Valvular Heart Disease

Real-Time Left Ventricular Pressure-Volume

Loops During Percutaneous Mitral Valve
Repair With the MitraClip System
Oliver Gaemperli, MD*; Patric Biaggi, MD*; Remo Gugelmann; Martin Osranek, MD;
Jan J. Schreuder, MD, PhD; Ines Bühler; Daniel Sürder, MD; Thomas F. Lüscher, MD;
Christian Felix, MD; Dominique Bettex, MD; Jürg Grünenfelder, MD; Roberto Corti, MD

Background—Percutaneous mitral valve repair with the MitraClip device has emerged as an alternative to surgery for
treating severe mitral regurgitation. However, its effects on left ventricular loading conditions and contractility have not
been investigated yet.
Methods and Results—Pressure-volume loops were recorded throughout the MitraClip procedure using conductance catheter
in 33 patients (mean age, 78±10 years) with functional (45%), degenerative (48%), or mixed (6%) mitral regurgitation.
Percutaneous mitral valve repair increased end-systolic wall stress (WSES; from [median] 184 mm Hg [interquartile range
(IQR), 140–200 mm Hg] to 209 mm Hg [IQR, 176–232 mm Hg]; P=0.001) and decreased end-diastolic WS (WSED;
from 48 mm Hg [IQR, 28–58 mm Hg] to 34 mm Hg [IQR, 21–46 mm Hg]; P=0.005), whereas the end-systolic pressure-
volume relationship was not significantly affected. Conversely, cardiac index increased (from 2.6 L∙min−1∙m−2 [IQR, 2.2–
3.0 L∙min−1∙m−2] to 3.2 L∙min−1∙m−2 [IQR, 2.6–3.8 L∙min−1∙m−2]; P<0.001) and mean pulmonary capillary wedge pressure
decreased (from 15 mm Hg [IQR, 12–20 mm Hg] to 12 mm Hg [IQR, 10–13 mm Hg]; P<0.001). Although changes
in WSES were not correlated with changes in cardiac index, changes in WSED correlated significantly with changes in
mean pulmonary capillary wedge pressure (r=0.63, P<0.001). Total mechanical energy assessed by the pressure-volume
area remained unchanged, resulting in a more favorable index of forward output (cardiac index) to mechanical energy
(pressure-volume area) after mitral valve repair. On follow-up (153±94 days), New York Heart Association functional
class was reduced from 2.9±0.6 to 1.9±0.5 (P<0.001) at 3 months, and echocardiographic follow-up documented a
stepwise reduction in end-diastolic volume (from 147 mL [IQR, 95–191 mL] to 127 mL [IQR, 82–202 mL]; P=0.036).
Conclusions—Percutaneous mitral valve repair improves hemodynamic profiles and induces reverse left ventricular
remodeling by reducing left ventricular preload while preserving contractility. In nonsurgical candidates with
compromised left ventricular function, MitraClip therapy could be considered an alternative to surgical mitral valve repair.
(Circulation. 2013;127:1018-1027.)
Key Words: catheters ■ hemodynamics ■ mitral valve annuloplasty ■ mitral valve insufficiency
■ pressure-volume loops

A novel percutaneous method for mitral valve repair

(MVR) has recently been developed.1 Conceptually,
this technique is based on the surgical method developed
the main determinants of LV pump performance, are yet to
be investigated.

by Alfieri, which consists of edge-to-edge approxima-

tion of the middle scallops of the mitral valve leaflets by
percutaneous delivery of a mitral clip, thereby creating a
double-orifice mitral valve.2 As a result of promising ini-
tial clinical experiences with percutaneous edge-to-edge
MVR,3–7 the MitraClip device has been implanted in >6000
patients worldwide. However, data on the hemodynamic con-
sequences of percutaneous MVR are scarce,8,9 and its effect
on left ventricular (LV) preload, afterload, and contractility,
Clinical Perspective on p 1027
Simultaneous in vivo pressure-volume (PV) measurements
with a conductance catheter (CC) placed in the LV allow real-
time assessment of the LV PV relationship.10 In fact, percu-
taneous MVR provides a unique pathophysiological model
for assessing the immediate hemodynamic effects of MR
reduction on LV performance, eliminating any confounding
factors from cardiopulmonary bypass or chordal ablation.
Preliminary experiences suggest that despite an initial slight

Received August 4, 2012; accepted January 10, 2013.

From the Andreas Grüntzig Cardiac Catheterization Laboratories (O.G., R.G., M.O., I.B., D.S., T.F.L., R.C.), Echocardiography, Cardiovascular Center
(P.B.), Department of Anesthesiology (C.F., D.B.), and Cardiovascular Surgery (J.G.), University Hospital Zurich, Zurich, Switzerland, and CD Leycom,
Zoetermeer, the Netherlands (J.J.S.).
*Drs Gaemperli and Biaggi contributed equally to this article.
Correspondence to Oliver Gaemperli, MD, Andreas Grüntzig Laboratories and Cardiac Imaging, Cardiovascular Center, University Hospital Zurich,
Ramistrasse 100, 8091 Zurich, Switzerland. E-mail oliver.gaemperli@usz.ch
© 2013 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.112.135061

