Download Diffuse myocardial fibrosis in the systemic right ventricle of patients

European Heart Journal – Cardiovascular Imaging (2013) 14, 963–968
doi:10.1093/ehjci/jet014
Diffuse myocardial fibrosis in the systemic right
ventricle of patients late after Mustard or Senning
surgery: an equilibrium contrast cardiovascular
magnetic resonance study
Carla M. Plymen 1,2,3, Dan M. Sado 1,2, Andrew M. Taylor 1,3*, Aidan P. Bolger 4,
Pier D. Lambiase 2, Marina Hughes 3, and James C. Moon 1,2
1
The Centre for Cardiovascular Imaging, UCL Institute for Cardiovascular Science, London, UK; 2Department of Cardiology, The Heart Hospital, 16-18 Westmoreland Street,
London W1G 8PH, UK; 3Cardiorespiratory Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK; and 4East Midlands Congenital Heart
Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK
Received 20 August 2012; accepted after revision 16 January 2013; online publish-ahead-of-print 6 February 2013
After atrial redirection surgery (Mustard–Senning operations) for transposition of the great arteries (TGA), the systemic right ventricle (RV) suffers from late systolic failure with high morbidity and mortality. Mechanisms of late RV
failure are poorly characterized. We hypothesized that diffuse interstitial expansion representing diffuse fibrosis is
greater in systemic RVs of patients following Mustard–Senning surgery and that it would be associated with other
markers of heart failure and disease severity.
.....................................................................................................................................................................................
Methods
We used equilibrium contrast cardiovascular magnetic resonance (CMR) imaging to quantify extracellular volume
and results
(ECV) in the septum and RV free wall of 14 adults presenting to a specialist clinic late after surgery for TGA
(8 Mustard, 6 female, median age 33). These were compared with 14 age-and sex-matched healthy volunteers.
Patients were assessed with a standardized CMR protocol, NT-brain natriuretic peptide (NT-proBNP), and cardiopulmonary exercise (CPEX) testing.
The mean septal ECV was significantly higher in patients than controls (0.254 + 0.036 vs. 0.230 + 0.032; P ¼ 0.03).
NT-proBNP positively related to septal ECV (P ¼ 0.04; r ¼ 0.55). The chronotropic index (CI) during CPEX testing
negatively related to the ECV (P ¼ 0.04; r ¼ 20.58). No relationship was seen with other CMR or CPEX parameters.
R.V free wall ECV was difficult to measure (heavy trabeculation, sternal wires, blood pool in regions of interest) with
high and poor inter-observer reproducibility: this analysis was abandoned.
.....................................................................................................................................................................................
Conclusion
Septal interstitial expansion is seen in adults late after atrial redirection surgery for TGA. It correlates well with NTproBNP and CI and may have a role in the development of RV systolic impairment. Measuring interstitial expansion in
the RV free wall is difficult using this methodology.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Congenital heart disease † Systemic right ventricle † Cardiovascular magnetic resonance imaging † Diffuse fibrosis
Introduction
Although intra-atrial repair (Mustard and Senning operations) of
transposition of the great arteries (TGA) has been largely been
superseded by the arterial switch operation, there remains a sizeable
population of adults under a regular follow-up who underwent such
early palliative surgery. With the morphologic right ventricle (RV)
supporting the systemic circulation, there is a high burden of early
morbidity and mortality from heart failure and sudden cardiac
death.1 Survival rates have been calculated at 76% by 20 years of
age2 with a mean age at death of 27 years.3 Long-term outcome in
this cohort relates to the function of the systemic RV.4
* Corresponding author: Tel: +44 20 7405 9200 (ext. 5616), Fax: +44 20 7813 8262, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
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Aims
964
Methods
Study population
Fourteen adult patients with previous Senning or Mustard surgery for
TGA, followed up in a dedicated congenital heart disease heart failure
clinic at our Institution, were prospectively recruited between June
2009 and June 2010. All patients underwent the measurement of
NT-pro BNP, CPEX testing, and CMR imaging within a 3-month
period. None required admission for decompensated heart failure
during this time. These patients were compared with 14 age- and
gender-matched normal subjects, as there is some evidence to
suggest an increase in extracellular volume (ECV) with age.20 All
normal subjects underwent cardiac history and examination, 12-lead
ECG and CMR to ensure they did not have any underlying cardiovascular disease. The study had institutional approval and all patients and
normal subjects gave informed consent to participate in the study.
