Download Reduced Systolic Torsion in Chronic “Pure” Mitral Regurgitation

Reduced Systolic Torsion in Chronic “Pure”
Mitral Regurgitation
Daniel B. Ennis, PhD; Tom C. Nguyen, MD; Akinobu Itoh, MD; Wolfgang Bothe, MD;
David H. Liang, MD; Neil B. Ingels, PhD; D. Craig Miller, MD
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Background—Global left ventricular (LV) torsion declines with chronic ischemic mitral regurgitation (MR), which may
accelerate the LV remodeling spiral toward global cardiomyopathy; however, it has not been definitively established
whether this torsional decline is attributable to the infarct, the MR, or their combined effect. We tested the hypothesis
that chronic “pure” MR alone reduces global LV torsion.
Methods and Results—Chronic “pure” MR was created in 13 sheep by surgically punching a 3.5- to 4.8-mm hole (HOLE)
in the mitral valve posterior leaflet. Nine control (CNTL) sheep were operated on concurrently. At 1 (WK-01) and 12
weeks (WK-12) postoperatively, the 4D motion of implanted radiopaque markers was used to calculate global LV
torsion. MR-grade in HOLE was greater than CNTL at WK-01 and WK-12 (2.5⫾1.1 versus 0.6⫾0.5, P⬍0.001 at
WK-12). HOLE LV mass index was larger at WK-12 compared with CNTL (195⫾14 versus 170⫾17 g/m2, P⬍0.01),
indicating LV remodeling. Global LV systolic torsion decreased in HOLE from WK-01 to WK-12 (4.1⫾2.8° versus
1.7⫾1.7°, P⬍0.01), but did not change in CNTL (5.5⫾1.8° versus 4.2⫾2.7°, P⫽NS). Global LV torsion was lower in
HOLE relative to CNTL at WK-12 (P⬍0.05) but not at WK-01 (P⫽NS).
Conclusions—Twelve weeks of chronic “pure” MR resulting in mild global LV remodeling is associated with significantly
increased LV mass index and reduced global LV systolic torsion, but no other significant changes in hemodynamics.
MR alone is a major component of torsional deterioration in “pure” MR and may be an important factor in chronic
ischemic mitral regurgitation. (Circ Cardiovasc Imaging. 2009;2:85-92.)
Key Words: mechanics 䡲 mitral valve 䡲 myocardium 䡲 ventricles 䡲 torsion
C
hronic ischemic mitral regurgitation (CIMR) remains
one of the most challenging life-threatening clinical
problems in cardiac surgery, affects a large number of
patients, leads to congestive heart failure which limits life
expectancy and functional capacity, and has major adverse
implications on U.S. health care costs.1
pairment of LV torsion may increase transmural differences
in stress and foment deleterious LV remodeling or reduce the
elastic energy stored in the myocardium, thereby impairing
filling.5 In this way decreases in LV torsion as seen in CIMR
may contribute to a vicious cycle wherein “MR begets MR.”6
It has not been definitively established, however, whether the
reduced LV torsion in CIMR is a direct result of the infarct,
the MR, or a combination of the 2.
With respect to the treatment options for patients with
CIMR, sorting out the impact of MR from that of ischemia on
ventricular function may have important clinical consequences. For example, the surgical treatment options for
patients with CIMR include coronary artery bypass grafting
(CABG) or mitral valve annuloplasty or replacement. Currently, the most common technique to restore valve competence is the placement of an undersized annuloplasty ring.
There exists, however, an ongoing debate about whether or
not mitral valve annuloplasty at the time of CABG improves
outcomes over and above CABG alone.7–9
Hypothetically, if the reduction in LV torsion could be
attributed to ischemia alone, then CABG might be sufficient
Clinical Perspective see p 92
In CIMR, the mitral valve leaks, yet the leaflets appear
normal. The mitral regurgitation (MR) associated with CIMR
is the result of left ventricular (LV) geometric and microstructural2 remodeling that leads to alterations in the geometry of the mitral valve, annulus, and subvalvular apparatus.
These alterations include annular dilation, which reduces
leaflet coaptation, and papillary muscle displacement, which
leads to leaflet tethering.
Uncorrected CIMR is associated with decreased LV torsion.3 LV torsion in the normal heart reflects a balance
between epicardial and endocardial function and helps to
produce a nearly homogeneous transmural distribution of
myocardial stress and fiber strain during ejection.4 An im-
Received April 16, 2008; accepted January 8, 2009.
From the Department of Cardiothoracic Surgery (D.B.E., T.C.N., A.I., W.B., N.B.I., D.C.M.) and the Division of Cardiovascular Medicine (D.H.L.),
Stanford University, Stanford, Calif; and the Research Institute (N.B.I.), Palo Alto Medical Foundation, Palo Alto, Calif.