1018
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 Gaemperli et al   Pressure-Volume Loops During MitraClip   1019
decrease in LV ejection fraction, percutaneous edge-to-edge
MVR did not negatively affect cardiac output,8,9 and so far,
no reports of acute low-output states after MVR have been
published, even in patients with markedly compromised LV
function.9 However, the mechanisms by which percutaneous
edge-to-edge MVR may influence LV pump performance and
affect LV preload, afterload, and contractility are still to be
determined.
Thus, the purposes of this study were to investigate the
immediate changes in LV PV relationships during percutane-
ous edge-to-edge MVR with the MitraClip device using a CC
and to relate these findings to acute hemodynamic changes
and midterm clinical outcomes.
Methods
Patient Population and Study Design
We included consecutive patients undergoing percutaneous MVR
with the MitraClip system at the University Hospital Zurich, Zurich,
Switzerland. Patients were selected for the procedure if they had
moderate to severe (3+) or severe (4+) mitral regurgitation (MR),11
met Class I or IIa recommendations for mitral valve surgery accord-
ing to current guidelines,12,13 and were considered high risk for sur-
gery. Each subject’s eligibility for percutaneous MVR was discussed
by an interdisciplinary heart valve team that included an interven-
tional cardiologist, a cardiac surgeon, an echocardiographer, and a
cardiac anesthetist. Exclusion criteria were rheumatic heart disease,
endocarditis, mitral valve orifice area ≤2.0 cm2, extensive prolapse
of flail leaflets (prolapse width >25 mm, flail gap >20 mm), or any
interventional or surgical procedure within 30 days of the index pro-
cedure. All patients gave written informed consent to be included in
a prospective MitraClip registry (MitraSwiss registry). The protocol
of the MitraSwiss registry includes invasive hemodynamic data col-
lection through catheterization of the left- and right-sided chambers
of the heart and was approved by the local institutional review board.
MVR Procedure
Percutaneous MVR with the MitraClip device (Abbott Vascular
Structural Heart, Menlo Park, CA) was performed according to
standard technique described elsewhere9 with echocardiographic
(3-dimensional transesophageal echocardiography) and fluoroscopic
guidance. General anesthesia was established with a continuous in-
fusion of intravenous propofol and remifentanil, and patients were
ventilated routinely with an inspiratory oxygen fraction (FiO2)
of 60% to 80%, which was maintained over the entire duration of
the procedure. Acute procedural success was defined as successful
MitraClip implantation with MR reduction to grade 2+ or less by
echocardiography.
Instrumentation
Simultaneous LV PV measurements were performed with a CC (CD
Leycom, Zoetermeer, the Netherlands). This catheter is a pigtail-
shaped central-lumen 7F flexible catheter that is placed in the LV
via a 0.025-in J-tipped guidewire. It contains a solid-state pressure
sensor and 12 electrodes situated at regular intervals along the cath-
eter and is connected to a PV signal processor (Inca, CD Leycom).
The conductance method calculates continuous LV volume tracings
by measuring parallel electric conductance between adjacent elec-
trodes, and it has been successfully validated against cine computed
tomography and electroconductive balloons in animals.14,15 The cor-
rect position of the CC was verified by fluoroscopy and by inspection
of the segmental conductance signals. Arterial oxygen saturation was
obtained from the distal catheter lumen. Volume calibration was per-
formed by LV volumes from transthoracic 3-dimensional echocar-
diography (obtained under general anesthesia in the operating room
immediately before the start of the procedure).
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PV loops were recorded during steady-state conditions before and
after MitraClip implantation, avoiding excessive arrhythmia from
premature beats. Recorded variables were averaged from several
heartbeats (at least 10 seconds for sinus rhythm or at least 15 seconds
in atrial fibrillation) to minimize inaccuracies from beat-to-beat varia-
tions and changes in venous return resulting from mechanical venti-
lation. In a subgroup of 31 patients, a repeat baseline recording was
performed to assess the reproducibility of CC measurements.
Catheterization of the right side of the heart was performed with
a 6F single-lumen balloon-tipped flow-directed Swan-Ganz catheter
(Arrow International, Inc, Reading, PA) to measure mean pulmonary
capillary wedge pressure (PCWP), PCWP v-wave, mean pulmonary
artery pressure, pulmonary artery oxygen saturation, and right atrial
pressure. Left atrial pressure was measured through the transseptal
sheath. All hemodynamic measurements were conducted during the
index MVR procedure before MitraClip implantation and were re-
peated immediately after deployment of the last clip.
Variables and Data Analysis
CC data analysis was performed with dedicated data acquisition and
analysis software (Conduct NT, version 3.18.1, CD Leycom) by con-
sensus of 2 readers unaware of the clinical history and the success of
the MVR procedure. In addition to instantaneous LV volumes and
pressure, this software calculates load-independent parameters of LV
contractility:16 The end-systolic PV relationship (ESPVR) represents
the ratio of LV pressure to LV volume at the end of ventricular sys-
tole (uppermost left corner of the PV loop).17 The Starling contrac-
tile index (SCI) is calculated as the maximal rate of pressure change
over time during isovolumetric contraction (dP/dtmax) normalized to
end-diastolic volume (EDV). The (external) stroke work (eSW) was
calculated as the area within the PV loop and normalized to EDV to
obtain preload-recruitable stroke work (PRSW). PV area (PVA), a
measure of total mechanical energy generated by ventricular contrac-
tion, was calculated as the sum of eSW and elastic potential energy
according to the following equation18:
PVA = eSW + 0.5× ESP 2 / ESPVR (1)
LV preload and afterload were estimated from end-diastolic (WSED)
and end-systolic (WSES) wall stress,19,20 respectively, which were cal-
culated according to the following equation for time-dependent WS:21
WS(t ) = P (t )×(1 + 3× V (t ) / Vwall )(2)
where WS(t) is LV WS, P(t) is LV pressure, and V(t) is LV volume
at a given time point throughout the cardiac cycle. This equation as-
sumes that WS is fairly uniform throughout the ventricular wall and
is relatively independent of the geometry of the LV.22 LV wall volume
(Vwall) was calculated according to the cube function formula, which
approximates the shape of the LV as a prolate ellipsoid of regular
configuration and a ratio of long- to short-axis length of 2:123:
Vwall = 0.8 × (IVSTd + PWTd + EDD) − EDD3 (3)
3
 
where IVSTd is the diastolic thickness of the interventricular sep-
tum, PWTd is the diastolic posterior wall thickness, and EDD is the
end-diastolic diameter measured on M-mode echocardiography.
Cardiac output and cardiac index (CI) were calculated with the
Fick method.24 Systemic vascular resistance and pulmonary vascular
resistance were calculated as the ratio between the pressure drop
along the vascular bed and the cardiac output and converted to metric
units (dynes∙s∙cm−5).
Clinical and Echocardiographic Follow-up
Clinical follow-up was obtained from follow-up visits, in-hospital
records, and/or direct interview of the patient or his/her general prac-
titioner. Clinical end points included death, recurrent hospitalization
for congestive heart failure, mitral valve surgery, and New York Heart
Association functional class.
1020  Circulation  March 5, 2013