NT-pro brain natriuretic peptide
The peripheral venous blood was collected from each patient after
they had rested for a minimum of 20 min. Samples were centrifuged
and immediately analysed via sandwich immunoassay, using electrochemiluminescence (E 170 Module, Roche Diagnostics, Basel,
Switzerland).
CMR
CMR was performed using a 1.5T Siemens Avanto scanner (Siemens
Medical Systems, Erlangen, Germany), with the assessment of ventricular volumes as previously described.21,22 Manual segmentation of the
ventricles, with the exclusion of the major RV trabeculae from the
blood pool volume, was undertaken. Quantification of aortic
forward flow volume, using phase contrast volumetry, provided an internal quantitative guide to the RV stroke volume and improved the
accuracy of volumetric quantification in the presence of tricuspid
valve regurgitation.23 Volumes were indexed to the body surface area.
Equilibrium contrast CMR
EQ-CMR, as previously validated against histology in aortic stenosis
and hypertrophic cardiomyopathy,17 is an add-on to a standard clinical
scan. We quantified the tissue volume of distribution, a marker of the
ECV, of the routine clinical contrast agent, Gadoteratemeglumine
(gadolinium-DOTA, marketed as Dotarem & Guerbet S.A., France),
which partitions freely between the plasma and interstitial space but
does not enter cells. Interstitial tissue volume is primarily determined
by the amount of extracellular matrix. EQ-CMR involves three steps:
(i) a standard gadolinium bolus followed by constant infusion to eliminate contrast kinetic effects and achieve an EQ state throughout the
body; (ii) signal intensity (T1) measurement pre- and post-contrast
equilibrium using CMR; and (iii) a direct measure of blood volume of
contrast distribution, by taking a complete blood count, and equating
the blood volume of contrast distribution to one minus the haematocrit. The ECV is then calculated as24:
ECV =
(1 −haematocrit) × (1/T1myocardiumpost−contrast −1/T1myocardiumpre−contrast )
.
(1/T1bloodpost−contrast −1/T1bloodpre−contrast )
In this study, T1 mapping was performed using the same method as
previously described, fast low angle single shot inversion recovery
(FLASH IR) at increasing inversion times, in a mid-short axis slice.17
The blood T1 was assessed using a region of interest within the LV
cavity. The myocardial T1 was assessed using a region of interest
within the interventricular septum and also within the RV free wall.
Cardiopulmonary exercise testing
CPEX was performed on an electronically braked ergometer cycle
(Lode, Groningen, Holland) with computerized breath-by-breath ventilator gas analysis (MedGraphics, MN, USA). Prior to exercising, height
and weight were measured and all sensors calibrated. Patients wore a
full-face mask connected to an expiratory limb pneumotachograph,
allowing sampling of mouth tidal PCO2 and PO2. A 12-lead ECG
was recorded at rest, continuously during exercise and into recovery.
Patients were encouraged to exercise to full capacity on an incremental protocol. Workload increased at 15– 25 W depending on the
underlying fitness level; however, the ramping protocol included an
initial loadless 3 min of cycling to allow equilibration. Criteria for
ending the test included clinical need or patient exhaustion; having
aimed for, or achieved a respiratory exchange rate .1.01. A period
of active recovery (slow pedalling) followed maximal exertion.
Cuff blood pressure was checked every 2 min, and transvenous
oxygen saturations were measured continuously via a probe positioned over the right supraorbital artery. Peak oxygen uptake
(pVO2), anaerobic threshold (AT), and ventilatory response to CO2
production (VE/VCO2) were derived from the respiratory gas analysis
during maximal exertion. VE/VCO2 was measured as the ratio at the
AT. In turn, AT was determined by using the modified V-slope
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Cardiovascular magnetic resonance (CMR) imaging is an accurate
and reproducible method for assessing systolic function of the systemic RV and is widely regarded as the best available imaging modality for this purpose.5,6
Other markers of heart failure severity, including high circulating
brain natriuretic peptide (NT-proBNP) levels and impaired cardiopulmonary exercise (CPEX) performance, have also been
described in adults with congenital heart disease.7 – 9 Both measures have been shown to relate to long-term prognosis in
mixed cohorts with congenital heart disease (CHD) and in those
with a systemic RV.10 – 15
Myocardial fibrosis is considered to be a marker of disease
severity and its presence is used to monitor disease progression
and regression.16 In those with previous Mustard or Senning
surgery, focal fibrosis, assessed using the late gadolinium enhancement (LGE) technique, has been found to correlate with systolic
function of the systemic RV and with documented arrhythmia.17
However, the LGE method does not allow the evaluation of
diffuse fibrosis and this latter has been found to correlate with systemic RV end-diastolic volume and ejection fraction in a small
cohort described by Broberg et al.18 Our group has previously validated equilibrium contrast CMR (EQ-CMR) against cardiac biopsy
determination of diffuse fibrosis for the assessment of left ventricular interstitial expansion (a surrogate marker of diffuse fibrosis in
most disease states) in patients with severe aortic stenosis and
hypertrophic cardiomyopathy.19 The technique is similar to that
of Broberg, but the use of EQ removes uncertainties regarding
contrast kinetics in heart failure or renal impairment and does
not require an assumption of pseudo-equilibrium.
