CLINICAL PERSPECTIVE

This Article Abstract Full Text (PDF) All Versions of this Article: 113/21/2524    most recent CIRCULATIONAHA.105.596502v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Notomi, Y. Articles by Thomas, J. D. Search for Related Content PubMed PubMed Citation Articles by Notomi, Y. Articles by Thomas, J. D. Related Collections Cardio-renal physiology/pathophysiology Echocardiography Related Article

(Circulation. 2006;113:2524-2533.)
© 2006 American Heart Association, Inc.

Imaging

Enhanced Ventricular Untwisting During Exercise

A Mechanistic Manifestation of Elastic Recoil Described by Doppler Tissue Imaging

Yuichi Notomi, MD; Maureen G. Martin-Miklovic, RDCS; Stephanie J. Oryszak, BA, CCRP; Takahiro Shiota, MD; Dimitri Deserranno, PhD; Zoran B. Popovic, MD; Mario J. Garcia, MD; Neil L. Greenberg, PhD; James D. Thomas, MD

From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio. Dr Notomi is currently at The Hayama Heart Center, Kanagawa, Japan.

Correspondence to James D. Thomas, MD, FACC, FAHA, Department of Cardiovascular Medicine/F15, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail thomasj{at}ccf.org

Received October 20, 2005; revision received February 20, 2006; accepted March 10, 2006.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— The cascade of events by which early diastolic left ventricular (LV) filling increases with exercise is not fully elucidated. Doppler tissue imaging (DTI) can detect myocardial motion, including torsion, whereas color M-mode Doppler (CMM) can quantify LV intraventricular pressure gradients (IVPGs).

Methods and Results— Twenty healthy volunteers underwent echocardiographic examination with DTI at rest and during submaximal supine bicycle exercise. We assessed LV long-/short-axis function, torsion, volume, inflow dynamics, and early diastolic IVPG derived from CMM data. LV torsion and untwisting velocity increased with exercise (torsion, 11±4° to 24±8°; untwisting velocity, –2.0±0.7 to –5.6±2.3 rad/s) that was associated with an increase in IVPG (1.4±0.5 to 3.7±1.2 mm Hg). Untwisting in normal subjects occurred during isovolumic relaxation and early filling, significantly before long-axis lengthening or radial expansion. The clinical feasibility of this method was tested in 7 patients with hypertrophic cardiomyopathy (HCM); torsion was higher at rest but did not increase with exercise (16±4° to 14±6°), whereas untwisting was delayed and unenhanced (–1.6±0.8 to –2.3±1.2 rad/s). In concert, IVPG was similar at rest (1.2±0.3 mm Hg), but the exercise response was blunted (1.6±0.8 mm Hg). In normal subjects and HCM patients, there was a similar linear relation between IVPG and untwisting rate, with an overall correlation coefficient of r=0.75 (P<0.0001).

Conclusions— LV untwisting appears to be linked temporally with early diastolic base-to-apex pressure gradients, enhanced by exercise, which may assist efficient LV filling, an effect that appears blunted in HCM. Thus, LV torsion and subsequent rapid untwisting appear to be manifestations of elastic recoil, critically linking systolic contraction to diastolic filling.

Key Words: diastole • echocardiography • exercise • heart failure • physiology

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
During exercise, myocyte shortening and titin compression are greater than in the resting state because of the inotropic effects of increased sympathetic activity and circulating catecholamines, leading to a decreased end-systolic volume. Helically oriented myofibers create left ventricular (LV) torsional deformation^1,2 and allow sarcomeres to shorten uniformly^3,4 and store elastic energy in compressed titin⁵ and transmural shear between the myofibril sheets.⁶ As a result, titin expands with greater force from its shorter end-systolic position, causing myocytes to lengthen more rapidly during exercise,^5,7 thus altering the elastic properties of the LV wall and lowering LV chamber pressure. Exercise has also been shown to increase base-to-apex intraventricular pressure gradients (IVPGs), associated with enhanced acceleration of blood across the mitral valve, allowing filling to be maintained at low left atrial pressure (LAP).⁸ A possible mechanism of IVPGs is dynamic ventricular shape change (ellipticalization) during isovolumic relaxation (IVR),⁹ representing "a complex interaction of torsional and linear deformation...[meaning] that the untwist of the ventricle is a component of the elastic restoring forces."¹⁰ The force or tension in the myocardium cannot be measured in vivo, making it difficult to study mechanistically. Much of the clinical knowledge of early diastole is therefore derived from pressure and transmitral flow measurements,^11–17 enhanced recently by the use of tissue velocities to assess long-axis function.¹⁸ LV untwisting has been shown to be dissociated in time from filling, accentuated by catecholamines,¹⁹ and related to LV pressure decay,²⁰ but the correlation and temporal coupling between untwisting and IVPG have not been shown, particularly with exercise. Doppler tissue imaging (DTI), now widely available in clinical echocardiographs, can yield myocardial velocity with better temporal resolution than magnetic resonance imaging and has recently been shown to measure LV torsion accurately.²¹