LV volumes at follow-up were assessed from 2-dimensional Table 1. Baseline Characteristics (n=33)
transthoracic echocardiography using the area-length method,25 and
systolic pulmonary pressure was estimated from peak tricuspid regur- Age, y 78±10
gitant jet velocity by use of the Bernoulli equation. Female sex, n (%) 14 (42)
BMI, kg/m2 25±4
Statistical Analysis Clinical features, n (%)
Statistical analysis was performed with the SPSS software pack-
Arterial hypertension 21 (64)
age (SPSS 12.0.1 for Windows, SPSS Corp). Quantitative data are
expressed as mean±SD or median with interquartile range (IQR) Hyperlipidemia 12 (36)
when appropriate, and categorical data are given in proportions Diabetes mellitus 6 (18)
and percentages. Statistical comparisons of quantitative data were
performed with a 2-tailed Wilcoxon signed-rank test for paired Coronary artery disease 14 (42)
samples. The Friedman test was used for repeated measurements of   Previous MI 7 (21)
LV volumes. Categorical data were compared by use of the Fisher   Previous PCI 8 (24)
exact test. Results from different measurements were correlated
with the Spearman method. Reproducibility of PV measurements   Previous CABG 7 (21)
was tested by the use of linear regression and Bland-Altman lim- Previous mitral valve surgery 3 (9)
its of agreement. The reproducibility coefficient was calculated as Atrial fibrillation 15 (45)
1.96 times the SD of the differences, as proposed by Bland and
Altman.26 A value of P<0.05 was considered statistically significant COPD 3 (9)
for all tests. Previous stroke 4 (12)
Impaired renal function (eGFR <60 mL/min) 20 (61)
Results Cancer 4 (12)
Patient Population Left ventricular ejection fraction, % 50±18
Of 37 consecutive patients undergoing percutaneous MVR, NYHA functional class, n (%)
hemodynamic data and PV loops were obtained in 33 patients. II 8 (24)
In 4 patients, technical problems, catheter malfunction, or III 20 (61)
inadvertent catheter dislodgement hindered successful data IV 5 (15)
recording. The patients’ baseline characteristics are shown Surgical risk, %
in Table 1. The type of MR was degenerative (DMR) in 16
Logistic EuroSCORE 20±17
patients (48%), functional (FMR) in 15 patients (45%), and
STS mortality score 6±5
mixed in 2 patients (6%). MR severity at baseline was 3+ in 7
patients (21%) and 4+ in 26 patients (79%). Three patients had STS mortality and morbidity score 27±12
previously undergone surgical MVR with ring annuloplasty BMI indicates body mass index; CABG, coronary artery bypass grafting; COPD,
(n=2) or Alfieri stitch (n=1). chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration
rate; EuroSCORE, European System for Cardiac Operative Risk Evaluation; MI,
myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous
Procedural Outcome coronary intervention; and STS, Society of Thoracic Surgeons. Data are given as
MitraClip implantation was successful in 31 of 33 patients mean±SD unless otherwise stated.
(acute procedural success rate, 94%) with an average of 1.9
implanted clips per patient (1 clip in 7 patients, 2 clips in 21
increased significantly by 0.9 L/min and 0.5 L∙min−1m−2,
patients, 3 clips in 4 patients, and 4 clips in 1 patient). The
respectively (Figure 1). There was no significant correlation
procedure failed in 2 patients because of excessive posterior
between changes in EF and changes in CI during percutaneous
annular calcification with poor echocardiographic image qual-
MVR (r=−0.33, P=0.06).
ity (n=1) or partial clip detachment (n=1). Postinterventional
complication rates were low, and there were no in-hospital
deaths. Two patients required vasopressor therapy over 1 to
Afterload, Preload, and LV Contractility
3 days after the procedure, but none had intra-aortic balloon Percutaneous MVR increased WSES by 30 mm Hg (P=0.001)
counterpulsation. and lowered WSED by 8 mm Hg (P=0.005; Table 2). However,
no significant changes were observed for SCI and ESPVR
Hemodynamic Data (Figure 1). After percutaneous MVR, PRSW decreased by 3
All hemodynamic variables were obtained under general mm Hg (P=0.001).
anesthesia before and immediately after the MitraClip pro- None of the aforementioned variables of contractility
cedure and are summarized in Table 2. Percutaneous MVR (ESPVR, SCI, PRSW) correlated significantly with changes
significantly reduced LV end-diastolic pressure and mean pul- in mean pulmonary artery pressure and/or CI except PRSW,
monary artery pressure by (median) 3 mm Hg, mean PCWP which showed a poor to moderate but statistically significant
by 5 mm Hg, and PCWP v-wave by 7 mm Hg, whereas mean correlation (r=0.395, P=0.025) with CI. Changes in WSES did
arterial pressure was increased by 9 mm Hg. EDV remained not relate to changes in CI (r=0.004, P=0.98), but there was
unchanged, whereas end-systolic volume increased by 11 mL moderate to good correlation between changes in WSED and
after MVR (P=0.006). This resulted in a reduction of ejection changes in mean PCWP (r=0.63, P<0.001; Figure 2). Figure 3
fraction (EF) from 55% (IQR, 45% to 65%) to 42% (IQR, shows individual examples for PV loops before and after per-
31% to 56%; P<0.001). Nonetheless, cardiac output and CI cutaneous MVR.
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 Gaemperli et al   Pressure-Volume Loops During MitraClip   1021