Correspondence to Daniel B. Ennis, Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Falk CVRB
CV-015, Stanford, CA 94305-5488. E-mail [email protected]
© 2009 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
85
DOI: 10.1161/CIRCIMAGING.108.785923
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Circ Cardiovasc Imaging
March 2009
Figure 1. Diagram of the anatomic location
of all implanted markers. Markers at the apical and basal levels (Nos. 1, 2, 4, 5, 7, 8,
10, 11, 13) were used to calculate LV global
torsion. Lower right inset is a photograph of
the hole in the posterior mitral valve leaflet
taken during bypass surgery. APM indicates
anterior papillary muscle; PPM, posterior
papillary muscle. The gray arrows indicate
the directions of rotation at the apex and
base that give rise to LV torsion.
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to either restore or stop the deterioration of LV torsion. If,
however, MR alone contributes to impaired LV torsion,
mitral valve repair may be important for minimizing the
deterioration in LV torsion.
The goal of this study was to sort out the impact of MR
alone on LV torsion in an ovine model of chronic “pure” MR.
We tested the hypothesis that chronic “pure” MR alone
reduces global LV torsion.
Methods
Animal Welfare
All animal procedures were approved by our Institutional Animal
Care and Use Committee and followed guidelines set forth by the
National Institutes of Health. Results from some of the animals used
in this report were described previously.10 The authors had full
access to and take full responsibility for the integrity of the data. All
authors have read and agree to the manuscript as written.
Adult male sheep (Dorsett-hybrid) were premedicated with an
injection of ketamine, anesthetized, intubated, mechanically ventilated, and sedation was maintained with inhalational isoflurane.
Blood pressure, body temperature, blood gases (CO2 and O2), and
ionic concentrations were monitored throughout the study.
Surgery
A left lateral thoracotomy was performed under surgically sterile
conditions to expose the heart for the implantation of miniature
radiopaque markers. Thirteen LV markers were placed subepicardially to silhouette the LV chamber. One marker was placed at the
apex and 4 each were placed in the septal, anterior, lateral, and
posterior walls at apical, midequatorial, and basal levels (Figure 1).
These markers were used to generate the results reported herein. To
investigate changes in regional function additional beads were
implanted transmurally in the antero-basal and lateral-equatorial
LV wall.10
The animal was then placed on cardiopulmonary bypass, the heart
arrested, and the left atrium opened to provide access to the mitral
valve annulus, leaflets, and subvalvular apparatus. To investigate
changes in annular and leaflet function, markers were sewn to the
mitral valve annulus, leaflets, and on the papillary muscle tips.
Animals were randomized into a control group (CNTL, n⫽8) and
a chronic “pure” mitral regurgitation (PMR) group (HOLE, n⫽12)
while on bypass. In HOLE animals, a 3.5- to 4.8-mm hole was
created in the posterior leaflet using an aortic hole punch to generate
“pure” mitral regurgitation. The animals were then weaned off
bypass. A Konigsberg micromanometer pressure transducer was
placed in the LV chamber through the apex and exteriorized. The
chest was closed in layers, and the animal was recovered and
returned to the holding facility. Throughout the whole study period
the animals were followed for clinical signs of heart failure (tachypnea, lethargy, and anorexia). Body weight and transthoracic echocardiographic MR-grade were also monitored.
Data Collection—Catheterization Laboratory
At 1 (WK-01) and 12 (WK-12) weeks all animals underwent
examination in the catheterization laboratory. As before, the animals
were premedicated with ketamine, anesthetized, intubated, mechanically ventilated, and sedation was maintained with inhalational
isoflurane. LV pressure (LVP) was recorded using the implanted
Konigsberg pressure transducer and aortic pressure (AoP) was
recorded using a micromanometer catheter (Millar Instruments)
introduced via the left carotid artery. Pressure and ECG data were
recorded at 240 Hz and synchronized with the recording of the x-ray
images. MR was graded qualitatively (0 to 4⫹) by an expert
echocardiographer (D.L.) on the basis of transesophageal echocardiography color doppler regurgitant jet extent and width.11
Marker motion was recorded during normal sinus rhythm with
controlled apnea12 using biplane cine fluoroscopy at 60 frames/s.
After WK-01 data collection the animals were recovered and
returned to animal care facility. After the WK-12 study the animals
were euthanized with a bolus infusion of potassium chloride (80
mEq).
Data Analysis
The animals selected for this study were required to have all LV
markers in place, regardless of the successful placement of the other
markers. During 3 consecutive heartbeats, each markers’ image
coordinates were digitized using custom computer aided detection
software13 and merged to reconstruct 3D marker motion.14
The 3D LV marker coordinates were used to calculate the volume
of space-filling tetrahedra that approximate the total LV volume
during the cardiac cycle. The change in LV volume calculated from
subepicardial markers is an accurate measurement of the change in
LV chamber volume,15 despite the inclusion of the LV wall volume.