In this prospective study, we used EQ-CMR to evaluate diffuse
fibrosis in adults late after atrial redirection surgery for TGA, comparing the results to both normal subjects and also other heart
failure parameters to determine its usefulness as a measure of
disease severity.
C.M. Plymen et al.
965
Diffuse myocardial fibrosis in the systemic right ventricle
method. The chronotropic index (CI) was calculated as has been previously described13 as: ( peak HR 2 resting HR) over (220-age-resting
HR).
Statistical analysis
The Kolmogorov – Smirnov test was used to assess normality. Values
are expressed as mean + SD, median (25 – 75th percentile values),
or percentages, as appropriate. Univariate comparisons were performed by Student’s t-test, Mann– Whitney U test, and x2 test for normally distributed, non-normally distributed and categorical variables
respectively. Pearson’s or Spearman’s correlation coefficients were
used as appropriate to look for univariate associations between continuous variables (SPSS, Inc., Chicago, USA and GraphPad Software,
Inc., La Jolla, USA). Differences were considered to be significant at
a P-value ,0.05.
Results
Patient and control subject
characteristics
CMR
The mean indexed RV end-diastolic volume (RVEDVi) was 79 +
13 mL/min2, mean indexed RV end-systolic volume (RVESVi)
35 + 4 mL/min2, and mean RV ejection fraction (RVEF) 59 + 5%
(Table 1). No patients had any focal, macroscopic areas of LGE.
The mean septal ECV in patients was 0.254 + 0.036, which was
significantly higher than that of normal subjects (0.230 + 0.032;
P ¼ 0.03). There was no correlation between CMR measures of
systemic RV volume or systolic function to septal ECV.
Table 1 EDVi and ESVi refer to indexed ventricular
volumes during diastole and systole, respectively
d-TGA
(n 5 14)
Controls
(n214)
P-value
34 + 7
10 (7– 20)
32 (24– 49)
–/ –
0.64
–/–
8/6
14/20
–/–
–/–
................................................................................
Age, years
Age at surgery,
median (range),
months
Male/female
8/6
NYHA functional
12/2
class I/II
CMR: systemic ventricular
EDVi, mL/m2
79 + 13
70 + 15
0.11
ESVi, mL/m2
EF, %
35 + 4
59 + 5
25 + 8
66 + 5
0.002
0.002
Septal ECV
0.254 + 0.036
0.23 + 0.032
0.03
EQ-CMR and NT-proBNP
The median NT-proBNP was 19.5 (14 –45) pmol/L. NT-proBNP
showed a positive relationship with septal ECV, P ¼ 0.04; r ¼ 0.55
(Figure 2).
EQ-CMR and CPEX testing
CPEX testing provided the following data: mean CI 0.69 + 0.21,
mean pVO2 22 + 8 mL/kg/min, and mean VE/VCO2 slope 28 + 5.
There was no association between septal ECV and either pVO2
(P ¼ 0.24; r ¼ 0.38) or VE/VCO2 slope (P ¼ 0.60; r ¼ 0.18).
There was, however, a significant negative correlation between
septal ECV and chronotropic index (P ¼ 0.04; r ¼ 0.58; Figure 3).
Discussion
This study suggests that diffuse fibrosis is more pronounced in the
myocardium of the systemic RV of adults late after palliation of
TGA compared with controls. The extent of interstitial expansion
was related to known markers of disease severity and outcome
parameters (NT-proBNP and chronotropic index) suggesting a
potential causative role.