Table 2. Hemodynamic Variables

Before MitraClip After MitraClip Median Difference P
Pressures and volumes
EDV, mL 147 (106 to 183) 138 (104 to 185) −9 (−21 to 5) 0.18
ESV, mL 57 (39 to 112) 84 (43 to 118) 11 (0 to 25) 0.006
EDP, mm Hg 14 (11 to 17) 11 (8 to 14) −3 (−4 to 0) 0.002
MAP, mm Hg 64 (56 to 72) 68 (60 to 77) 9 (0 to 14) 0.02
mPAP, mm Hg 28 (24 to 32) 25 (22 to 29) −3 (−5 to 0) 0.001
mPCWP, mm Hg 15 (12 to 20) 12 (10 to 13) −5 (−8 to −2) <0.001
vPCWP, mm Hg 22 (16 to 30) 14 (13 to 16) −7 (−18 to −2) <0.001
mLAP, mm Hg 15 (10 to 21) 11 (9 to 14) −3 (−7 to 0) 0.001
Afterload and preload
WSES, mm Hg 184 (140 to 200) 209 (176 to 232) 30 (10 to 58) 0.001
WSED, mm Hg 48 (28 to 58) 34 (21 to 46) −8 (−19 to 2) 0.005
Load-independent parameters of LV contractility
SCI, mm Hg∙mL−1∙s−1 4.8 (3.1 to 8.9) 5.8 (3.7 to 9.2) 0.2 (−0.5 to 1) 0.23
ESPVR, mm Hg/mL 1.6 (0.7 to 2.6) 1.2 (0.8 to 2.1) −0.1 (−0.3 to 0.1) 0.12
PRSW, mm Hg 41 (29 to 60) 30 (24 to 52) −3 (−13 to 1) 0.001
LV myocardial energetics
eSW, mm Hg∙mL 6357 (3756 to 7671) 4490 (2957 to 6754) −579 (−2287 to 228) 0.004
PVA, mm Hg∙mL 9169 (6691 to 12 033) 8634 (6951 to 10 717) −52 (−1937 to 1181) 0.66
Forward output and resistances
CO, L/min 4.4 (3.5 to 5.6) 5.6 (4.6 to 6.5) 0.9 (0.3 to 1.9) <0.001
CI, L∙min−1∙m−2 2.6 (2.2 to 3.0) 3.2 (2.6 to 3.8) 0.5 (0.2 to 1.1) <0.001
SVR, dynes∙s∙cm−5 995 (796 to 1261) 995 (633 to 1092) −95 (−209 to 12) 0.03
PVR, dynes∙s∙cm −5
174 (129 to 282) 176 (99 to 286) −20 (−65 to 19) 0.27
CI indicates cardiac index; CO, cardiac output; EDP, end-diastolic pressure; EDV, end-diastolic volume; ESPVR, end-systolic pressure-volume relationship; ESV,
end-systolic volume; eSW, external stroke work; LV, left ventricular; MAP, mean arterial pressure; mPAP, mean pulmonary artery pressure; mPCWP, mean pulmonary
capillary wedge pressure; mLAP, mean left atrial pressure; PRSW, preload-recruitable stroke work; PVA, pressure-volume area; PVR, pulmonary vascular resistance;
SCI, Starling contractile index; SVR, systemic vascular resistance; vPCWP, pulmonary capillary wedge pressure v-wave; WSED, end-diastolic wall stress; and WSES,
end-systolic wall stress. All values are given as median (interquartile range).

LV Myocardial Energetics
Percutaneous MVR decreased eSW (Table 2) but increased
potential energy (from 2769 mm Hg∙mL [IQR, 1796–
4763 mm Hg∙mL] to 3921 mm Hg∙mL [IQR, 2221–5474
mm Hg∙mL];P=0.001). As a result, PVA remained unchanged.
The ratio of forward cardiac output to PVA (multiplied by
heart rate to account for 1 minute of PVA) increased signifi-
cantly after MitraClip implantation from 0.0084 mm Hg−1
(IQR, 0.0065–0.0106 mm Hg−1) to 0.0091 mm Hg−1 (IQR,
0.0082– 0.0145 mm Hg−1; P=0.007; Figure 4).
Comparison Between DMR and FMR
Table 3 shows a comparison of hemodynamics and CC data
for DMR (n=16) and predominantly FMR (functional plus
mixed, n=17). There was a similar reduction in mean pulmo-
nary artery pressure and mean PCWP in both groups; how-
ever, the decreases in end-diastolic pressure and WSED and
the increase in CI were larger in the DMR group (P<0.05).
Notably, changes in WSES were similar in both groups with
no excess afterload increase in the FMR group. Interestingly,
changes in ESPVR and PRSW appeared more favorable
for FMR, whereas for SCI, no significant differences were
found between the groups (Table 3). Individual changes in
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hemodynamic parameters are displayed for DMR and FMR
patients in Figure 5.
Reproducibility of CC Measurements
Reproducibility of measurements and derived values with
the CC was good with the following correlation coefficients:
EDV, r=0.97; end-systolic volume, r=0.96; end-diastolic
pressure, r=0.86; PRSW, r=0.96; SCI, r=0.96; ESPVR,
r=0.81; WSES, r=0.80; and WSED, r=0.86 (P<0.001 for all).
Bland-Altman limits of agreement were narrow with the
following reproducibility coefficient (given in percent of
the average value): EDV, 26%; end-systolic volume, 52%;
end-diastolic pressure, 32%; PRSW, 31%; SCI, 38%; WSES,
32%; and WSED, 39%, except for ESPVR, which had larger
variability (109%). There was no significant bias.
Clinical and Echocardiographic Follow-up
During a follow-up period of 153±94 days, 5 patients (15%)
died and 4 patients (12%) were readmitted for congestive
heart failure. New York Heart Association functional class
decreased from 2.9±0.6 to 1.9±0.5 (P<0.001) at 3 months.
Echocardiographic follow-up was available in 22 patients at
69±48 days after the index procedure. MR severity was 1+ in
1022  Circulation  March 5, 2013