Sphericity index (SI) was calculated as the ratio of the length of the
LV long axis and the LV diameter16 (SI⬎1 is an elongated
ellipsoidal heart, SI⫽1 is spherical). Sheep weight, W (kg), was used
to approximate the body surface area using a formulae (body surface
area⫽0.087⫻W0.67) provided by Fischer et al.17 End diastolic (ED),
end isovolumic contraction (IVC), end systolic (ES), and end
isovolumic relaxation (IVR) cardiac cycle time points were determined semiautomatically from plots of LV pressure-volume loops.
The body surface area was then used to calculate indexed values of
the LV end-diastolic volume index (LVEDVI), LV end-systolic
volume index (LVESVI), and LV mass index (LVMI). Peak systolic
Ennis et al
Reduced Systolic Torsion in Chronic Mitral Regurgitation
Table 1. Hemodynamics for Control and Chronic
“Pure” Mitral Regurgitation Animals at 1 and
12 Weeks Postoperatively
WK-01
CNTL,
n⫽9
Table 2. LV Torsion for the Control and Chronic “Pure” MR
Group at 1 and 12 Weeks Postoperatively During Each Phase of
the Cardiac Cycle
WK-12
HOLE,
n⫽13
CNTL,
n⫽9
WK-01
HOLE,
n⫽13
WK-12
CNTL,
n⫽9
HOLE,
n⫽13
CNTL, n⫽9
MR (grade)
0.6⫾0.5
2.7⫾0.7*
0.6⫾0.5
2.5⫾1.1*
IVC
0.6⫾0.9
0.4⫾1.4
⫺1.3⫾1.8*
HR, min⫺1
112⫾10
109⫾12
106⫾19
108⫾14
Ejection
4.8⫾1.3
3.7⫾1.7
5.5⫾2.7
Weight, kg
54⫾4
56⫾9
LVMi, g/m2
...
...
87
57⫾6
57⫾6
IVR
⫺1.7⫾1.5
⫺1.8⫾1.2
170⫾17
195⫾14*
Filling
⫺3.7⫾1.4
⫺2.3⫾2.1
⫺4.5⫾2.3
5.5⫾1.8
4.1⫾2.8
4.2⫾2.7
0.4⫾1.6*
HOLE,
n⫽13
⫺1.8⫾1.5*
3.4⫾1.4†
0.0⫾1.8*
⫺1.7⫾2.1‡
LVEDVi, mL/m2
110⫾22
121⫾23
117⫾31
133⫾33
ED-ES
LVESVi, mL/m2
86⫾19
92⫾20
87⫾26
100⫾22
LVPmax, mm Hg
90⫾10
95⫾13
100⫾18
101⫾16
All measures are degrees. *P⬍0.01 within group; †P⬍0.05 between
groups; and ‡P⬍0.01 between groups.
ED-ES indicates systolic torsion from end diastole to end systole.
LVEDP, mm Hg
19⫾5
22⫾4
8⫾6†
8⫾7†
Sphericity Index
1.4⫾0.3
1.3⫾0.2
1.4⫾0.2
1.2⫾0.2
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*P⬍0.01 between groups (same week) and †P⬍0.01 within group (different
weeks).
HR indicates heart rate; LVEDP, LV end-diastolic pressure.
(LVPmax) and LV end-diastolic pressure were extracted from the LV
pressure curves.
Calculation of Gobal LV Torsion
Global LV torsion was calculated from the apical LV markers (Nos.
2, 5, 8, 11) and the basal LV markers (Nos. 4, 7, 10, 13, Figure 1).
An internal cylindrical coordinate (R, ⍜, Z) for each marker was
calculated using the LV long-axis defined as a vector pointing from
the centroid of the basal markers to the centroid of the apical
markers. Ventricular torsion within each wall (anterior, lateral,
posterior, and septal) was then calculated as the difference between
the basal ⍜ coordinate and the apical ⍜ coordinate for all time
points. Global ventricular torsion was calculated as the average
torsion of the 4 wall regions, averaged across 3 consecutive heartbeats. Positive torsion values indicate counterclockwise rotation of
the apex relative to the base about the LV long-axis when viewed
from apex-to-base. Negative torsion values indicate clockwise rotation when viewed from apex-to-base relative to ED. The global
ventricular torsion during the cardiac cycle was then decomposed
into torsion during IVC, ejection, IVR, filling, and systolic torsion
from ED to ES. Significant regional differences (eg, anterior versus
lateral wall torsion) were not evident (data not shown). Note, that we
have defined torsion for all phases of the cardiac cycle though some
authors prefer that this term be reserved only for ejection.
Changes in ventricular torsion as a function of LV volume during
ejection were also quantified. A least squares estimate of the slope of the
torsion-volume curve during ejection for each group was computed.