Editorial p 2477

Clinical Perspective p 2533

To better assess how LV mechanics in early diastole responds to exercise,²² we investigated the time course of LV untwisting at rest and submaximal exercise in healthy volunteers and in patients with hypertrophic cardiomyopathy (HCM), relating it to LV volume, long- and short-axis function, and LV inflow dynamics, including the IVPG,^9,23 which may be considered a manifestation of diastolic suction.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
Twenty healthy adult volunteers (mean±SD age, 34±7 years; 8 women) had LV torsional deformation assessed by DTI at rest and during supine bicycle exercise. Entry criteria included (1) no evidence of structural cardiovascular disease by 2D echocardiography; (2) the absence of past or present systemic disease; (3) height and weight percentiles within the normal range of age, and weight percentiles within 25% of the height percentile; and (4) normal blood pressure. To assess the feasibility of applying this methodology in the clinical environment, we recruited 7 patients with a clinical and echocardiographic diagnosis of HCM (mean±SD age, 41±9 years; 2 women; P=0.057 [age] and P=0.43 [sex] versus normal subjects). In these patients, the mean resting pressure gradient across the LV outflow tract (LVOT) was 18±24 mm Hg, rising to 33±40 mm Hg (P=0.077) with amyl nitrite. The study protocol was approved by the institutional review board of the Cleveland Clinic Foundation, and written, informed consent was obtained from all subjects before the study.

Exercise Testing
Exercise testing was performed with a supine bicycle (Stress Echo Bed, Medical Positioning, Kansas City, Mo) at an initial workload of 25 W with a 25-W increase in resistance at 2-minute intervals. Lead II of the ECG was monitored continuously, and blood pressure was measured at rest and every minute during testing. Because the focus was on submaximal exercise, when the subject’s heart rate reached 100 bpm, echocardiographic data were collected.

Echocardiography
We collected DTI datasets in the apical, middle, and basal short-axis planes and in the apical 4-chamber plane with a Vivid 7 apparatus (GE Medical Systems, Milwaukee, Wis) with an M3S probe. The velocity range of DTI was set at 16 to 20 cm/s to avoid aliasing. We used internal landmarks to acquire proper short-axis images, as reported recently.²¹ We acquired standard 2D and Doppler data (including pulsed-wave Doppler at LV inflow and outflow and color M-mode Doppler [CMM] along the LV inflow tract) as well. LV end-diastolic and end-systolic volumes and ejection fraction were estimated by a modified Simpson’s rule from apical imaging planes. Stroke volume was measured from systolic velocity in the LVOT. We estimated early diastolic peak IVPG by applying the Euler equation to the transmitral CMM.¹⁶ We also estimated mean LAP by the ratio of peak early filling velocity to flow propagation velocity (ie, [E/Vp]).^24,25 All of these echocardiographic data were obtained at rest and during submaximal exercise.

DTI Data Analysis
LV Torsional Deformation
We defined LV torsion²¹ (in degrees) and torsional velocity (in rad/s, Vtor) as the net difference between the apical and basal LV rotation and rotational velocity (Vrot), respectively: equation

equation

LV rotation was calculated by integrating the LV rotational velocity at each level: equation

LV rotational velocity was calculated from datasets at 4 points on each short-axis DTI image: the septal and lateral regions (Vlat and Vsep, respectively) for tangential velocity, and the anterior and posterior regions (Vant and Vpos, respectively) for radial velocity, to obtain the LV radius [r(t)]: equation

where r₀ is the end-diastolic radius.

LV Long- and Short-Axis Motion and LV Volume
LV long- and short-axis myocardial motion was assessed by averaging the velocities at the most basal, septal, and lateral regions in the 4-chamber DTI image and the difference between anterior and posterior velocities in the midventricular short-axis DTI image. These 2 orthogonal velocity datasets were integrated to obtain both long-axis [L(t)] and short-axis [S(t)] lengths for LV volume estimation. LV volume [V_LV(t)] was calculated as a modified general ellipsoid according to the equation described by Rankin et al²⁶: equation

These analyses were performed with a personal computer equipped with customized software within the EchoPAC platform (GE Medical Systems, Milwaukee, Wis). Temporal plots of myocardial velocities derived from each sample region and the ECG for several cardiac cycles were transferred to a spreadsheet program (Excel 2000, Microsoft Corp, Seattle, Wash) for the aforementioned calculations. All calculations for LV rotation/torsion and long-/short-axis motion were averaged for at least 3 consecutive beats.

For temporal analysis, the time sequence was normalized to the percentage duration of systole, with onset of the ECG QRS interval defining t=0%, and aortic valve closure (from the LVOT velocity) defining end systole, where t=100%. Time intervals are provided in milliseconds as well.

Statistics
All values in Table 1, Figure 6, and the text are given as mean±SD but are shown as mean±SE in Figures 1, 2, 3, and 5. Paired and unpaired t tests were used when appropriate. Linear regression analysis was performed to determine the relation between systolic twisting and diastolic untwisting and between diastolic untwisting and IVPG. For all statistics, values of P<0.05 were considered statistically significant.

View this table: [in this window] [in a new window]   TABLE 1. Response to Exercise in Normal Subjects

View this table: [in this window] [in a new window]   TABLE 1. Continued

View larger version (40K): [in this window] [in a new window]   Figure 1. LV torsional behavior at rest and during exercise in normal subjects. Averaged LV rotational and torsional velocity profiles in 20 subjects are shown, derived from an average of 3 beats each. Upper panels: LV rotational and torsional velocity profiles at rest and during exercise. Lower panels: LV rotation and torsion profiles at rest and during exercise (obtained by integrating each velocity). Blue, light green, dark green, and violet lines indicate apical, middle, and basal rotations and LV torsion, respectively. MC indicates mitral valve closure; AO, aortic valve opening; Ej, peak ejection flow velocity in the outflow tract; AC, aortic valve closure (ie, end systole); MO, mitral valve opening; Pk-IVPG, peak IVPG (the timing is inserted with arrow); Pk-E, peak early filling velocity; and En-E, end of early filling. The time sequence was normalized to systolic duration; ie, t=0 indicates the onset of the QRS interval of the ECG, and t=100, end systole (AC). Error bars are marked at every 10% of systolic duration.