Lifelong maintenance of the systemic circulation by the morphological RV results in a heart failure phenotype that is associated
with significant early morbidity and premature mortality.2,3 Evidence is emerging that myocardial fibrosis, determined histologically or by CMR, is a key factor in the development of
ventricular dysfunction in patients with both acquired and congenital heart disease where pressure overload is the principal
insult.17,18 Further, LGE on CMR has been linked to prolongation
of ECG parameters associated with inhomogenous electrical activation associated with sudden cardiac death17. Quantifying myocardial fibrosis in patients with systemic RVs also provides an
additional measure of disease severity. Further studies are
needed to investigate the clinical usefulness of EQ-CMR in predicting the outcome in this group.
We have previously validated EQ-CMR as a novel non-invasive
technique to quantify diffuse myocardial fibrosis in adults with
left ventricular disease19. In the present prospective study, we
used a similar method to identify and quantify diffuse myocardial
fibrosis in adults with atrial switch palliation of TGA. Our results
are similar to those of Broberg et al. 18 who used a bolus technique
as opposed to EQ-CMR. There are a number of T1 mapping-based
techniques in development by CMR currently.25 The use here of an
infusion of gadolinium, to reach contrast equilibrium, eliminates
contrast kinetics, which can alter in an individual over time (for
example, due to changes in body weight or renal function) which
may permit more precise evaluation of changes over time in any
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The fourteen patients (six females) had a mean age of 33.7 + 6.5
years and the median age at palliation of 9.7(7– 20) months
(Table 1). Six (43%) had Senning palliation. Details of the 14
normal subjects (six females, median age 32, range 24 –49) are
also in Table 1.
Right ventricular free wall ECV
We were unable to accurately assess the ECV in the right ventricular free wall (or any other right ventricular segment away from the
septum) using the current method. This was mainly due to trabeculation that resulted in myocardial regions of interest partial
voluming with the blood. The presence of blood in the region of
interest will falsely elevate the ECV. The problem is illustrated in
Figure 1. This assessment was therefore abandoned and only
septal ECV is reported.
966
C.M. Plymen et al.
Figure 1 FLASH IR short-axis images from a patient with a systemic right ventricle taken at an inversion time of 700 ms on contrast infusion
are shown. In (A) the anatomy is depicted (RV, right ventricle and LV, left ventricle). In (B) the problems in assessing right ventricular free wall T1
are shown. The region of interest draws partial volumes both blood and myocardium due to trabeculation. Although less important, artefact
from sternal wires is also present (arrowed). Partial voluming with the myocardium and the blood was a problem in nearly all patients in all right
ventricular segments.
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Figure 2 Graph shows positive relationship between increasing
NT-proBNP and Septal ECV.
Figure 3 A significant negative relationship between CI and
septal ECV.
individual, important both in the clinical and research settings. The
technique has been validated against histology in aortic stenosis
and hypertrophic cardiomyopathy19. Although the bolus gadolinium technique is perhaps simpler, the total CMR scan time in
our cohort remained at 1 h for all patients, as we gave the
bolus and infusion early in the protocol while continuing to scan
other parameters during equilibration. Despite the differences in
study method, the results obtained in both small studies are
similar, and suggest that CMR diffuse fibrosis assessment is a
useful biomarker in this cohort of patients.
Earlier work has confirmed that focal myocardial scar, as represented by localized LGE of the myocardium on CMR imaging, can
be present in patients with atrial switch palliated TGA, and relates
to the systolic function of the systemic RV17. This finding most
likely reflects localized surgical insult or coronary insufficiency
(due to RV hypertrophy or abnormal coronary circulation). In
967
Diffuse myocardial fibrosis in the systemic right ventricle
and fibrosis in conjunction with the effects of corrective surgery.
Akoum et al. 36 has recently demonstrated significant correlations
between atrial fibrosis using LGE and sinus node disease supporting pathological studies and recent murine models of the process.
Therefore, although our study did not seek to identify diffuse fibrosis at the sinus node, given the early palliative intervention and subsequent lifelong adverse physiology, it is likely that the septal
hypertrophy identified is not an isolated process and similar
changes are occurring in the atria and SA node leading to chronotropic incompetence which could be explored as CMR resolution
of fibrosis improves.
The septal fibrosis seen on EQ-CMR may therefore underlie the
conduction pathway problems that develop in such patients, possibly due to myocardial disarray. It will be interesting to see
whether the degree of abnormality can predict future development of conduction block and the need for pacing.
Limitations
Our study is limited in the size and further larger-scale investigation is needed. Although the results show the potential for the
technique to be useful, newer methods for T1 mapping have recently become available and show the potential for higher resolution whole heart mapping in three breath holds.37 These could
allow more accurate assessment of the RV free wall, which we
were unable to assess in this study. Further, this study was
limited in that no echocardiographic diastolic data were
acquired—this will need further study and inclusion in future work.