Statistical Analysis
The results are presented as mean⫾1 SD. To determine whether
there were significant differences between the CNTL and HOLE
groups at both WK-01 and WK-12, 2-way repeated measures
ANOVA was performed (SigmaStat 3.5, Systat Software). A HolmSidak multiple comparisons procedure was used. The threshold for
statistically significance was P⬍0.05. Statistical differences both
“between groups” (CNTL versus HOLE at WK-01 or CNTL versus
HOLE at WK-12) and “within groups” (HOLE WK-01 versus HOLE
WK-12 or CNTL WK-01 versus CNTL WK-12) were considered.
Results
Hemodynamics
Hemodynamic data are shown in Table 1. MR grade was
significantly elevated in HOLE relative to CNTL at both
WK-01 (2.7⫾0.7 versus 0.6⫾0.5, P⬍0.01) and WK-12
1.7⫾1.7*†
(2.5⫾1.1 versus 0.6⫾0.5, P⬍0.01). There were no significant
differences within CNTL or within HOLE between WK-01
and WK-12. Therefore, MR grade was elevated throughout
the experiment in the HOLE group and was typically
moderate-severe to severe, whereas the CNTL group had
trace MR on average throughout the experiment. Aortic
cross-clamp times for the HOLE and CNTL groups were
significantly different (34⫾3 and 29⫾3 minutes, P⬍0.01).
Creation MR in the HOLE group accounts for the time
difference.
LVMI at WK-12 (the only time point available) was
significantly increased in HOLE compared with CNTL
(195⫾14 versus 170⫾17 g, P⬍0.01). There were, however,
no significant differences between groups or over time for
heart rate, body weight, LV end-diastolic volume index, LV
end-systolic volume index, peak systolic LV pressure (LVPmax),
or sphericity index. LV end-diastolic pressure, however, was
decreased from WK-01 to WK-12 in both CNTL and HOLE.
Global LV Torsion—No Week-01 Differences
A summary of the phases of global LV torsion is found in
Table 2 and graphically depicted in Figure 2. There were no
significant differences between CNTL and HOLE groups at
WK-01, indicating that 1 week of PMR did not result in a
significant alteration in global LV torsion during any phase of
the cardiac cycle.
Global LV Torsion—Similar Week-12 Changes
Twelve weeks after surgery there were significant differences
within the CNTL group (WK-01 versus WK-12) for torsion
during IVC and IVR. LV cocking during IVC was restored
from WK-01 to WK-12 in the CNTL group (0.6⫾0.9° versus
⫺1.3⫾1.8°, P⬍0.01) and torsion recoil during IVR nearly
abolished (⫺1.7⫾1.5° versus 0.4⫾1.6°, P⬍0.01).
Similarly, at WK-12 the HOLE group demonstrated a
restoration from WK-01 of LV cocking during IVC
(0.4⫾1.4° versus ⫺1.8⫾1.5°, P⬍0.01) and a significant
decrease in the magnitude of IVR recoil (⫺1.8⫾1.2° versus
0.0⫾1.8°, P⬍0.01). These changes in the HOLE group
paralleled those of the CNTL group, thus are likely associated
with recovery from surgery.
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Circ Cardiovasc Imaging
March 2009
Table 3. Rate of Ventricular Torsion for Control and Chronic
“Pure” Mitral Regurgitation Animals at 1 and 12 Weeks
Postoperatively During Each Phase of the Cardiac Cycle
WK-01
CNTL, n⫽9
IVC
Ejection
9.8⫾12.4
34.3⫾7.5
WK-12
HOLE, n⫽13
CNTL, n⫽9
HOLE, n⫽13
5.4⫾17.0
⫺14.5⫾17.5*
⫺17.2⫾17.6*
26.6⫾11.3
38.1⫾11.8
IVR
⫺16.3⫾11.3
⫺17.9⫾11.1
Filling
⫺15.0⫾3.5
⫺9.2⫾10.6
3.5⫾13.7*
⫺23.7⫾15.6
25.8⫾10.3†
⫺2.1⫾18.4*
⫺7.9⫾14.1‡
All measures are degrees/second. *P⬍0.01 within group; †P⬍0.05 between
groups; and ‡P⬍0.01 between groups.
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Figure 2. LV torsion for CNTL and chronic “pure” MR (HOLE)
group at 1 (WK-01) and 12 (WK-12) weeks postoperatively during 5 phases of the cardiac cycle. Notably, global LV torsion
during ejection, filling, and systole (ED to ES) all demonstrated
significant changes between HOLE and CNTL groups at WK-12.
Furthermore, LV systolic torsion was reduced at WK-12 in HOLE
compared with HOLE at WK-01. Significant differences both
within CNTL and HOLE during IVC and IVR were also observed.
ED-ES, systolic torsion from end-diastole to end-systole. All
measures are degrees. **P⬍0.01 within group; †P⬍0.05
between groups; ‡P⬍0.01 between group.