View larger version (25K): [in this window] [in a new window]   Figure 2. Myocardial velocity profile of 3 LV motion components during systole and early diastole in normal subjects. Averaged LV twisting and velocity profiles in 20 subjects are shown, derived from an average of 3 beats each. Long- (red line) and short- (orange line) axis myocardial velocities and the LV torsional velocity (purple line, systolic twisting and diastolic untwisting) profile at rest and during exercise are shown. After the contraction/systolic-twisting phase, the diastolic process has started. LV untwisting precedes both long-axis lengthening and short-axis expansion. During exercise, the LV untwisting velocity was markedly enhanced, keeping the temporal sequence in early diastole. Abbreviations, time sequence, and error bars are the same as in the legend to Figure 1.

View larger version (25K): [in this window] [in a new window]   Figure 3. LV torsion-volume loops at rest and during exercise in normal subjects. Averaged LV torsion and volume profiles in 20 subjects are shown, derived from an average of 3 beats each. The loops start from the onset of the QRS interval (q) and end after early filling (En-E). Upper panels: Relation between LV torsion (in degrees) and LV volume (percent end-diastolic volume, %EDV). Lower panels: Relation between LV torsion (normalized to peak systolic torsion) and LV volume (percent stroke volume, %SV). Pk-UnTw indicates timing of peak LV untwisting velocity; Pk-IVPG, timing of peak IVPG. Other abbreviations are the same as in the legend to figure 1. Error bars are marked at every 10% of systolic duration. Red and blue lines denote systole and early diastole, respectively.

The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

Top Abstract Introduction Methods Results Discussion References

 
DTI was acquired at an average of 148±19 frames per second (ie, a 6.9±0.8-ms interval). Submaximal workload averaged 124±29 W in normal subjects and 114±28 W in patients with HCM (P=0.86 versus controls) without an increase in the LVOT pressure gradient (30±53 mm Hg, P=0.54 versus rest).

Hemodynamic and LV functional responses and LV inflow and myocardial velocity responses to exercise in normal subjects are shown in Table 1. Exercise increased LV ejection and stroke volume (10±14% increase and 20±23% increase, respectively) owing to a decrease in end-systolic volume (19±29% decrease). LV filling increased, characterized by increased early filling (velocity-time integral until peak early filling, 41±38%; E-wave acceleration, 97±65%; and color velocity propagation of early filling, 68±44% increase) owing to an increased IVPG from 1.4±0.5 to 3.7±1.2 mm Hg (190±99% increase). Exercise also decreased isovolumic relaxation time (IVRT) significantly but did not alter LAP in normal subjects.

LV torsion occurred mainly by counterclockwise apical rotation, augmented by somewhat less clockwise basal rotation during systole, reversing abruptly in early diastole (Figure 1). During exercise, LV rotation was augmented at both apical and basal levels (9±3° to 19±7° and –3±2° to –7±4°, respectively; P<0.0001 for both), increasing LV torsion from 11±4° to 24±8°. LV untwisting began just before end systole at rest and during exercise (13±24 and 21±26 ms before aortic valve closure; P<0.03 and P<0.002, respectively).

Enhancement of the 3 components of LV myocardial velocity (ie, long axis, short axis, and LV twisting) in normal subjects is shown in Figure 2. Although each velocity component rose with exercise, LV systolic twisting velocity (135±107%) increased significantly more than did long-axis shortening (42±23%) and short-axis contraction (42±31%) during systole (P=0.0013 and 0.0014, respectively), whereas LV untwisting velocity was similarly more augmented (197±120%) than early diastolic long-axis lengthening (40±28%) and short-axis expansion (82±46%) (P=0.0001 and 0.003, respectively). In these normal subjects, maximum ventricular untwisting occurred around the time of mitral valve opening, shortening further during exercise (P<0.005). Importantly, peak IVPG, shown previously to occur between mitral valve opening and peak early filling,¹¹ was significantly later than peak ventricular untwisting (P<0.02 at rest and P<0.01 during exercise). Thus, peak untwisting precedes peak IVPG, which in turn precedes peak early filling (P<0.0001 at rest and exercise). In contrast, peak long-axis lengthening and short-axis expansion tracked transmitral filling quite closely, with their peak velocities occurring virtually synchronously with peak E velocity, suggesting that these are a consequence rather than a cause of transmitral filling.

To describe the relation between LV torsion and volume (derived from the long- and short-axis dimensions), we constructed LV torsion-volume loops (Figure 3). During systole, the relation between increasing torsion and decreasing volume was nearly linear, whereas during diastole, the relation between rapid untwisting (uncoiling) and increasing volume was distinctly nonlinear. Considering absolute values, the upper panels of Figure 3 show that exercise impacted torsion much more than LV volumes; however, when the torsion-volume loops were normalized to the peak torsion and stroke volume, the exercise loop was very similar to the resting one (Figure 3, lower panels).

Approximately 40% (at rest) and 30% (during exercise) of LV untwisting occurred during IVR, reaching a maximum just after mitral valve opening, when 20% of the stroke volume had entered the LV. By the peak of the E wave, 80% to 90% of untwisting was completed and was essentially finished by the end of the E wave, with the subsequent LV volume increase due to expansion in the short and long axes. Interestingly, the timing of peak IVPG occurred near the point of maximal curvature in the diastolic torsion-volume segment.

