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Original Research |
1 Department of Cardiology, VU University Medical Center, Amsterdam, The
Netherlands.
2 Present address: Department of Cardiology, Glenfield Hospital, Groby Rd.,
Leicester LE3 9QP, United Kingdom.
3 Department of Pulmonology, VU University Medical Center, Amsterdam, The
Netherlands.
4 Department of Pathology, VU University Medical Center, Amsterdam, The
Netherlands.
Received August 4, 2005;
accepted after revision May 25, 2006.
G. P. McCann was supported by a European Society of Cardiology clinical
training fellowship, the East Midlands Heart and East Midlands Pacemaker
Research Funds.
Abstract
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SUBJECTS AND METHODS. Fifteen patients (age, 45.6 ± 13 years; 13 New York Heart Association class III) with pulmonary artery hypertension (11 idiopathic, four systemic sclerosis) were studied. All patients had undergone a comprehensive diagnostic workup, and pulmonary artery hypertension (mean pulmonary artery pressure, 54 ± 16 mm Hg) was confirmed by cardiac catheterization. Cardiac MRI was performed on a 1.5-T scanner to determine ventricular volumes and mass. Delayed contrast enhancement of a mass was seen 10-20 minutes after the IV injection of 0.2 mmol/kg of gadopentetate dimeglumine using an inversion recovery gradient-echo sequence.
RESULTS. All patients showed delayed contrast enhancement at the insertion points of the right ventricular free wall to the interventricular septum (15 inferior, 13 anterior). The mean weight of the delayed contrast-enhanced myocardial mass was 3.1 ± 1.9 g (size range, 0.3-3.9% of the total myocardial mass). The extent of the delayed contrast-enhancing myocardium was inversely related to the right ventricular ejection fraction (r = -0.63, p = 0.001), right ventricular stroke volume (r = -0.67, p = 0.006), and right ventricular end-systolic volume index (r = -0.51, p =0.05) but not to any invasively measured hemodynamic index or N-terminal pro brain natriuretic peptide.
CONCLUSION. Myocardial delayed contrast enhancement occurs frequently in patients with severe symptomatic pulmonary artery hypertension and is inversely related to measures of right ventricular systolic function.
Keywords: cardiac MRI • cardiopulmonary imaging • delayed contrast enhancement • MR contrast agents • MRI • pulmonary artery hypertension • right ventricular function
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Cardiac MRI is the gold standard technique for the assessment of ventricular function and quantification of volumes and mass without geometric assumptions [4]. Right ventricular volumes, mass, and function can be quantified with excellent intra- and interobserver variability [5] and good interstudy reproducibility [6]. The addition of delayed contrast-enhanced cardiac MRI with the inert extracellular contrast agent gadopentetate dimeglumine (Magnevist, Schering) allows in vivo visualization of both infarct-related scars [7] and more diffuse myocardial fibrosis associated with various cardiomyopathies [8-12]. Although there are numerous reports of delayed contrast-enhanced cardiac MRI in conditions affecting the left ventricle, only one study has focused on PAH [13]. Delayed contrast enhancement was seen in the interventricular septum at the right ventricular insertion points in 23 of 25 patients, and the extent of enhancement was related to right ventricular dysfunction and pulmonary hemodynamics [13].
We aimed to assess the presence and extent of delayed contrast enhancement on cardiac MRI in patients with severe PAH. We hypothesized that hyperenhancement would be present in the right ventricle and that the extent of hyperenhancement would correlate with systolic function and hemodynamic indexes of severity.
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Cardiac MRI
All images were acquired on a 1.5-T clinical scanner (Sonata, Siemens
Medical Solutions) with prospective ECG gating during repeated breath-holds of
6-15 seconds, depending on the patient's heart rate.
Cine Imaging
After scout imaging was performed, a steady-state free precession sequence
(true fast imaging with steady-state free precession [FISP]) was used to
acquire functional images of the heart. Sequence parameters were TR/TE,
3.1/1.6; flip angle, 60°; slice thickness, 5.0 mm; slice spacing, 5.0 mm;
13-15 segments per heart beat, giving a temporal resolution of 40-46
milliseconds. The matrix was 256 x 156, and the field of view was
altered (300-400 x 204-352 mm) according to individual patient body size
to minimize infolding, giving an in-plane spatial resolution of 1.2-1.6
x 1.3-2.2 mm.