Global LV Torsion—Differential
Week-12 Changes
Global LV torsion during ejection, filling, and systole (ED to
ES) all demonstrated significant changes between HOLE and
CNTL groups at WK-12. Global ventricular torsion during
ejection was decreased for HOLE at WK-12 compared with
CNTL at WK-12 (3.4⫾1.4° versus 5.5⫾2.7°, P⬍0.05).
Similarly, global ventricular torsion during filling was decreased in HOLE at WK-12 relative to CNTL at WK-12
(⫺1.7⫾2.1° versus ⫺4.5⫾2.3°, P⬍0.01). These results indicated impaired torsion during ejection and decreased untwisting during filling for HOLE relative to CNTL at WK-12.
LV systolic (ED to ES) torsion was reduced at WK-12 in
HOLE compared with both HOLE at WK-01 (1.7⫾1.7°
versus 4.1⫾2.8°, P⬍0.01) and CNTL at WK-12 (1.7⫾1.7°
versus 4.2⫾2.7°, P⬍0.05). Thus, LV systolic torsion was
impaired after 12 weeks of chronic “pure” MR.
Rates of Global LV Torsion—No
Week-01 Changes
A summary of the rates of global LV torsion during IVC,
ejection, IVR, and filling is shown in Table 3 and in Figure 3.
There were no significant differences in any cardiac phase
component of the rate of global ventricular torsion between
the CNTL and HOLE groups at WK-01, indicating that 1
week of PMR did not have a deleterious impact.
Rates of Global LV Torsion—Similar
Week-12 Changes
The rate of ventricular torsion during IVC, however, significantly decreases and changes sign from WK-01 to WK-12 in
both CNTL (9.8⫾12.4°/s versus ⫺14.5⫾17.5°/s, P⬍0.01)
and HOLE (5.4⫾17.0°/s versus ⫺17.2⫾17.6°/s, P⬍0.01)
groups. Furthermore, the rate of ventricular torsion during
IVR significantly increased from WK-01 to WK-12 in both
the CNTL (⫺16.3⫾11.3°/s versus 3.5⫾13.7°/s, P⬍0.01) and
HOLE (⫺17.9⫾11.1°/s versus ⫺2.1⫾18.4°/s, P⬍0.01)
groups. These similar changes in the rates of global LV
torsion may reflect ventricular changes associated with postoperative recovery.
Rates of Global LV Torsion—Differential
Week-12 Changes
Global LV torsion within the CNTL GROUP was not
significantly different during ejection or filling from WK-01
to WK-12. There was, however, a significant decrease in the
rate of global LV torsion during ejection at WK-12 between
the CNTL and HOLE groups (38.1⫾11.8°/s versus 25.8⫾10.3°/s,
P⬍0.05). Furthermore, the rate of global LV torsion during
filling was significantly decreased in magnitude at WK-12
between CNTL and HOLE (⫺23.7⫾7.9°/s versus
⫺7.9⫾14.1°/s, P⬍0.01). These results indicate that the rates of
global LV torsion during both ejection and filling decrease in
magnitude after 12 weeks of chronic “pure” MR.
Global Torsion Versus LV Volume
The least squares estimate of the slope of the torsion-volume
curve during ejection for each group is compared in Table 4.
The path of the torsion-volume curve during ejection was
very linear. At WK-01 there was no difference between the
CNTL and HOLE groups (⫺0.35⫾0.12°/mL versus
⫺0.29⫾0.18°/mL). At WK-12, however, the HOLE group
slope was significantly different from both CNTL at WK-12
(⫺0.18⫾0.06°/mL versus ⫺0.32⫾0.10°/mL, P⬍0.05) and
HOLE at WK-01 (⫺0.18⫾0.06°/mL versus ⫺0.29⫾0.18°/
mL, P⬍0.05).
Global LV Torsion—PV Loop
Global LV torsion is color-mapped on mean PV-loops for the
CNTL and HOLE groups at WK-01 and WK-12 in Figure 4.
This method of displaying the torsion data provides a way to
qualitatively appreciate global ventricular torsion during each
phase of the cardiac cycle.
At WK-01 both the CNTL and HOLE groups demonstrated
very similar patterns of global ventricular torsion during IVC,
ejection, IVR, and filling phases. At WK-12, however, both
CNTL and HOLE groups have regained cocking during IVC.