Figure 4A relates maximum systolic torsion to peak untwisting velocity, with a strong linear correlation both at rest and during exercise. Figure 4B extends this temporally, showing that peak untwisting is predictive of peak IVPG at rest and especially with exercise.

View larger version (18K): [in this window] [in a new window]   Figure 4. Relation between peak systolic torsion, peak diastolic untwisting velocity, and peak IVPG, estimated by the Euler equation applied to CMM data at rest and during exercise in normal subjects. Open/closed squares indicate rest/exercise.

Table 2 shows the correlations between peak untwisting and other parameters of diastolic function, including E-wave velocity, acceleration, timing, and long- and short-axis expansion. Note that a number of correlations did not reach statistical significance for rest and/or exercise alone, likely due to the relatively homogeneous sample of normal volunteers, but these became highly significant when rest and exercise were pooled.

View this table: [in this window] [in a new window]   TABLE 2. Correlation Between LV Untwisting Velocity and Diastolic Function Indices

HCM Patients
Acquisition of all echocardiographic data for this protocol was feasible in all 7 HCM patients both at rest and during exercise.

In contrast to Figure 3, the HCM patients showed delayed untwisting that was not significantly augmented with exercise (Figure 5). Indeed, the timing of peak untwisting was almost coincident with peak early filling (peak untwisting versus peak early filling, 136±17% of systolic duration versus 140±8% at rest, P=0.646; 140±17% versus 137±6% during exercise, P=0.667).

View larger version (23K): [in this window] [in a new window]   Figure 5. Myocardial velocity profile of 3 LV motion components during systole and early diastole and a torsion-volume loop for patients with HCM. Averaged data from 7 subjects are shown, each derived from an average of 3 beats. The color of the line for each myocardial velocity, abbreviations, and the color of the line in the torsion-volume loop are same as in Figures 1 and 3. The time sequence was also normalized to systolic duration. Note the lesser enhancement of LV untwisting, compared with that of normal subjects’ response shown in Figure 1.

Overall, peak systolic torsion was greater than that in normal subjects at rest, but it was less efficient at generating untwisting and was not augmented by exercise (Figure 6A). At rest, peak untwisting velocity was slightly lower in HCM than in normal subjects (–1.6±0.8 versus –2.0±0.7 rad/s, P=0.200), as was the peak IVPG (1.2±0.3 versus 1.4±0.5 mm Hg, P=0.288). These differences became more dramatic with exercise, however, with the HCM patients showing much lower untwisting velocities (–2.3±1.2 versus –5.6±2.3 rad/s, P<0.0001) and IVPGs (1.6±0.8 versus 3.7±1.2 mm Hg, P<0.0001; Figure 6B). Interestingly, at both rest and during exercise, the data points relating untwisting velocity and IVPG lay along a regression line not significantly different from that for normal subjects.

View larger version (16K): [in this window] [in a new window]   Figure 6. Response of peak systolic twisting, untwisting velocity, and IVPGs to exercise in normal subjects and in patients with HCM. Open/closed squares/triangles indicate rest/exercise in normal subjects/exercise in HCM. NS indicates not significant.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study has described, at rest and during exercise, the quantitative and temporal relation of LV torsion to the dynamic events of early diastole, in particular IVPG. LV systolic torsion and rapid untwisting increased significantly with exercise, storing additional potential energy, which was released as increased diastolic suction. LV untwisting started near end systole until just after mitral valve opening, a critical interval for pressure decay in the LV and effective ventricular filling, particularly during exercise. By making the link between systolic torsion and untwisting velocity and subsequently IVPG and diastolic filling, we believe we have shown a potential mechanistic connection between systolic events and diastolic dysfunction.

Courtois et al¹¹ measured IVPG, assuming that IVPGs reflected released energy from elastic recoil.²³ However, no study to date has directly related IVPG to elastic recoil from ventricular untwisting. Importantly, all measurements were made with commercially available echocardiography systems. Indeed, the approach worked well in the complex geometry of HCM, wherein we showed that both untwisting and IVPG were severely reduced with exercise but that the quantitative relation between untwisting and IVPG was indistinguishable from that of normal subjects, lending confidence that this is a true mechanistic relation.

Systolic Torsion for Diastolic Untwisting
During exercise, stroke volume increased by 20%, with a concomitant reduction in end-systolic volume. Nikolic et al¹² and Yellin et al²⁷ have demonstrated that the restoring force magnitude is inversely related to end-systolic volume. The actual location of this elastic storage remains controversial, but it likely involves both the myocyte and the myocardial interstitium. Helmes et al⁵ cite titin-based restoring forces at the sarcomere level, showing that the relengthening velocity of the sarcomere is inversely related to end-systolic length, a microscopic analogy of ventricular contraction below equilibrium volume. Conversely, Ashikaga et al⁶ have shown significant deformation within the myocardium as the counterwound helixes contract against each other, storing significant energy in the interstitium as a global LV "spring".^28,29 Extending our previous observations that IVPG increases with improvement in systolic function after revascularization,¹⁷ we now show that torsion and untwisting appear to be the mechanism by which systolic contraction contributes to IVPG, thereby linking systole and diastole.