Standard long-axis views—four-chamber, two-chamber, and three-chamber
(left ventricular outflow tract)—and right ventricular two- and
three-chamber views were obtained. A stack of short-axis slices, planned on
the four-chamber view, perpendicular to the interventricular septum and
parallel to the plane of the mitral valve, was acquired, with complete
coverage from the base to the apex. The stack of short-axis slices allows
calculation of left ventricular and right ventricular mass, volume, and
ejection fraction without any geometric assumptions
[17]. The extent of
pericardial effusion was graded according to maximum diameter of fluid seen in
any view (0, none; 1, trace; 2, 
10 mm; and 3, > 10 mm)
[2]. The left ventricular
eccentricity index was calculated at mid ventricular level in the short-axis
orientation [2] at end-diastole
and during maximal septal displacement during early diastole. Tricuspid
regurgitation was graded semiquantitatively by assessing the area of signal
void in the right atrium.
Delayed Contrast Enhancement
Delayed contrast-enhanced images were acquired by copying the image
position for each of the short-axis slices and long-axis views as for cine
images, 10-20 minutes (mean, 14 minutes) after the administration of 0.2
mmol/kg of gadopentetate dimeglumine (Magnevist, Schering) using a 2D
inversion recovery fast gradient-echo sequence
[18] with triggering on
alternate cycles to late diastole (
100 milliseconds before the next Q
wave on the ECG). Sequence parameters were 9.6/4.4; matrix, 256 x 208;
flip angle, 25°; slice thickness, 5.0 mm; and slice spacing, 5.0 mm.
Meticulous attention was paid to the inversion time to null normal myocardium
with typical values of 250-300 milliseconds. Patients with severe tricuspid
regurgitation and right ventricular dysfunction tended to require a lower
inversion time—approximately 200-220 milliseconds—for optimal
nulling. In two patients a single-shot sequence rather than a segmented
sequence was used to minimize breathing artifacts
[19]. If doubt existed about
the presence of hyperenhancement, the phase-encoding direction was switched to
enable differentiation from image artifacts.
Because hyperenhancement was not usually seen in the standard long-axis
views, a modified two-chamber view planned perpendicularly through the
inferior right ventricular insertion point was performed in several patients
to show enhancement in a long-axis view. The presence of hyperenhancement was
agreed on by two experienced observers. Endocardial and epicardial borders
were traced manually, excluding trabeculations and papillary muscles.
Hyperenhancement was defined by visual analysis, during which the window
setting could be freely adjusted to the personal preference of the observer.
Hyperenhanced regions were manually contoured on each short-axis slice, and
the total volume of hyperenhancement was calculated by the software package
MASS (Medis) and converted to mass by multiplying by 1.05. Delayed
contrast-enhanced mass was expressed as a percentage of the total (left
ventricular plus right ventricular) myocardial mass. Semiautomatic analysis,
by setting a window threshold for signal intensity, was not performed because
doing so can lead to large overestimations of hyperenhancement compared with
manual contouring [20].
Interobserver agreement for the presence of abnormal delayed contrast
enhancement (
, 0.76)
[18] and interobserver (5%
± 18%) and intraobserver (4% ± 7%) variability for
quantification of delayed contrast-enhanced mass
[20] were excellent for our
group of patients.
Cardiac Catheterization
Diagnostic right heart catheterization was performed with a balloon-tipped,
flow-directed 7-French Swan-Ganz catheter (131HF7, Baxter Health Care) within
2 days of cardiac MRI measurements in 14 patients. The other patient underwent
catheterization at diagnosis but it was not repeated at the time of cardiac
MRI, and hemodynamic data are not included for this patient. Right atrial,
right ventricular, pulmonary artery, and pulmonary capillary wedge pressures
were measured. Blood was sampled with the catheter positioned in the main
pulmonary artery. Arterial oxygen saturation was measured from blood sampled
from the radial artery. Cardiac output was assessed by the Fick oxygen method,
and pulmonary vascular resistance was calculated using the standard
formula.
N-Terminal Pro Brain Natriuretic Peptide
The N-terminal pro brain natriuretic peptide (N-BNP) was measured using a
commercially available assay within 48 hours of cardiac MRI.