Despite the presence of RV hypertrophy in the patient cohort,
the assessment of diffuse fibrosis in the anterior free wall of the RV
was technically problematic. The ubiquitous presence of trabeculation within the systemic RV free wall leaves very few areas of the
compacted RV myocardium during diastole that are without blood
pool contamination. If zones of the blood pool are included in the
myocardial analysed region of interest, the ECV would be falsely
elevated. Metal artefact from sternal wires also contributed to
artefact in this zone in many patients.
Conclusion
This is a proof of a concept study to investigate and quantify diffuse
fibrosis in the myocardium of adults with a systemic RV using a
non-invasive CMR technique. We find that diffuse fibrosis is
present in the septum of adults with a systemic RV, late after
Senning, or Mustard palliation for TGA. The extent of diffuse fibrosis showed association with NT-proBNP measurement and may
aid in the identification of patients at risk of developing bradyarrhythmia. Larger and longer-term studies are needed to determine
whether such diffuse fibrosis is of prognostic significance and
whether its extent can be modified with therapeutic intervention.
Funding
C.M.P. and D.M.S. are funded by clinical fellowships from the British
Heart Foundation. J.C.M. and P.L. receive funding from the Higher
Education Funding Council for England. A.M.T. is funded via the UK
National Institute for Health Research and Foundation Leducq.
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our study, we did not find that the ECV related to measures of RV
size or systolic function. This may reflect the small cohort size
involved, or may suggest early pathophysiological detection of
disease such that diffuse fibrosis is a precursor to measurable RV
dysfunction. It is worth noting that the mean RVEF of this study
cohort was within the perceived normal range. It is possible that
such diffuse fibrosis may relate to diastolic dysfunction in the systemic RV. In our study, diastolic function was not assessed with
MRI, as echocardiographic techniques for diastology have a temporal resolution and sensitivity that far surpasses that of current
MR techniques. Echocardiographic correlation may be crucial for
further investigation of this issue.
Interestingly, diffuse fibrosis was found to relate to NT-proBNP.
This is an established neurohormonal marker of disease in the
general cardiology population.26 It is also increasingly being recognized as a valuable tool in CHD, and specifically in TGA, where it
correlates to systemic RV function as determined by CMR.27 In the
general, cardiology population NT-proBNP has an established role
in detecting asymptomatic left ventricular dysfunction in high-risk
populations28 and in predicting cardiovascular events in those
with preserved ventricular function.29 The finding of diffuse fibrosis
on CMR imaging in the setting of preserved RV systolic function
may represent a similar early warning sign.
Septal ECV also showed a negative correlation to the chronotropic index, but no relation to pVO2 or VE/VCO2—both established independent markers of the outcome in CHD. Giardini
et al.30 studied adults with a systemic RV and previous Mustard
or Senning palliation and proposed a VE/VCO2 slope cut-off
.35.4 as being predictive of 4-year mortality or cardiac-related admission, suggesting that our cohort was quite well managed at the
time of study. Similarly, values for pVO2 in this cohort were above
the levels previously published as predictors of adverse events in
congenital cohorts.11 Adults with a systemic RV often describe
themselves as well and asymptomatic, despite objective evidence
to the contrary.31 Formal exercise testing has, however, found
that the majority with a systemic RV have chronotropic incompetence and furthermore, that in a proportion of those studied, such
inability to increase heart rate was unrelated to metabolic parameters, suggesting that this alone may be causing exercise intolerance.12 Whether our finding represents early detection of ensuing
RV dysfunction remains to be determined; however, it is likely that
any underlying cause is multifactorial. It is of interest to note that a
study of adults with hypertrophic cardiomyopathy also found a relationship between LGE on CMR and blunted heart rate response
on exercise.32 Such LGE has been found to be an independent predictor of deficient exercise capacity in such cohorts,33 however,
relationship to outcome and underlying mechanism is not yet
established.
It is important to note here the small but a significant annual incidence of bradyarrhythmias and complete heart block that occur
in our population. Such arrhythmias increase with time during the
follow-up2, and published frequency of pacemaker insertions varies
from 5 to 11%2,34 It is well recognized that sick sinus syndrome is
associated with a diffuse fibrotic process in the sinoatrial node and
indeed a recent murine model has recapitulated this.35 Furthermore, the patients presented in this paper develop increased
atrial wall stress and stretch which will promote local hypertrophy
968
Conflict of interest: none declared.
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