100% A 100% B
* *
50% * 50% *
Percent changes
* +19% +21%
+6%
-8%
0% -10%
0%
-18% -14% -17%
-28%
-33%

-50% * -50%
*
*
-100% mPAP mPCWP vPCWP EDP CI -100% ESPVR SCI PRSW WSES WSED

Figure 1. Percent changes in (A) hemodynamic variables (pressures and cardiac index) and (B) variables of left ventricular performance
obtained with the conductance catheter after percutaneous mitral valve repair. Each box plot shows median (thick lines, with the numeric
value inserted in the box), quartiles (upper and lower box boundaries), and extreme values (whiskers). The small circles indicate outlier val-
ues. CI indicates cardiac index; EDP, end-diastolic pressure; ESPVR, end-systolic pressure-volume relationship; mPAP, mean pulmonary
artery pressure; mPCWP, mean pulmonary capillary wedge pressure; PRSW, preload-recruitable stroke work; SCI, Starling contractile
index; vPCWP, pulmonary capillary wedge pressure v-wave; WSED, end-diastolic wall stress; and WSES, end-systolic wall stress. *P<0.05.

15 patients, 2+ in 4 patients, and 4+ in 3 patients. A signifi- not significantly affected. Third, total mechanical energy
cant stepwise reduction in EDV (from 147 mL [IQR, 95–191 (PVA) remains unchanged; therefore, myocardial oxygen
mL] to 127 mL [IQR, 82–202 mL]; P=0.036) was observed consumption is not expected to increase after MVR. Fourth,
over the entire period of observation (Figure 6). End-systolic these beneficial hemodynamic changes, combined with a
volume tended to decline after discharge, but the changes preserved LV contractility, appear to reverse LV remodeling
fell short of significance (P=0.058). There was no significant by reducing EDV and are associated with an improvement in
correlation of any of the contractility parameters at baseline functional status.
(ESPVR, SCI, PRSW) with changes in EDV and end-systolic
volume. Systolic pulmonary pressure on echocardiography Changes in LV Loading Conditions
was decreased at follow-up compared with baseline (median, Surgical observations have raised the concern that remov-
32 mm Hg [IQR, 28 – 44 mm Hg] versus 43 mm Hg [IQR, ing the low-impedance regurgitant flow into the left atrium
35 – 52 mm Hg]; P=0.039). Changes in echocardiographic may abruptly impair LV performance, resulting in an acute
parameters (including volumes and EF) were similar among postoperative low-output state.27–30 However, these obser-
DMR and FMR patients. vations are confounded by factors such as changes in LV
geometry induced by chordal ablation and extracorporeal
Discussion circulation, both of which may underlie deterioration of LV
The present study addressed the immediate effects of contractility.27
percutaneous MVR with the MitraClip on LV performance We observed a significant 21% increase in LV afterload
(including LV contractility, afterload, and preload) as (estimated from WSES) after percutaneous MVR, which likely
assessed by CC and their relationship to hemodynamic contributes to the acute decline in LV EF observed after MVR.
changes and clinical outcomes. Our results can be The reduction in the regurgitant fraction decreases systolic
summarized as follows: First, successful percutaneous MVR offloading by occluding the low-impedance left atrial pathway.
results in an acute increase in LV afterload and a reduction in However, in our study population, a large increase in systolic
preload. However, the significant increase in forward cardiac load did not predict low cardiac output after MVR (Figure
output and decrease in pulmonary pressure indicate that 2A). Conversely, a significant 17% reduction in LV preload
the beneficial effect of end-diastolic unloading outweighs could be observed. This effect of diastolic LV unloading was
the potentially negative afterload increase. Second, despite associated with a reduction in pulmonary pressures (Figure
an acute decline in EF after the MVR procedure, LV 2B). Therefore, the beneficial effect of diastolic LV unload-
contractility measured by load-independent parameters is ing appears to outweigh the potentially negative afterload

A 4.0
r=0.004
B 10
r=0.63
P=0.98 P<0.001
5
3.0
∆mPCWP (mmHg)
∆CI (mL/min/m2)

0 Figure 2. Correlation of changes in end-

2.0 systolic wall stress (ΔWSES) with changes
-5
in cardiac index (ΔCI; A) and in end-
-10 diastolic wall stress (ΔWSED) with mean
1.0
pulmonary capillary wedge pressure
-15 (ΔmPCWP; B) during the percutaneous
0.0 mitral valve repair procedure. The regres-
-20
sion line is given in the graph.
-1.0 -25
-100 0 100 200 -60 -40 -20 0 20
∆WSES (mmHg) ∆WSED (mmHg)

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 Gaemperli et al   Pressure-Volume Loops During MitraClip   1023

