings in the basal LV segments, where we observed early relaxation of the subepicardium in the circumferential direction and shortening of the subendocardium in the longitudinal direction. However, these observations cannot be generalized for the entire length of the LV wall because deformation of the apex proceeds along a reverse sequence, with relaxation of the subendocardium preceding that of the subepicardium. PSS. The occurrence of PSS in healthy subjects was reported by Voigt et al. (30). The role of PSS as a normal physiologic event is further clarified in this investigation. The PSS of the apical subepicardium and basal subendocardium results in the development of an apex-to-base and subendocardial-tosubepicardial gradient of relaxation that probably facilitates rapid expansion of the LV cavity near the apex causing a rapid decrease of LV pressure during IVR. Further shortening of the apical subepicardial fibers is seen during the early diastolic period of LV filling and correlates with the time required by the LV in reaching the lowest diastolic pressure. We speculate that this prolonged mechanical activity of the apical subepicardium represents an active component of LV relaxation that promotes suction in early diastole. The PSS of the apical subepicardium can be considered active because the time required for repolarization is prolonged in the apical subepi-
cardium. The reason for longitudinal PSS of the basal subendocardium, however, remains unclear and may reflect a heterogeneity in the process of electromechanical coupling because a delay in the onset of relaxation here does not match the repolarization sequence. Clinical implications. Meta-analyses of earlier studies suggest that 40% to 50% of patients with heart failure syndrome have diastolic dysfunction, with current estimates ranging up to 74% (31). Our findings highlight that diastolic restoration of the LV is not passive recoil, but involves synergistic utilization of active shorteninglengthening sequences for facilitating expansion of LV cavity near the apex. Loss of active mechanical coordination could contribute to the severity of diastolic dysfunction. For example, the specific role of the LV apex during isovolumic relaxation could explain why diastolic function is impaired markedly after sacrificing the LV apex in a volume reduction surgery, but not during an apex-sparing surgery (14). Another clinical situation that supports the important role of the LV apex in diastolic function is the clinical condition called transient LV apical ballooning syndrome (32). Patients with this recently recognized condition develop transient dysfunction of the LV apex, and 3% to 46% of patients develop pulmonary edema or severe left-sided heart failure; some even require an aortic balloon counterpulsation (32).
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72
Sengupta et al. Timing of LV Deformation
171
Figure 9. Linear regression analysis and correlation of the apex-to-base difference in the onset of circumferential lengthening (X-axis) with the isovolumic relaxation (IVR) duration (Y-axis, A) and the time interval required for reaching minimum left ventricular (TLVmin) diastolic pressures (Y-axis, B).
These clinical features, however, revert with restoration of normal LV apex function. Methodologic considerations and limitations. Despite the open-chest and -pericardium model being a nonphysiologic condition, the observed apex-to-base sequences of deformation were consistent among all animals. We measured the apex-to-base differences in regional shortening and lengthening in the anterior free wall of the LV. Regional differences from other walls were not addressed in this study. Similarly, temporal differences in rotational motion of the LV (33) were not within the focus of the study and would require further investigations.
CONCLUSIONS During a cardiac cycle, the longitudinal shortening of subendocardial and subepicardial regions of the LV demonstrates apex-to-base temporal gradients that parallel apex-to-base differences in LV depolarization. Repolarization proceeds in a reversed sequence, with the apical subepicardium being last to repolarize. The corresponding subepicardial region shows persisting circumferential shortening beyond the period of aortic valve closure into IVR and the brief initial portion of early diastole. Short-lived apicalto-basal and subendocardial-to-subepicardial relaxation gradients at the onset of diastole may have a physiologic
Figure 10. Integrated overview of the left ventricular mechanical sequence during a cardiac cycle. Electric and mechanical activation are initiated in the apical subendocardial region. The subendocardial myofibers (righthanded helix) shorten, producing a brief twist along the right-handed helix direction during the isovolumic contraction period (phase 1) (33). During ejection (phase 2), the subendocardial and subepicardial layers shorten sequentially from the apex toward the base. The direction of apical twist is along the left-handed helix direction owing to dominating intrinsic twist imparting features of subepicardial myocytes (21), while the basal region torques briefly along the right-handed helical direction. Shortening of the subepicardium near the apex and the subendocardium near the base continues beyond aortic valve closure during the isovolumic relaxation (phase 3). This is accompanied with untwisting of the relaxed subendocardial layer with lengthening and enlargement of the left ventricular (LV) cavity at the apex. Shortening of the subepicardium near the apex continues briefly beyond the isovolumic relaxation period and is accompanied with further opening of the left ventricular cavity during early diastole (phase 4). The subsequent period of diastole is characterized by relaxation in both layers. The relaxation is further facilitated in the later phase of diastole by atrial contraction (phase 5). Phases 1 to 5 are described in Figure 6.