Statistical Analyses
Analyses were performed using the computer software package Minitab,
version 11.21 (Minitab). All ventricular volumes and masses were indexed by
body surface area. The relationship between the weight of hyperenhanced mass
and clinical, hemodynamic, and cardiac MRI variables was assessed using linear
regression analysis for continuous and logistic regression analysis for
categoric variables. Variables entered into the regression analyses were the
clinical variables age, sex, time since diagnosis, N-BNP (log transformed to
normalize data), and the 6-minute walking distance; the hemodynamic variables
right atrial pressure, mean PAP, right ventricular end-diastolic pressure,
pulmonary vascular resistance, and cardiac index; and the cardiac MRI
variables right ventricular and left ventricular end-diastolic and
end-systolic volumes, masses, and ejection fractions, left ventricular
eccentricity index, tricuspid regurgitation grade, and pericardial effusion
grade. A formal power calculation was not performed at the time of study
planning because to our knowledge there had been no previous publications on
delayed contrast enhancement in PAH to guide sample size requirements. Results
are expressed as mean ± SD or median, and interquartile range is given
where stated. A p value of less than 0.05 was considered
statistically significant.
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Delayed Contrast Enhancement
All patients showed hyperenhancement of ventricular myocardium (mean
weight, 3.1 ± 1.9 g; size range, 0.3-3.9% of total myocardial mass) in
the interventricular septum. Hyperenhancement occurred almost exclusively at
the right ventricular insertion points (15 inferior, 13 anterior) and was more
prominent toward the base of the heart (Figs.
1A,
1B,
1C,
1D and
2A,
2B,
2C,
2D). No subendocardial or
transmural enhancement and no hyperenhancement were seen in the right
ventricular or left ventricular free walls. The extent of hyperenhancement was
not correlated with any clinical or hemodynamic variable but was inversely
correlated with stroke volume index (r = -0.67, p = 0.006) and right
ventricular ejection fraction (r = -0.63, p = 0.01) measured on cardiac MRI. A
trend was seen toward significance for the correlation with the right
ventricular end-systolic volume index (r = -0.51, p = 0.052).
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Comparison with Previous Studies
Our findings are similar to the those in the only other report of delayed
contrast enhancement in PAH, a study by Blyth et al.
[13], in which 23 of 25
patients had hyperenhancement affecting the right ventricular insertion
points. The extent of hyperenhancement was similar, as were the correlations
with right ventricular volumes and the inverse correlation with the right
ventricular ejection fraction
[13]. We did not find a
significant correlation with invasively measured PAP, probably because of the
different populations in the two studies. The subjects in our study tended to
have more severe disease, as manifested by greater PAPs, right ventricular
volumes, reduced systolic function, and longer duration of illness. In the
study by Blyth et al., patients were not receiving any specific treatment for
pulmonary hypertension, whereas most of our patients were being reassessed for
response to treatments that reduce PAP. This fact may explain why delayed
contrast enhancement did not correlate with invasive hemodynamics in our
study.
Delayed contrast enhancement of the septal right ventricular insertion point has also been reported in congenital heart disease with right ventricle overload [21, 22]. In transposition of the great arteries, in which right ventricular pressures may be similar to those in severe PAH, the extent of hyperenhancement also correlates inversely with right ventricular ejection fraction [21].
Cause of Delayed Contrast Enhancement in PAH
Delayed contrast enhancement has been characterized best in relation to
ischemic heart disease. The typical pattern is of transmural or subendocardial
enhancement following the territory supplied by one or more coronary arteries
[7,
18,
23]. In this situation,
hyperenhancement represents a collagenous scar formation
[7]. The extent of delayed
enhancement on cardiac MRI has also correlated significantly with myocardial
collagen, but not with myocyte disarray, in a single patient with hypertrophic
obstructive cardiomyopathy who underwent heart transplantation
[24]. In other forms of
cardiomyopathy, late enhancement is also likely to represent interstitial
fibrosis [9,
11]. Enhancement at the right
ventricular insertion points has been seen, particularly in patients with
hypertrophic cardiomyopathy
[10,
25], and may reflect focal
fibrosis [26]. Myocardial
disarray is frequently seen at the right ventricular junctions, even in
healthy subjects [27], but
disarray was not related to enhancement in an individual patient with
hypertrophic obstructive cardiomyopathy
[24].