Figure 3. Left ventricular

(LV) response to percutane-
ous mitral valve repair (MVR)
with the MitraClip system in
6 individuals with functional
mitral regurgitation (FMR; left
column, A–C) and degenera-
tive mitral regurgitation (DMR;
right column, D–F). Ejection
fractions at baseline were as
follows: A, 25%; B, 25%; C,
29%; D, 68%; E, 65%; and F,
63%. Pressure-volume (PV)
loops before MVR are given
in black and after MVR in red.
Note somewhat heterogeneous
PV responses among different
individuals. However, in the
majority, end-systolic pressure
(ESP) tends to increase after
MVR. Furthermore, most of the
patients show an immediate
increase in end-systolic volume
(except for patient B with a
markedly dilated LV at base-
line). Changes in cardiac index
were as follows: A, 13%; B,
39%; C, 6%; D, 41%; E, 16%;
and F, −9%.

increase. An acute decrease in LV afterload in heart failure
patients by intra-aortic balloon pumping has been shown to
induce acute leftward shifts of the LV PV plane along the
patient’s end-systolic elastance curve, resulting in an acute
increase in stroke volume and a concomitant decrease in pre-
load.31 Conversely, it can be expected that decreasing the LV
Figure 4. Ratio of forward cardiac output (CO; in mL/min)
divided by pressure-volume area (PVA; in mm Hg∙mL) multiplied
by heart rate (HR; in bpm) before and after percutaneous mitral
valve repair (MVR). Each box plot shows median (thick lines),
quartiles (upper and lower box boundaries), and extreme values
(whiskers). Small circles indicate outlier values.
Downloaded from http://circ.ahajournals.org/ by guest on March 17, 2015
offloading effects of MR will acutely increase the afterload
along the patient’s end-systolic elastance.
Contrary to the general notion, afterload tends to be high
in chronic MR as a result of progressive ventricular enlarge-
ment, particularly in the decompensated stage.20,32 Thus, an
uncontrolled increase in LV afterload, also called afterload
excess, is an important concern after MR correction because
it may lead to further deterioration of LV function. Several
studies have documented a significant increase in systolic
LV load after successful mitral valve surgery in patients with
chronic decompensated MR but not in the chronic compen-
sated stage.19,33 It may well be that some of our patients were
in the chronic decompensated stage, which would explain the
increase in afterload. However, an important difference from
previously mentioned studies is that we assessed cardiac load-
ing conditions immediately (ie, minutes) after correction of
the MR, whereas others used echocardiographic assessment
several days after surgery, allowing early LV remodeling to
take place.
Compared with patients with DMR, the reduction in LV
preload (measured by end-diastolic pressure and WSED) and
increase in CI were significantly lower in FMR patients.
These differences in ventricular unloading after MVR in
DMR versus FMR patients can be explained by fundamen-
tally different pathophysiologic mechanisms underlying the
1024  Circulation  March 5, 2013

Table 3. Hemodynamic Variables Before and After Mitral Valve Repair According to Mitral Regurgitation Type
Degenerative (n=16) Nondegenerative (Functional + Mixed) (n=17)
Median
Baseline After MVR Median Difference Difference, % Baseline After MVR Difference Difference, % P*

EDP, mm Hg 14 (10 to 18) 9 (7 to 12) −4 (−9 to −1) −30 (−40 to −11) 14 (11 to 17) 12 (10 to 15) 0 (−4 to 3) 0 (−24 to 17) 0.01
mPAP, mm Hg 28 (24 to 34) 26 (22 to 32) −2 (−9 to 2) −8 (−23 to 6) 29 (23 to 32) 25 (20 to 29) −3 (−4 to −1) −10 (−13 to −4) 0.99
mPCWP, mm Hg 19 (13 to 22) 12 (9 to 13) −7 (−10 to −2) −34 (−49 to −16) 15 (12 to 18) 12 (10 to 14) −3 (−6 to 0) −26 (−35 to 0) 0.11
WSES, mm Hg 149 (130 to 189) 185 (150 to 212) 28 (6 to 62) 23 (4 to 40) 200† (181 to 244) 225‡ (191 to 275) 32 (9 to 58) 16 (4 to 33) 0.54
WSED, mm Hg 40 (25 to 57) 25 (18 to 34) −13 (−25 to −2) −37 (−42 to −11) 53 (38 to 60) 44‡ (36 to 60) 0 (−16 to 7) 1 (−27 to 15) 0.02
SCI, mm Hg∙ 7.9 (6.4 to 10.8) 9.1 (5.9 to 10.7) −0.0 (−0.8 to 1.1) 0 (−9 to 15) 3.1† (2.3 to 4.7) 3.7‡ (2.6 to 5.5) 3.7 (2.6 to 5.5) 7 (−7 to 30) 0.14
mL−1∙s−1
ESPVR, mm Hg/mL 2.2 (1.7 to 3.7) 2.0 (1.1 to 2.9) −0.3 (−0.7 to 0.0) −16 (−33 to 0) 0.7† (0.5 to 1.5) 0.8‡ (0.5 to 1.4) 0.0 (−0.1 to 0.1) 7 (−16 to 19) 0.02
PRSW, mm Hg 54 (44 to 67) 43 (29 to 58) −10 (−22 to −2) −20 (−43 to −3) 29† (17 to 40) 24‡ (17 to 37) −3 (−6 to 3) −11 (−20 to 16) 0.04
eSW, mm Hg∙mL 6470 (4530 4479 (2992 −1709 (−3326 −31 (−49 to −2) 6351 (3083 4778 (2672 67 (−1436 1 (−20 to 15) 0.02
to 7651) to 6447) to −80) to 8407) to 7924) to 447)
CI, L∙min−1∙m−2 2.6 (2.3 to 3.7) 3.7 (2.7 to 5.2) 1.1 (0.3 to 1.7) 34 (11 to 63) 2.5 (2.1 to 3.4) 2.7‡ (2.4 to 3.6) 0.3 (0.1 to 0.6) 14 (2 to 28) 0.02
CI indicates cardiac index; EDP, end-diastolic pressure; ESPVR, end-systolic pressure-volume relationship; eSW, external stroke work; mPAP, mean pulmonary artery
pressure; mPCWP, mean pulmonary capillary wedge pressure; MVR, mitral valve repair; PRSW, preload-recruitable stroke work; SCI, Starling contractile index; WSED,
end-diastolic wall stress; and WSES, end-systolic wall stress.
*P value for comparison of relative changes between groups.
†P<0.05 for between-group comparisons of baseline variables.
‡P<0.05 for between-group comparisons of postprocedural variables.