We have previously shown³⁰ that peak diastolic annular movement precedes peak early filling in normal subjects. The present study shows that peak untwisting occurs 60 ms earlier than long-axis lengthening or short-axis expansion at rest and exercise, indicating the importance of this mechanical sequence for relaxation and suction. The occurrence of untwisting before filling¹⁹ and radial expansion³¹ has been reported in dogs and in studies with implanted markers^31–33 and magnetic resonance imaging tissue tagging^19,20,34,35; our results are consistent, providing data in normal humans and those with HCM. Although a full study of HCM pathophysiology awaits a larger dedicated study, our feasibility data are intriguing, with torsion higher than in normal subjects at rest (as Young et al³⁶ reported) but with delayed and depressed untwisting, reflecting ineffective uncoiling of the myocardium.³⁷ Moreover, during exercise, the HCM ventricle failed to increase torsion, untwisting, and IVPG, consistent with the report of Ciampi et al³⁸ on exercise-induced systolic dysfunction in HCM, thus providing an explanation for the diastolic dysfunction commonly seen in this disorder. Delayed LV untwisting was also reported to cause abnormal relaxation in aortic stenosis,³⁹ confirming the importance of this temporal sequence to normal diastolic function. Using these methods to explore exercise tolerance in patients with heart disease^22,40 is an important future study. The high-frame-rate nature of this methodology is also suitable to exploration of ventricular activation and isovolumic contraction. For example, the initial small negative torsion shown in Figures 1 through 3 may be explained by electrical activation beginning in the endocardium.²

Diastolic Untwisting for LV Suction
"Suction" is a term often used variously in diastolic function, sometimes referring to the relaxation of small, nonfilling ventricles to subatmospheric pressure, as shown well by Yellin et al,²⁷ and sometimes referring to the "negative compliance" of the ventricle in early diastole, when pressure continues to drop despite an increase in volume. Here we refer to the way IVPG promotes the movement of blood to the apex, allowing efficient filling at low mean LAP. The present study shows that 40% of LV untwisting occurs by the time of mitral valve opening both at rest and during exercise in normal subjects. IVRT is determined by the rate of LV pressure decay and LAP. During exercise, the shortened IVRT caused by the increased rate of LV pressure decay without an elevated LAP helps to prolong the suction phase, which we consider to include IVRT and the acceleration phase of early filling (acknowledging that the influence of IVPG is not so precisely delimited in time). Furthermore, in normal subjects, the torsion-volume loop (Figure 3) shows that rapid untwisting continues after mitral valve opening, so that an additional 40% of the untwisting occurs by the time of peak early filling, reflecting the time during which IVPGs are present within the ventricle. In other words, the potential energy stored during systole is converted to kinetic energy during early diastole, thus effectively bridging the 2 periods. Lele et al⁴¹ reported that the inability to increase filling without a significant rise in LAP was a major limitation of peak exercise capacity. One way to quantify this suction is to recognize the "hysteresis" between systole and diastole in the torsion-volume loop (in essence, looking at the area enclosed by the loop and viewing LV torsional deformation as a process of intrinsic loading/unloading [storing/restoring force] producing LV "suction work" [or filling work]; Figure 3, upper panels) Interestingly, HCM patients showed delayed and depressed untwisting and a loop with a much less enclosed area (Figure 4). Further assessment of LV torsional mechanics by this loop quantification in various disease states is a promising area for future study.

Because the rate of LV filling increased with exercise, it is possible that the more rapid decline in LV pressure with exercise would not continue after mitral valve opening unless aided by other factors. As shown in Figure 3, the rapid untwisting (against volume change) occurs in normal subjects during IVRT and the subsequent suction phase until peak IVPG, where the torsion-volume loop shows an inflection point. The temporal sequence of peak untwisting velocity, peak IVPG, and peak early filling velocity argue for mechanohemodynamic causality (like a cascade effect) in early diastole.

It is unknown whether early diastolic ventricular untwisting would also be observed in a preparation of nonfilling diastole.²⁷ Nikolic et al¹² observed that the equilibrium volume–end-systolic volume difference was 45% of stroke volume. This volume corresponds to 50% to 60% of untwisting, where IVPG nears a maximum (Figure 3).

This untwisting progression is comparable to the pressure decay seen in the apical LV.¹¹ That is, the first 40% of LV untwisting contributes to the large rapid pressure fall of IVRT, and the next 40% of untwisting produces an additional pressure fall, as well as the LV suction to pull blood efficiently into the apex. In this way, LV untwisting can be correlated with both the relaxation time constant (during IVR)²⁰ and IVPG (after mitral valve opening to peak early filling), as we have shown here.

Apical rotation is the main creator of global LV systolic twist, and apical backrotation also plays the dominant role in the subsequent diastole. The rapid apical backrotation reduces wall stress and causes a faster decline in LV pressure while creating the IVPG, pulling blood into the apex without an increase in LAP, even during exercise. Although a similar peak early filling velocity was observed in HCM subjects during exercise, these appeared to result from an elevated LAP and not an increased IVPG. Davis et al⁴² and Steine et al¹⁵ have previously speculated on the importance of apical relaxation for LV suction. Thus, it is now reasonable to conceptualize enhanced ventricular untwisting as a mechanistic manifestation of elastic recoil.

Limitations
There are inherent limitations to 2D echocardiography in attempting to define 3D deformation. We took care to orient our scan accurately, but some misalignment is inevitable, particularly during exercise.

LV torsion was derived from multiple DTI images, which because of the Doppler effect only capture the component of velocity parallel to the ultrasound beam. However, our method isolates both the rotational velocity and radial motion to be aligned with the beam. Future work in non-Doppler velocimetry (eg, B-mode speckle tracking⁴³) might resolve this issue further, whereas use of 3D datasets would allow determination of torsion from a single dataset. The effect of maximal exercise was beyond the scope of the present study, but DTI has sufficient temporal resolution to study this, although excessive respiratory movement may degrade the images somewhat. LV torsion and volume assessment during maximal dobutamine infusion might overcome this obstacle. The relevance to invasively measured tau is also interesting, but we did not invasively measure that parameter in this study.