172
Sengupta et al. Timing of LV Deformation
significance in facilitating active restoration of the LV cavity in early diastole. Acknowledgments The authors thank Randall R. Kinnick, Steve Krage, and Kay D. Parker for their technical and veterinary assistance and Jennifer L. Milliken for her secretarial assistance. Reprint requests and correspondence: Dr. Marek Belohlavek, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected].
REFERENCES 1. Reckova M, Rosengarten C, deAlmeida A, et al. Hemodynamics is a key epigenetic factor in development of the cardiac conduction system. Circ Res 2003;93:77– 85. 2. Scher AM. Studies of the electrical activity of the ventricles and the origin of the QRS complex. Acta Cardiol 1995;50:429 – 65. 3. Liu G, Iden JB, Kovithavongs K, Gulamhusein R, Duff HJ, Kavanagh KM. In vivo temporal and spatial distribution of depolarization and repolarization and the illusive murine T wave. J Physiol 2004;555:267– 79. 4. Sedmera D, Reckova M, Bigelow MR, et al. Developmental transitions in electrical activation patterns in chick embryonic heart. Anat Rec A Discov Mol Cell Evol Biol 2004;280:1001–9. 5. Rothenberg F, Nikolski VP, Watanabe M, Efimov IR. Electrophysiology and anatomy of embryonic rabbit hearts before and after septation. Am J Physiol Heart Circ Physiol 2005;288:H344 –51. 6. Ashikaga H, Omens JH, Ingels NB Jr., Covell JW. Transmural mechanics at left ventricular epicardial pacing site. Am J Physiol Heart Circ Physiol 2004;286:H2401–7. 7. Hotta S. The sequence of mechanical activation of the ventricle. Jpn Circ J 1967;31:1568 –72. 8. Prinzen FW, Augustijn CH, Allessie MA, Arts T, Delhaas T, Reneman RS. The time sequence of electrical and mechanical activation during spontaneous beating and ectopic stimulation. Eur Heart J 1992;13:535– 43. 9. Kirn B, Starc V. Contraction wave in axial direction in free wall of guinea pig left ventricle. Am J Physiol Heart Circ Physiol 2004;287: H755–9. 10. Buckberg GD, Coghlan HC, Torrent-Guasp F. The structure and function of the helical heart and its buttress wrapping. V. Anatomic and physiologic considerations in the healthy and failing heart. Semin Thorac Cardiovasc Surg 2001;13:358 – 85. 11. Torrent-Guasp F, Buckberg GD, Clemente C, Cox JL, Coghlan HC, Gharib M. The structure and function of the helical heart and its buttress wrapping. I. The normal macroscopic structure of the heart. Semin Thorac Cardiovasc Surg 2001;13:301–19. 12. Goetz WA, Lansac E, Lim HS, Weber PA, Duran CM. Left ventricular endocardial longitudinal and transverse changes during isovolumic contraction and relaxation: a challenge. Am J Physiol Heart Circ Physiol 2005;289:H196 –201. 13. Urheim S, Edvardsen T, Steine K, et al. Postsystolic shortening of ischemic myocardium: A mechanism of abnormal intraventricular filling. Am J Physiol Heart Circ Physiol 2003;284:H2343–50. 14. Koyama T, Nishimura K, Soga Y, Unimonh O, Ueyama K, Komeda M. Importance of preserving the apex and plication of the base in left ventricular volume reduction surgery. J Thorac Cardiovasc Surg 2003;125:669 –77.