origin of heart failure in these 2 subgroups. In DMR, the MR. However, in FMR, the pathophysiology of heart fail-
effect of MR on the LV is predominantly volume overload, ure is more complex and involves reduced contractility as a
which can be effectively reversed by reducing or abolishing result of ischemic or dilated cardiomyopathy. Hence, in this

30 40 P<0.001
P=0.002
35
25
30
mPCWP (mmHg)
EDP (mmHg)

20
25
15 20
15
10
10
5
5
0 0
Bef ore MVR Af ter MVR Bef ore MVR Af ter MVR

Degenerative MR Functional MR

P=0.12
450 P=0.001 6
400
5
ESPVR (mmHg/mL)

350
WSES (mmHg)

300 4
250
3
200
150 2
100
1
50
0 0
Bef ore MVR Af ter MVR Bef ore MVR Af ter MVR
Figure 5. Individual changes in hemodynamic and conductance catheter parameters according to type of mitral regurgitation (MR): black,
degenerative MR; blue: functional MR. Box plots show median (thick lines), quartiles (upper and lower box boundaries), and extreme
values (whiskers). EDP indicates end-diastolic pressure; ESPVR, end-systolic pressure-volume relationship; mPCWP, mean pulmonary
capillary wedge pressure; and WSES, end-systolic wall stress.