Conclusions
LV untwisting (1) occurs from end systole until just after mitral valve opening; (2) precedes the peak IVPG, which itself precedes peak early filling and LV dilation and lengthening; (3) increases with submaximal exercise more significantly than does LV lengthening or expansion; (4) provides a mechanistic link between systolic torsion and IVPG at rest and during exercise in normal subjects; and (5) plays a similar role in HCM, even though it is delayed and unenhanced in this disorder.

Thus, we believe that LV untwisting during IVRT facilitates LV suction by generating IVPG, with enhancement during exercise. LV untwisting appears to be a measurable manifestation of elastic recoil.

	Acknowledgments

 
Sources of Funding

Dr Notomi is funded through a postdoctoral fellowship grant of the Ohio Valley affiliate of the American Heart Association (0325237B), and the present study is part of that grant. This work supported by the National Space Biomedical Research Institute through NASA NCC 9-58, Department of Defense (Ft Dietrick, Md; USAMRMC grant No. 02360007), National Institutes of Health (NIH) grant AG17479-02. This work was also supported in part by the NIH, National Center for Research Resources, General Clinical Research Center grant MO1 RR-018390, and by an equipment grant from General Electric (Milwaukee, Wis).

Disclosures

James D. Thomas has received research support and lecture honoraria from General Electric. The other authors report no conflicts.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. 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: 339–347.[Abstract/Free Full Text]
   
2. Ingels NB Jr, Hansen DE, Daughters GT 2nd, Stinson EB, Alderman EL, Miller DC. Relation between longitudinal, circumferential, and oblique shortening and torsional deformation in the left ventricle of the transplanted human heart. Circ Res. 1989; 64: 915–927.[Abstract/Free Full Text]
   
3. Arts T, Veenstra PC, Reneman RS. Epicardial deformation and left ventricular wall mechanisms during ejection in the dog. Am J Physiol. 1982; 243: H379–H390.[Medline] [Order article via Infotrieve]
   
4. Arts T, Reneman RS. Dynamics of left ventricular wall and mitral valve mechanics—a model study. J Biomech. 1989; 22: 261–271.[CrossRef][Medline] [Order article via Infotrieve]
   
5. Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003; 121: 97–110.[Abstract/Free Full Text]
   
6. 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–H647.[Abstract/Free Full Text]
   
7. Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res. 2004; 94: 284–295.[Abstract/Free Full Text]
   
8. Rovner A, Greenberg NL, Thomas JD, Garcia MJ. Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure. Am J Physiol Heart Circ Physiol. 2005; 289: H2081–H2088.[Abstract/Free Full Text]
   
9. Nikolic SD, Feneley MP, Pajaro OE, Rankin JS, Yellin EL. Origin of regional pressure gradients in the left ventricle during early diastole. Am J Physiol. 1995; 268: H550–H557.[Medline] [Order article via Infotrieve]
   
10. Nikolic SD, Yellin EL, Dahm M, Pajaro O, Frater RW. Relationship between diastolic shape (eccentricity) and passive elastic properties in canine left ventricle. Am J Physiol. 1990; 259: H457–H463.[Medline] [Order article via Infotrieve]
    
11. Courtois M, Kovacs SJ Jr, Ludbrook PA. Transmitral pressure-flow velocity relation: importance of regional pressure gradients in the left ventricle during diastole. Circulation. 1988; 78: 661–671.[Abstract/Free Full Text]
    
12. Nikolic S, Yellin EL, Tamura K, Vetter H, Tamura T, Meisner JS, Frater RW. Passive properties of canine left ventricle: diastolic stiffness and restoring forces. Circ Res. 1988; 62: 1210–1222.[Abstract/Free Full Text]
    
13. Thomas JD, Choong CY, Flachskampf FA, Weyman AE. Analysis of the early transmitral Doppler velocity curve: effect of primary physiologic changes and compensatory preload adjustment. J Am Coll Cardiol. 1990; 16: 644–655.[Abstract]
    
14. Cheng CP, Igarashi Y, Little WC. Mechanism of augmented rate of left ventricular filling during exercise. Circ Res. 1992; 70: 9–19.[Abstract/Free Full Text]
    
15. Steine K, Stugaard M, Smiseth OA. Mechanisms of retarded apical filling in acute ischemic left ventricular failure. Circulation. 1999; 99: 2048–2054.[Abstract/Free Full Text]
    
16. Greenberg NL, Vandervoort PM, Firstenberg MS, Garcia MJ, Thomas JD. Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol. 2001; 280: H2507–H2515.[Abstract/Free Full Text]
    
17. Firstenberg MS, Smedira NG, Greenberg NL, Prior DL, McCarthy PM, Garcia MJ, Thomas JD. Relationship between early diastolic intraventricular pressure gradients, an index of elastic recoil, and improvements in systolic and diastolic function. Circulation. 2001; 104 (suppl I): I-330–I-335.[Medline] [Order article via Infotrieve]
    
18. Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol. 1998; 32: 865–875.[Abstract/Free Full Text]
    
19. Rademakers FE, Buchalter MB, Rogers WJ, Zerhouni EA, Weisfeldt ML, Weiss JL, Shapiro EP. Dissociation between left ventricular untwisting and filling: accentuation by catecholamines. Circulation. 1992; 85: 1572–1581.[Abstract/Free Full Text]
    