Histologic studies of PAH have focused on changes in the pulmonary vasculature [28]. We, like other authors [13], failed to identify any reports of histologic changes in the right ventricular myocardium in patients with PAH despite the importance of right ventricular function to prognosis [3]. Given that all the patients in our study and all but two (with mild disease and normal right ventricular function) of 25 in a previous report [13] showed delayed contrast enhancement at the right ventricular insertion points, we think that histologic results obtained in two patients with PAH who died and underwent postmortem autopsy, but who did not undergo cardiac MRI during the study period, are likely to be representative of PAH patients in general. In these two patients, fibrosis was present at the right ventricular insertion points (Appendix 1 and Fig. 3A, 3B, 3C) suggesting that this is the causal mechanism of delayed contrast enhancement in our study. However, we also saw evidence of interstitial space expansion, which may increase the volume of distribution of gadopentetate dimeglumine and contribute to hyperenhancement in these areas. Indeed, inflammation is an early response to pressure overload leading to interstitial fibrosis [29] and is also associated with delayed contrast enhancement in acute myocarditis [30]. The small increase in fat, seen at a distance from the perivascular regions, may also contribute to hyperenhancement in these areas because fat also has a high signal intensity on the inversion recovery gradient-echo sequence used for delayed contrast enhancement.
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These findings suggest that the insertion points are particularly prone to developing fibrosis. These junctional areas have considerable forces acting on them—the circumferential strain of left ventricular myocardial shortening and right ventricular longitudinal shortening—which may explain why myocardial disarray and some fibrosis not extending into the mid myocardium may be observed in healthy individuals [27]. In PAH, the force generation required for right ventricular systolic emptying is greatly increased and there is the added abnormal interventricular septal motion, which may create further shear stress at the interventricular septal insertion points. However, the pattern of delayed contrast enhancement is specific neither to the underlying cause [13] nor to PAH [10, 25].
Significance of Delayed Contrast Enhancement
The extent of delayed contrast enhancement in this study was moderately
correlated with cardiac MRI parameters of right ventricular dysfunction. Right
ventricular systolic dysfunction is closely related to right heart failure,
the commonest cause of death in PAH
[1,
31], but right ventricular
ejection fraction is difficult to measure with echocardiography, and there is
a lack of outcome studies with cardiac MRI-measured ejection fraction. No
significant correlation was seen with any other hemodynamic or clinical
variable that has been shown to predict outcome in PAH
[3,
15]. Therefore, the
significance of contrast enhancement is unclear and remains to be elucidated
in a longitudinal study of PAH. Delayed contrast enhancement in hypertrophic
cardiomyopathy correlates with risk factors for sudden death
[10] and, in transposition of
the great arteries, with clinical events, including syncope and nonsustained
ventricular tachycardia [21].
One may speculate that the focal nature of the delayed contrast enhancement in
PAH, which probably represents fibrosis, may act as a trigger for potentially
fatal ventricular tachyarrhythmias contributing to the risk of sudden cardiac
death.
Study Limitations
The patients in this study were highly selected, and therefore our results
may not be applicable to patients with less severe PAH. The cause and
significance of delayed contrast enhancement in PAH need to be determined in
future studies. Because this is a cross-sectional study, we are uncertain
whether delayed contrast enhancement precedes right ventricular dysfunction,
and we cannot say that they are causally related. As in other conditions, the
extent of delayed contrast enhancement may vary with time
[32,
33], although because the PAP
remains elevated we assume the stimuli causing hyperenhancement will also
remain, making regression of hyperenhancement less likely. The severity of
tricuspid incompetence was assessed semiquantitatively on steady-state free
precession imaging and may be underestimated in comparison with fast
gradient-echo imaging.
Conclusion
Delayed enhancement on cardiac MRI occurs frequently in patients with
severe symptomatic PAH and is inversely related to measures of right
ventricular systolic function. The significance of hyperenhancement in this
population needs to be determined in a longitudinal study.
APPENDIX 1: Histology of Pulmonary Artery Hypertension
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Both patients showed similar histologic changes. The results for patient A are shown in Figure 3A, 3B, 3C. The mid interventricular septum had an essentially normal appearance with closely packed cardiomyocytes and minimal fatty deposition in the perivascular regions (Fig. 3C). At the insertion points of the right ventricle to the interventricular septum (Figs. 3A and 3B) was seen cardiomyocyte disarray with marked expansion of extracellular spaces adjacent to areas of interstitial or replacement fibrosis and increased fat deposition, beyond the perivascular regions.
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