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 Gaemperli et al   Pressure-Volume Loops During MitraClip   1025
Echocardiography
250 n=22
Conductance Catheter
200
Volume (mL)
150
100
50
0
Baseline CC CC Follow-Up
Echo Pre MVR Post MVR Echo
Figure 6. End-diastolic (EDV) and end-systolic (ESV) left ven-
tricular volumes at baseline, during MitraClip implantation (mitral
valve repair [MVR]), and at follow-up in 22 patients with full
echocardiographic follow-up. Note that volumes at baseline and
follow-up were obtained by echocardiography (echo), whereas
volumes during the index MVR procedure were obtained from
conductance catheter (CC).
subgroup, the hemodynamic response to percutaneous MVR
is more difficult to predict. Nonetheless, although afterload
was higher in FMR patients at baseline, there was no excess
afterload increase after MVR compared with DMR (Table
3). However, it should be noted that the sample size for both
subgroups was small, which precludes any firm clinical
conclusion.
Effects of Percutaneous MVR on LV Contractility
We could demonstrate that despite a significant acute decline
in EF, percutaneous MVR did not significantly affect LV con-
tractility measured by ESPVR estimating the end-systolic
elastance, a load-independent index of LV contractility. The
SCI also did not change significantly; however, its applica-
tion as a load-independent index of contractile state during
an MVR procedure is questionable because it will already
increase by decreasing protosystolic regurgitation. In addi-
tion, PRSW as an index of contractile state is not applicable
for MVR because eSW decreases as a result of the decrease
in MR.
Previous work has also shown substantial disparity between
EF and end-systolic indexes of LV contractility in the presence
of MR.34 Interestingly, neither load-independent parameters
of LV contractility nor EF demonstrated a clinically relevant
correlation to cardiac output, indicating that the improvement
in hemodynamic status is achieved through the reduction of
regurgitant flow rather than any substantial changes in LV
contractility.
Deterioration of LV contractility occurs late in the natu-
ral history of chronic MR and marks the transition into the
chronic decompensated stage.32,35 These patients represent a
challenge to available treatment options because LV changes
may have reached an irreversible stage when outcomes of
surgical interventions are poor.36 Therefore, it is crucial to
avoid interventions that will lead to further deterioration of
LV contractility. Interestingly, changes in load-independent
Downloaded from http://circ.ahajournals.org/ by guest on March 17, 2015
contractility parameters appeared even more favorable in
our group of patients with FMR (with even a 7% increase in
SCI and ESPVR) compared with DMR (Table 3). Thus, per-
cutaneous MVR with the MitraClip device appears to spare
LV contractility and therefore may still be considered a
EDV valuable treatment option for chronic FMR in patients with
poor ventricular contractility. On the other hand, percutane-
ous MVR does not eliminate MR in all patients, which may
contribute to poor outcomes in a subset of patients.
ESV
Effect of Percutaneous MVR on LV Energetics
Percutaneous MVR resulted in an energy transfer from eSW
to potential energy. This shift represents a loss of efficiency
in the transfer of energy from the PVA to external mechani-
cal work (eSW) and was described earlier as a physiological
response to an abrupt increase in afterload in experimental
animal models.18 However, net total mechanical energy mea-
sured by the PVA (the main determinant of myocardial oxygen
consumption) remained unchanged after MVR. Thus, the ratio
of forward cardiac output to PVA (multiplied by heart rate)
increased significantly by a median of 23%. This indicates
that percutaneous MVR may improve forward cardiac output
by approximately one fourth for a given unit of total mechani-
cal energy (PVA) and hence myocardial oxygen consumption.
This may be a particularly attractive feature in patients with
ischemic cardiomyopathy in whom myocardial oxygen deliv-
ery may be compromised and therefore an increased oxygen
demand could lead to significant myocardial ischemia.
Relationship of CC Measurements and
Hemodynamic Changes to Clinical and
Echocardiographic Outcomes
Although LV volumes do not decrease immediately after
MVR, there is a downward trend in the first months after the
procedure, with a decrease in EDV indicating a favorable
reverse LV remodeling. This reverse remodeling may be a
result of improved hemodynamic conditions from removing
(or reducing) MR (ie, lower LV filling pressures, improved
CI) combined with a sparing of LV contractility. Notably, low-
contractility parameters at baseline did not predict adverse
LV remodeling on follow-up. The reduction of systolic pul-
monary pressures on echocardiography suggests a sustained
improvement of loading conditions over the ensuing months
after percutaneous MVR.
There is evidence from prior work that the salutary hemo-
dynamic changes elicited by percutaneous MVR translate into
improved clinical outcomes.9 Nonetheless, despite the short
follow-up, event rates (death, readmission for congestive heart
failure) were considerable, given the substantial comorbid sta-
tus of our patients. However, the limited number of subjects
and the lack of a control group preclude any firm conclusion
about the relationship of the observed hemodynamic changes
with any potential clinical benefit. A recent nonrandomized
study documented superiority of percutaneous MVR over
medical treatment in patients with predominantly FMR,37 indi-
cating that despite high event rates, percutaneous MVR still
offers a clinical benefit over medical treatment. Nonetheless,
larger prospective, randomized trials are eagerly awaited to
confirm this hypothesis.
1026  Circulation  March 5, 2013
Limitations
We acknowledge a limited sample size. Additionally, a large
number of statistical tests were performed without correction
for multiplicity. However, given the novelty of the percuta-
neous MVR technique and the complexity of intraprocedural
CC measurements, the sample size appeared reasonable to
reach clinically meaningful conclusions. We cannot exclude
a potential influence of intraprocedural fluctuations in cath-
eter positioning, temperature, blood viscosity, and/or salinity
on parallel conductance, affecting estimations of LV volumes
measured by CC. However, given the percutaneous nature of
the procedure, loss of blood and electrolytes was limited and
therefore unlikely to play a significant confounding role.
We did not measure end-systolic elastance (ie, the slope
of the ESPVR, a load-independent index of LV contractility)
because doing so generally requires an intervention such as
inflation of an occlusive balloon in the inferior vena cava.
Finally, by the very nature of the procedure, all measure-
ments were acquired during general anesthesia, which is
known to underestimate loading conditions compared with
the conscious nonsedated state.9 Therefore, absolute values
for preload, afterload, and contractility parameters may be dif-
ferent in the conscious state. Additionally, hyperoxygenation
resulted in higher mixed venous oxygen saturations and con-
sequently higher values for cardiac output and CI calculated
by the Fick method than would be expected for this popula-
tion. Finally, assumptions about resting oxygen consumption
do not necessarily apply to the anesthetized patient and are a
further limitation of the Fick principle. However, because pre-
procedural and postprocedural measurements were obtained
under the same conditions, the relative changes in the latter
parameters are expected to represent true changes.
Clinical Implications
Despite significant morbidity and mortality, many patients
with severe MR are denied surgery because of a high surgi-
cal risk and poor outcomes.38 Percutaneous MVR with the
MitraClip system represents a novel and promising treatment
alternative in nonsurgical candidates. The present study dem-
onstrates that by preserving LV contractility, reducing regurgi-
tant mitral flow, and lowering LV preload, percutaneous MVR
may have beneficial hemodynamic effects. Larger prospective
trials are needed to confirm whether these beneficial hemody-
namic effects translate into improved clinical outcomes.
Sources of Funding
The study was supported financially by a research grant from Abbott
Vascular.
Disclosures
Drs Gaemperli, Biaggi, Lüscher, and Corti have received speak-
er’s or consultant honoraria from Abbott Vascular. Dr Schreuder
is an employee and a shareholder of CD Leycom, Zoetermeer, the
Netherlands. The other authors report no conflicts.
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Clinical Perspective
There is a lack of physiologic understanding of the mechanisms by which mitral valve repair may affect hemodynamic pro-
files, left ventricular (LV) loading conditions, and contractility. The MitraClip system is increasingly used for mitral valve
repair in patients at high surgical risk and allows us to study the acute effects of reducing mitral regurgitation on the LV
in a human beating heart model. This is clinically important because >50% of patients treated worldwide by percutaneous
mitral valve repair are patients with functional mitral regurgitation and reduced LV ejection fraction. Additionally, surgi-
cal studies have reported poor hemodynamic outcomes in patients with low LV ejection fraction after surgical mitral valve
repair or replacement. In contrast, the present study demonstrates, using advanced hemodynamic monitoring with real-time
pressure-volume loops, that percutaneous mitral valve repair has no adverse effect on LV contractility, reduces LV preload,
and slightly increases LV afterload. These effects translate into favorable hemodynamic outcomes (decrease in pulmonary
pressures, increase in cardiac index) even in patients with very low ejection fraction at baseline. Thus, the present study sug-
gests that percutaneous mitral valve repair is safe in patients with poor LV contractility and could be considered a therapeutic
option in patients who are poor candidates for surgery. Furthermore, real-time pressure-volume measurements may be used
to monitor immediate changes in LV loading conditions and contractility during the MitraClip procedure, particularly in
high-risk patients with very low ejection fraction.

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 Real-Time Left Ventricular Pressure-Volume Loops During Percutaneous Mitral Valve
Repair With the MitraClip System
Oliver Gaemperli, Patric Biaggi, Remo Gugelmann, Martin Osranek, Jan J. Schreuder, Ines
Bühler, Daniel Sürder, Thomas F. Lüscher, Christian Felix, Dominique Bettex, Jürg
Grünenfelder and Roberto Corti

Circulation. 2013;127:1018-1027; originally published online February 1, 2013;

doi: 10.1161/CIRCULATIONAHA.112.135061
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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