20. Dong SJ, Hees PS, Siu CO, Weiss JL, Shapiro EP. MRI assessment of LV relaxation by untwisting rate: a new isovolumic phase measure of tau. Am J Physiol Heart Circ Physiol. 2001; 281: H2002–H2009.[Abstract/Free Full Text]
    
21. Notomi Y, Setser RM, Shiota T, Martin-Miklovic MG, Weaver JA, Popovic ZB, Yamada H, Greenberg NL, White RD, Thomas JD. Assessment of left ventricular torsional deformation by Doppler tissue imaging: a validation study using tagged magnetic resonance imaging. Circulation. 2005; 111: 1141–1147.[Abstract/Free Full Text]
    
22. Little WC, Kitzman DW, Cheng CP. Diastolic dysfunction as a cause of exercise intolerance. Heart Fail Rev. 2000; 5: 301–306.[CrossRef][Medline] [Order article via Infotrieve]
    
23. Courtois M, Kovacs SJ, Ludbrook PA. Physiological early diastolic intraventricular pressure gradient is lost during acute myocardial ischemia. Circulation. 1990; 81: 1688–1696.[Abstract/Free Full Text]
    
24. Garcia MJ, Ares MA, Asher C, Rodriguez L, Vandervoort P, Thomas JD. An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol. 1997; 29: 448–454.[Abstract]
    
25. Firstenberg MS, Levine BD, Garcia MJ, Greenberg NL, Cardon L, Morehead AJ, Zuckerman J, Thomas JD. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers. J Am Coll Cardiol. 2000; 36: 1664–1669.[Abstract/Free Full Text]
    
26. Rankin JS, McHale PA, Arentzen CE, Ling D, Greenfield JC Jr, Anderson RW. The three-dimensional dynamic geometry of the left ventricle in the conscious dog. Circ Res. 1976; 39: 304–313.[Abstract/Free Full Text]
    
27. Yellin EL, Hori M, Yoran C, Sonnenblick EH, Gabbay S, Frater RW. Left ventricular relaxation in the filling and nonfilling intact canine heart. Am J Physiol. 1986; 250: H620–H629.[Medline] [Order article via Infotrieve]
    
28. Robinson TF, Factor SM, Sonnenblick EH. The heart as a suction pump. Sci Am. 1986; 254: 84–91.[Medline] [Order article via Infotrieve]
    
29. Krams R, Janssen M, Van der Lee C, Van Meegen J, De Jong JW, Slager CJ, Verdouw PD. Loss of elastic recoil in postischemic myocardium induces rightward shift of the systolic pressure-volume relationship. Am J Physiol. 1994; 267: H1557–H1564.[Medline] [Order article via Infotrieve]
    
30. Garcia MJ, Rodriguez L, Ares M, Griffin BP, Thomas JD, Klein AL. Differentiation of constrictive pericarditis from restrictive cardiomyopathy: assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol. 1996; 27: 108–114.[Abstract]
    
31. Beyar R, Yin FC, Hausknecht M, Weisfeldt ML, Kass DA. Dependence of left ventricular twist-radial shortening relations on cardiac cycle phase. Am J Physiol. 1989; 257: H1119–H1126.[Medline] [Order article via Infotrieve]
    
32. Moon MR, Ingels NB Jr, Daughters GT 2nd, Stinson EB, Hansen DE, Miller DC. Alterations in left ventricular twist mechanics with inotropic stimulation and volume loading in human subjects. Circulation. 1994; 89: 142–150.[Abstract/Free Full Text]
    
33. Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H, LeWinter MM. Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res. 2000; 87: 235–240.[Abstract/Free Full Text]
    
34. Dong SJ, Hees PS, Huang WM, Buffer SA Jr, Weiss JL, Shapiro EP. Independent effects of preload, afterload, and contractility on left ventricular torsion. Am J Physiol. 1999; 277: H1053–H1060.[Medline] [Order article via Infotrieve]
    
35. Rosen BD, Gerber BL, Edvardsen T, Castillo E, Amado LC, Nasir K, Kraitchman DL, Osman NF, Bluemke DA, Lima JA. Late systolic onset of regional LV relaxation demonstrated in three-dimensional space by MRI tissue tagging. Am J Physiol Heart Circ Physiol. 2004; 287: H1740–H1746.[Abstract/Free Full Text]
    
36. Young AA, Kramer CM, Ferrari VA, Axel L, Reichek N. Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy. Circulation. 1994; 90: 854–867.[Abstract/Free Full Text]
    
37. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy: clinical spectrum and treatment. Circulation. 1995; 92: 1680–1692.[Free Full Text]
    
38. Ciampi Q, Betocchi S, Lombardi R, Manganelli F, Storto G, Losi MA, Pezzella E, Finizio F, Cuocolo A, Chiariello M. Hemodynamic determinants of exercise-induced abnormal blood pressure response in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002; 40: 278–284.[Abstract/Free Full Text]
    
39. Stuber M, Scheidegger MB, Fischer SE, Nagel E, Steinemann F, Hess OM, Boesiger P. Alterations in the local myocardial motion pattern in patients suffering from pressure overload due to aortic stenosis. Circulation. 1999; 100: 361–368.[Abstract/Free Full Text]
    
40. Cheng CP, Noda T, Nozawa T, Little WC. Effect of heart failure on the mechanism of exercise-induced augmentation of mitral valve flow. Circ Res. 1993; 72: 795–806.[Abstract/Free Full Text]
    
41. Lele SS, Thomson HL, Seo H, Belenkie I, McKenna WJ, Frenneaux MP. Exercise capacity in hypertrophic cardiomyopathy: role of stroke volume limitation, heart rate, and diastolic filling characteristics. Circulation. 1995; 92: 2886–2894.[Abstract/Free Full Text]
    