Global LV torsion increases during ejection, but LV torsion at
ES is reduced in HOLE relative to CNTL. Both groups
demonstrate a continued increase in LV torsion during IVR
that peaks during mid-IVR, but the net change in torsion
Ennis et al
Reduced Systolic Torsion in Chronic Mitral Regurgitation
89
Figure 3. Rate of ventricular torsion for CNTL and
chronic PMR (HOLE) animals at 1 (WK-01) and 12
(WK-12) weeks postoperatively during 4 phases of
the cardiac cycle. The rate of torsion during IVC
significantly decreases and changes sign from
WK-01 to WK-12 in both CNTL and HOLE. The
rate of torsion during IVR increases from WK-01 to
WK-12 in both CNTL and HOLE. Notably, at
WK-12 there is a significant decrease in the magnitude of the rate of global LV torsion during ejection and filling between CNTL and HOLE. **P⬍0.01
within group; †P⬍0.05 between groups; ‡P⬍0.01
between groups.
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during IVR was nearly zero. The magnitude of torsion at the
end of IVR was higher in the CNTL group than the HOLE
group and the CNTL group exhibited greater negative torsion
during the subsequent filling phase.
Discussion
Depressed Ventricular Torsion
Twelve weeks of chronic PMR resulted in significant reductions in torsion during systole (ED to ES), ejection (end-IVC
to ES), and during filling (end-IVC to ED) relative to CNTL.
Only decreases in systolic torsion, however, were significantly different in HOLE at WK-12 compared with both
HOLE at WK-01 and CNTL at WK-12. The small difference
in aortic cross-clamp time, though statistically significant, is
not likely to induce differences in ventricular torsion between
the 2 groups.
Changes in systolic torsion must be understood in the
context of the restoration of ventricular cocking during IVC.
Cocking, an expected mode of torsion during IVC,18 –20 is
restored in both CNTL and HOLE at WK-12. The notable
change in systolic torsion in HOLE at WK-12 is primarily
attributable to a persistent reduction in torsion during ejection, combined with increased cocking during IVC.
To account for changes associated with the recovery from
the operation we focused on measures of torsion during
ejection—a phase of the cardiac cycle during which the
CNTL group undergoes no significant change from WK-01 to
WK-12. Ejection torsion in the HOLE group is significantly
reduced at WK-12 compared with CNTL but is not statistically different between WK-01 and WK-12 within HOLE,
indicating that it is not further depressed after 12 weeks of
PMR.
Furthermore, during ejection the slope of the torsionvolume curve is not different within the CNTL group, or
between CNTL and HOLE at WK-01. All slopes are approximately ⫺0.32°/mL, indicating that this relationship is preserved during acute PMR and in the postoperative recovery
period. This measure, however, is significantly decreased in
the HOLE group at WK-12 (⫺0.18°/mL) compared with both
CNTL at WK-12 and HOLE at WK-01. This significant
difference within the HOLE group may indicate that the
torsion-volume relationship continues to decline with persistent PMR.
Physiologic Adaptation to Pure MR
The physiological adaptation to chronic “pure” MR primarily
included a significant increase in LVMI. LVEDVI and
LVESVI were both increased 15% in HOLE compared with
CNTL at WK-12, but the results were not statistically
significant. The LV changes after 12 weeks of pure MR in
HOLE substantially differ from the larger LVMI, LVEDVI,
and LVESVI changes that are known to occur in patients with
longstanding chronic MR attributable, at least in part, to the
duration of the disease process. Our measures of LVEDVI
and LVESVI are derived from subepicardial markers, which
results in larger measures when compared with endocardialderived values as they include changes in myocardial mass.
Furthermore, though sphericity index in HOLE tended to be
lower (more spherical), no significant differences between
CNTL and HOLE were observed. The results derived from
endocardial measures may demonstrate significant differences if there are significant differences in wall thickness
between CNTL and HOLE. One strength of this study and
previous work10 is that it reflects a very early stage of the
Table 4. Slope of the Torsion vs LV Volume Curve During Ejection for Control and Chronic “Pure” Mitral
Regurgitation Animals at 1 and 12 Weeks Postoperatively
WK-01
Torsion-volume ejection slope, degrees/mL
WK-12
CNTL, n⫽9
HOLE, n⫽13
CNTL, n⫽9
HOLE, n⫽13
⫺0.35⫾0.12
⫺0.29⫾0.18
⫺0.32⫾0.10
⫺0.18⫾0.06*†
*P⬍0.05 within group; and †P⬍0.05 between groups.
90
Circ Cardiovasc Imaging
March 2009
diminished 1-week after surgery but recovered after 15-days
of rapid pacing (⫺0.5° versus ⫺1.2°). Our results are similar,
suggesting that this change in torsion may be largely attributable to postoperative recovery time and not dilated cardiomyopathy or chronic mitral regurgitation. The surgical intervention, which includes cardiopulmonary bypass and cardiac
arrest, may, however, alter the measured torsion as compared
with animals that forego this procedure, but still have epicardial makers implanted. Additional work is needed to compare
2 such groups.