JACC Vol. 47, No. 1, 2006 January 3, 2006:163–72 15. Belohlavek M, Pislaru C, Bae RY, Greenleaf JF, Seward JB. Real-time strain rate echocardiographic imaging: temporal and spatial analysis of postsystolic compression in acutely ischemic myocardium. J Am Soc Echocardiogr 2001;14:360 –9. 16. Anyukhovsky EP, Sosunov EA, Rosen MR. Regional differences in electrophysiological properties of epicardium, midmyocardium, and endocardium. In vitro and in vivo correlations. Circulation 1996;94: 1981– 8. 17. Millar CK, Kralios FA, Lux RL. Correlation between refractory periods and activation-recovery intervals from electrograms: effects of rate and adrenergic interventions. Circulation 1985;72:1372–9. 18. Haws CW, Lux RL. Correlation between in vivo transmembrane action potential durations and activation-recovery intervals from electrograms. Effects of interventions that alter repolarization time. Circulation 1990;81:281– 8. 19. Greenbaum RA, Ho SY, Gibson DG, Becker AE, Anderson RH. Left ventricular fibre architecture in man. Br Heart J 1981;45:248 – 63. 20. Streeter DD Jr., Spotnitz HM, Patel DP, Ross J, Jr., Sonnenblick EH. Fiber orientation in the canine left ventricle during diastole and systole. Circ Res 1969;24:339 – 47. 21. Davis JS, Hassanzadeh S, Winitsky S, et al. The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation. Cell 2001;107:631– 41. 22. Notomi Y, Setser RM, Shiota T, et al. Assessment of left ventricular torsional deformation by Doppler tissue imaging. Validation study with tagged magnetic resonance imaging. Circulation 2005;111: 1141–7. 23. Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 1998;98:1928 –36. 24. Cordeiro JM, Greene L, Heilmann C, Antzelevitch D, Antzelevitch C. Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle. Am J Physiol Heart Circ Physiol 2004;286:H1471–9. 25. Markhasin VS, Solovyova O, Katsnelson LB, Protsenko Y, Kohl P, Noble D. Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models. Prog Biophys Mol Biol 2003;82:207–20. 26. Laurita KR, Katra R, Wible B, Wan X, Koo MH. Transmural heterogeneity of calcium handling in canine. Circ Res 2003;92:668 –75. 27. Heinzel FR, Bito V, Volders PG, Antoons G, Mubagwa K, Sipido KR. Spatial and temporal inhomogeneities during Ca2⫹ release from the sarcoplasmic reticulum in pig ventricular myocytes. Circ Res 2002;91:1023–30. 28. Ishiwata T, Nakazawa M, Pu WT, Tevosian SG, Izumo S. Developmental changes in ventricular diastolic function correlate with changes in ventricular myoarchitecture in normal mouse embryos. Circ Res 2003;93:857– 65. 29. Ashikaga H, Criscione JC, Omens JH, Covell JW, Ingels NB Jr. Transmural left ventricular mechanics underlying torsional recoil during relaxation. Am J Physiol Heart Circ Physiol 2004;286:H640 –7. 30. Voigt JU, Lindenmeier G, Exner B, et al. Incidence and characteristics of segmental postsystolic longitudinal shortening in normal, acutely ischemic, and scarred myocardium. J Am Soc Echocardiogr 2003;16: 415–23. 31. Burlew BS. Diastolic dysfunction in the elderly—the interstitial issue. Am J Geriatr Cardiol 2004;13:29 –38. 32. Bybee KA, Kara T, Prasad A, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:858 – 65. 33. Gibbons Kroeker CA, Ter Keurs HE, Knudtson ML, Tyberg JV, Beyar R. An optical device to measure the dynamics of apex rotation of the left ventricle. Am J Physiol 1993;265:H1444 –9.