42. Davis KL, Mehlhorn U, Schertel ER, Geissler HJ, Trevas D, Laine GA, Allen SJ. Variation in tau, the time constant for isovolumic relaxation, along the left ventricular base-to-apex axis. Basic Res Cardiol. 1999; 94: 41–48.[CrossRef][Medline] [Order article via Infotrieve]
    
43. Notomi Y, Lysyansky P, Setser RM, Shiota T, Popovic ZB, Martin-Miklovic MG, Weaver JA, Oryszak SJ, Greenberg NL, White RD, Thomas JD. Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging. J Am Coll Cardiol. 2005; 45: 2034–2041.[Abstract/Free Full Text]
    

---

 

CLINICAL PERSPECTIVE

The ability of the heart to increase cardiac output with exercise is impressive enough, but the most remarkable physiological aspect of this phenomenon is the multifold increase in diastolic filling rate mandated by the disproportionately shortened diastole during tachycardia. This requires an increase in the transmitral pressure gradient, but rather than increase left atrial pressure, it has been shown that minimal LV pressure, particularly at the apex, decreases significantly. How does the heart convert the increased contractility of exercise into this enhanced filling? In this study, we used exercise echocardiography and tissue Doppler imaging to define the mechanical events linking systole to diastole. During systole, the normal heart twists gradually, storing energy in torsion and compression of the sarcomeric molecular spring titin, the interstitium, or both. With aortic valve closure, however, the ventricle abruptly untwists, with more than half of the torsion released during isovolumic relaxation. This recoil leads to a 1- to 2-mm Hg intraventricular pressure gradient between the base and the apex of the heart, which helps pull blood across the mitral valve. With exercise, the untwisting rate and intraventricular pressure gradient rise in concert almost 3-fold, significantly augmenting transmitral flow. In patients with hypertrophic cardiomyopathy, however, both untwisting and intraventricular pressure gradient are dramatically blunted with exercise, but the relation between them is similar to that in normal hearts. Therefore, we believe that torsion during systole stores energy, which is released during isovolumic relaxation to generate the diastolic suction that allows the ventricle to fill efficiently, even with the demands of exercise.

Related Article:

Issue Highlights
Circulation 2006 113: 2473. [Full Text]

This article has been cited by other articles:

				A T Burns, I G McDonald, J D Thomas, A MacIsaac, and D Prior Doin' the twist: new tools for an old concept of myocardial function Heart, August 1, 2008; 94(8): 978 - 983. [Abstract] [Full Text] [PDF]

				G. Dwivedi, M. P. Frenneaux, and J. E. Sanderson Letter by Dwivedi et al Regarding Article, "Left Ventricular Untwisting Rate by Speckle Tracking Echocardiography" Circulation, May 13, 2008; 117(19): e336 - e336. [Full Text] [PDF]

				J. Wang, D. S. Khoury, Y. Yue, G. Torre-Amione, and S. F. Nagueh Response to Letter Regarding Article, "Left Ventricular Untwisting Rate by Speckle Tracking Echocardiography" Circulation, May 13, 2008; 117(19): e337 - e337. [Full Text] [PDF]

				P. P. Sengupta, A. J. Tajik, K. Chandrasekaran, and B. K. Khandheria Twist Mechanics of the Left Ventricle: Principles and Application J. Am. Coll. Cardiol. Img., May 1, 2008; 1(3): 366 - 376. [Abstract] [Full Text] [PDF]

				A N Borg, J L Harrison, R A Argyle, and S G Ray Left ventricular torsion in primary chronic mitral regurgitation Heart, May 1, 2008; 94(5): 597 - 603. [Abstract] [Full Text] [PDF]

				A. T. Burns, A. La Gerche, D. L. Prior, and A. I. MacIsaac Reduced and delayed untwisting of the left ventricle in patients with hypertension and left ventricular hypertrophy: a study using two-dimensional speckle tracking imaging Eur. Heart J., March 2, 2008; 29(6): 825 - 825. [Full Text] [PDF]

				J. E Sanderson Left and right ventricular long-axis function and prognosis Heart, March 1, 2008; 94(3): 262 - 263. [Full Text] [PDF]

				M. M. Riordan and S. J. Kovacs Elucidation of spatially distinct compensatory mechanisms in diastole: radial compensation for impaired longitudinal filling in left ventricular hypertrophy J Appl Physiol, February 1, 2008; 104(2): 513 - 520. [Abstract] [Full Text] [PDF]

				P. P. Sengupta, V. K. Krishnamoorthy, W. P. Abhayaratna, J. Korinek, M. Belohlavek, T. M. Sundt III, K. Chandrasekaran, F. Mookadam, J. B. Seward, A. J. Tajik, et al. Disparate Patterns of Left Ventricular Mechanics Differentiate Constrictive Pericarditis From Restrictive Cardiomyopathy J. Am. Coll. Cardiol. Img., January 1, 2008; 1(1): 29 - 38. [Abstract] [Full Text] [PDF]

				D. J. Penny, J. P. Mynard, and J. J. Smolich Aortic wave intensity analysis of ventricular-vascular interaction during incremental dobutamine infusion in adult sheep Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H481 - H489. [Abstract] [Full Text] [PDF]

Y. Notomi, Z. B. Popovic, H. Yamada, D. W. Wallick, M. G. Martin, S. J. Oryszak, T. Shiota, N. L. Greenberg, and J. D. Thomas Ventricular untwisting: a