Alternate Mechanism of Reduced
Torsion Dynamics
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Figure 4. Average pressure-volume (PV) loops color coded for
global ventricular torsion (degrees). A, Average CNTL and HOLE
PV-loop at WK-01. There are no significant differences in any
hemodynamic, physiological, or torsion parameter at WK-01
except for MR-grade. B, Average CNTL and HOLE PV-loop at
WK-12. The HOLE group is volume shifted to the right after 12
weeks of chronic “pure” MR and the peak torsion at end ejection and during IVR is reduced compared with CNTL. Cocking
during IVC (negative torsion) is regained in both CNTL and
HOLE at WK-12.
disease process, shown by only mild signs of LV remodeling
(LVMI), before overt changes in traditionally measured
clinical indices.
The decreased global systolic torsion may be attributed to
the increase in LV end-diastolic volume index and the
significant increase in LV myocardial mass index. Because
our results are definitive with regards to changes in systolic
torsion and equivocal in regards to changes in LVEDVI, it
may be the case that ventricular torsion or the torsion-volume
slope during ejection is a more sensitive measure of LV
dysfunction and remodeling using the experimental conditions and quantitative methods reported herein.
Although parameters like LVEDVI and LVESVI trend
toward significant increases in the HOLE group, power
calculations demonstrate that a group size of 44 and 38,
respectively, would be needed to attain a power of 0.9 for an
alpha of 0.05. In comparison, the systolic torsion results have
a power of 0.96.
Postoperative Recovery
Changes in global LV torsion and rates of torsion reflect a
combination of the deleterious effects of chronic PMR and
the recovery from the operation. A primary advantage of this
study, compared with previous work,21 is the inclusion of a
sham operated control group. Changes in torsion during IVC
and IVR are very similar between the CNTL and HOLE
groups, and such changes may be attributed to recovery from
the surgical procedure between WK-01 and WK-12.
Tibayan et al,22 in a model of dilated cardiomyopathy that
also required the use of bypass, observed an increase in the
magnitude of early systolic cocking from ⫺0.7° in animals
1-week postsurgery to ⫺1.5° after 15-days of rapid pacing. In
the context of our results it appears that this may be attributed
to postsurgery recovery time. Similarly, Tibayan et al also
observed that early diastolic recoil (torsion from end-ejection
to 5% of LV-filling, similar to our IVR interval) was
Global LV torsion can be decreased by alterations in electric
conduction patterns. In normal myocardium the endocardium
is electrically and mechanically activated before the epicardium.23 It is understood that early activation of the endocardium may cause LV cocking during IVC.24,25 If the pattern of
electric activation was altered and endocardial activation was
made more coincident with epicardial activation then early
LV cocking would be reduced. It is possible that this is the
mechanism underlying the loss of LV cocking in both CNTL
and HOLE at WK-01 during the early postoperative period,
but further study is needed to confirm this. If this were the
case then it would seem that normal electric conduction
patterns were restored at WK-12 in both CNTL and HOLE,
and it would be difficult to ascribe such alterations to the MR
alone.
Another possible cause of reduced ventricular torsion in
chronic “pure” MR is heterogeneous transmural remodeling.
It is possible that at WK-12 the HOLE animals have undergone eccentric hypertrophy and maintained the radius to
wall-thickness ratio, but nonuniformly redistributed myocardial mass. If the epicardial fibers atrophy, while endocardial
fibers hypertrophy, wall thickness could be maintained or
increased, but ventricular torsion would decrease as the
balance between epicardial and endocardial force generation
remodeled. Investigations into the heterogeneity of transmural remodeling are ongoing. Also, it should be noted that
reduced torsion during ejection may also arise from paradoxical septal wall motion as a result of cardiopulmonary
bypass.26 Lastly, changes in torsion and torsion rates during
IVR and filling may not be attributed to the MR per se, but
rather to the effects of ventricular remodeling that deleteriously impacts torsion during diastole.
Each of these alternative mechanisms of reduced global
ventricular torsion warrants further investigation.
Comparison With Previous Results
Caution must be used when comparing observations of
ventricular rotation and ventricular torsion. Furthermore, it is
imperative to account for the definitions used by each author
to avoid confusion in interpreting and comparing results.
Tibayan et al21 demonstrated in a different model of
nonischemic chronic mitral regurgitation (Cope biopsy needle disruption of the leading edge of the posterior leaflet) that
maximum torsional deformation decreased (6.3° to 4.7°), and
torsion during early diastolic recoil (first 5% of filling)
decreased in magnitude (⫺3.8° to ⫺1.5°) from 1-week to
Ennis et al
Reduced Systolic Torsion in Chronic Mitral Regurgitation
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7-weeks. Though the methods of chronic MR creation differ,
the salient aspects of the experiments are very similar. Most
importantly the MR-grade (“moderate to severe”) and duration were similar. The presence of a sham operated control
group in our study, however, allowed us to control for the
impact of MR alone.
Another study by Tibayan et al,3 in a sheep model of
inferior myocardial infarction (MI), describes the differences
in ventricular torsion for animals that developed chronic
ischemic MR (CIMR) compared with those that did not show
significant MR. In the CIMR animals ventricular torsion was
significantly decreased in the posterior wall 7 weeks after
infarction, but the decrease in torsion in the non-MR infarct
group was not large enough to be statistically significant.
Hence, the decrease in LV torsion is greater in CIMR than in
MI alone. This indicates that MR is an important determinant
of decreased ventricular torsion. Our study specifically isolates the effects of MR alone and shows that ventricular
torsion is significantly decreased. Therefore, decreases in
ventricular torsion in CIMR or in “pure” MR are largely
attributable to the MR alone.
Limitations
This model provides a unique way to study the isolated
effects of “pure” MR without confounding factors such as
ischemia, infarction, disruption of subvalvular apparatus
(chordae tendinae or papillary muscles), or disruption of the
leaflets along the line of coaptation.
The invasiveness of the surgical procedure may acutely
and chronically alter ventricular function. Although the implanted myocardial marker technique affords certain advantages (high spatial and temporal resolution and the ability to
track precise tissue locations over long experimental durations) it also requires a thoracotomy and disruption of the
pericardium. The presence of a sham operated control groups
provides a way to account for the impact of surgery and
bypass. Although the only experimental difference between
the CNTL and HOLE groups is the surgical creation of the
mitral valve leaflet hole in the HOLE group, the study is not
without other confounding factors. In fact, parallel changes in
the CNTL and HOLE group over the course of 12 weeks
indicate that the effects of the operation on the ventricle are
still present at WK-01. Furthermore, the measures made with
subepicardially implanted markers in this study are precise
but do not afford the ability to quantify transmural differences
in the myocardial kinematics. Therefore, with the current
technique we are also unable to report on regional septal
dysfunction that may result from the bypass procedure.
Interestingly, MRI may not be able to capture the motion of
early systolic events attributable to ECG gating and tagging
pulse delays,27 and its lower temporal resolution compared
with echocardiography25 unless specialized pulse sequences
are used.
Conclusions
Twelve weeks of chronic “pure” MR resulted in significantly
reduced global LV torsion during systole, ejection, and
filling. The decreases in global torsion may be attributed to
subtle increases in LVEDVI and LVMI but may also be
91
attributable to ventricular microstructural remodeling. These
data suggest that in patients with CIMR the MR itself may
promote deterioration of LV torsion. MV repair in patients
with CIMR concomitant with CABG may therefore help to
slow down, stop, or even restore physiological LV torsion.
Sources of Funding
The authors gratefully acknowledge research support from NIH/
NHLBI Grants R01 HL-29589 and R01 HL-67025 (to D.C.M.) and
K99-R00 HL-087614 (to D.B.E.).
Disclosures
None.
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CLINICAL PERSPECTIVE
Uncorrected chronic ischemic mitral regurgitation (CIMR) is associated with decreased left ventricular (LV) torsion and
may contribute to a vicious cycle wherein “MR begets MR.” It has not been definitively established, however, whether the
reduced LV torsion in CIMR is a direct result of the infarct, the MR, or a combination of the two. Currently, the most
common technique to restore valve competence in patients with CIMR is the placement of an undersized annuloplasty ring.
There exists, however, an ongoing debate about whether or not mitral valve annuloplasty at the time of coronary artery
bypass grafting (CABG) improves outcomes over and above CABG alone. Hypothetically, if the reduction in LV torsion
can be attributed to MR alone, then mitral valve repair concomitant with CABG may be important for minimizing the
deterioration in LV torsion. Chronic “pure” MR was created in 13 sheep by surgically punching a 3.5- to 4.8-mm hole
(HOLE) in the mitral valve posterior leaflet. Nine control (CNTL) sheep were operated on concurrently. At 1 (WK-01) and
12 weeks (WK-12) postoperatively, the 4D motion of implanted radiopaque markers was used to calculate global LV
torsion. Global LV systolic torsion decreased in HOLE from WK-01 to WK-12 (4.1⫾2.8° versus 1.7⫾1.7°, P⬍0.01) but
did not change in CNTL (5.5⫾1.8° versus 4.2⫾2.7°, P⫽NS). These data suggest that in patients with CIMR the MR itself
may promote deterioration of LV torsion. MV repair in patients with CIMR concomitant with CABG may therefore help
to slow down, stop, or even restore physiological LV torsion.
Reduced Systolic Torsion in Chronic ''Pure'' Mitral Regurgitation
Daniel B. Ennis, Tom C. Nguyen, Akinobu Itoh, Wolfgang Bothe, David H. Liang, Neil B.
Ingels and D. Craig Miller
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Circ Cardiovasc Imaging. 2009;2:85-92; originally published online January 22, 2009;
doi: 10.1161/CIRCIMAGING.108.785923
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