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Cardiac Imaging |
1 From the Departments of Pulmonology (R.J.R., T.J.G., A.B., P.E.P., A.V.N.) and Physics and Medical Technology (J.T.M., T.J.C.F.), VU University Medical Center/Institute of Cardiovascular Research ICaR-VU, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Received January 26, 2004; revision requested April 6; revision received June 6; accepted September 22. Address correspondence to A.V.N. (e-mail: a.vonk@vumc.nl).
| ABSTRACT |
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MATERIALS AND METHODS: Study protocol was approved by institutional ethics review committee; all patients gave informed consent. Right-sided heart catheterization with vasodilator testing was performed in 39 adult subjects suspected of having pulmonary hypertension. There were 11 men and 28 women, aged 2175 years (mean, 46 years). Only two patients showed favorable response to vasodilators, defined by a decrease in PAP of more than 20%. Synchronous right- and left-ventricular pressure measurements and four-chamber magnetic resonance (MR) imaging were used to identify timing of maximal leftward ventricular septal bowing within cardiac cycle. Septal bowing was evaluated with MR, measured on short-axis cine heart images, and expressed as curvature (reciprocal of radius). Curvature was quantified on one image (the one that showed the most severe distortion of normal septal shape). The relationship between systolic PAP and septal curvature was tested with linear regression analysis. P < .05 was considered to indicate a statistically significant difference.
RESULTS: Of 39 subjects, 37 had pulmonary hypertension. Maximal distortion of normal septal shape was found during right ventricular relaxation phase. Systolic PAP was proportional to septal curvature: r = 0.77 (P < .001), slope = 114.7, and intercept = 67.2. In the two vasodilator responsive subjects, a significant reduction of leftward ventricular septal bowing was observed in response to reduction of right ventricular pressure.
CONCLUSION: In 37 patients with pulmonary hypertension, systolic PAP higher than 67 mm Hg may be expected when leftward curvature is observed.
Supplemental material: radiology.rsnajnls.org/cgi/content/full/2343040151/DC1
© RSNA, 2005
| INTRODUCTION |
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Earlier studies have shown that the end-systolic flattening of the interventricular septum occurs mainly because of RV pressure overload (1,3). In these studies, flattening and bowing of the septum were expressed quantitatively as curvature, where the curvature is defined as the reciprocal of the radius. By using echocardiography to evaluate the septal position in relation to the systolic RV pressure in groups of healthy children and children with congenital heart disease, King et al (1) found a correlation of r = 0.86 between septumcurvature and RV end-systolic pressure. This result may indicate that septum curvature could be used as a marker of systolic RV hypertension. In an animal study, Beyar et al (3) showed that LVSB during diastole occurs only at a transseptal pressure gradient (RV pressure LV pressure) higher than 5 mm Hg. Both studies suggest a near-linear relationship between septal curvature and the transseptal pressure gradient.
The purpose of this study was to investigate whether a relationship exists between septum shape and systolic pulmonary arterial pressure (PAP) in patients with pulmonary hypertension.
| MATERIALS AND METHODS |
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Patient Selection
The study protocol was approved by the institutional ethics review committee; all patients gave informed consent. All patients were referred to our center between late 1999 and the summer of 2003 for evaluation of suspected pulmonary hypertension because of evidence of pulmonary hypertension at echocardiography. Patients with a history of cardiopulmonary surgery, those with systemic hypertension (systolic blood pressure > 160 mm Hg), and those who were unable or not willing to undergo magnetic resonance (MR) imaging were not included. All others agreed to participate.
Between January 2000 and August 2003, we included 39 patients in our study: 28 women and 11 men. Mean age of the total group was 46 years (range, 2175 years), mean age of the men was 52 years (range 2675 years), and mean age of the women was 44 years (range, 2175 years). All included patients were in stable clinical condition, and background therapy with coumarine derivatives remained unchanged during the period needed to perform the measurements.
Invasive Measurement Procedure
All pressure measurements were acquired with fluid-filled catheters and standard pressure transducers. The procedures were performed by two specialists in invasive cardiology, both with more than 10 years of experience in catheterization. Care was taken to eliminate possible sources of measurement errors, such as air bubbles, incorrect transducer levels, and excessive length of tubing. Right-sided heart catheterization was performed with a single-lumen multipurpose catheter by using the transfemoral approach (6-F MPA 1; Cordis, Miami Lakes, Fla). Parameters obtained included systolic and end-diastolic RV pressures, as well as systolic and diastolic pressures and mean PAPs. A second sheath was placed in the femoral artery for measurement of the systemic blood pressure. In three patients, this sheath was used for insertion of a catheter into the LV (4-F Infiniti Pigtail; Cordis), thus allowing simultaneous measurement of RV and LV pressures.
All patients underwent a vasodilator challenge with 20 ppm of nitric oxide, followed by intravenous epoprostenol (Flolan; GlaxoSmithKline Netherlands, Zeist, the Netherlands) up to a dose of 12 ng per kilogram of body weight per minute to identify patients who respond acutely to calcium channel blockers and may benefit from long-term treatment with those agents (5). The patients who showed a favorable response to vasodilators, defined by a decrease in mean PAP and pulmonary vascular resistance of more than 20%, were given an oral dose of 10 mg of nifedipine (6). Systemic blood pressures and PAP were followed up to 1 hour after administration of nifedipine. The lowest PAP value in that period was recorded; in both cases, this minimum was reached approximately 30 minutes after the drug was administered.
MR Acquisition and Image Processing
Within the same week as the catheterization, MR imaging was performed in each patient by using a 1.5-T system (Vision or Sonata; Siemens Medical Solutions, Erlangen, Germany). The mean time interval between MR imaging and catheterization was 3 days (range, 07 days). The full acquisition protocol has been described in earlier studies (7,8).
In brief, first, a four-chamber view of the heart was localized, and then in this view, a breath-hold cine acquisition was performed. By using the end-diastolic cine frame of this four-chamber view, a series of parallel short-axis image planes was defined, starting at the base of the LV and RV and encompassing the entire LV and RV from base to apex. The most basal image plane was positioned close to the transition of ventricular myocardium to the atria (at a distance of half the section distance). This also ensured that the most basal part of the ventricles was covered. At every short-axis plane, a breath-hold cine acquisition was then performed.
For cine imaging with the Vision MR system (Siemens Medical Solutions), a gradient-echo pulse sequence was applied with segmented k-space, 7 ky lines per heartbeat, and a data acquisition window of 80 msec. Echo sharing (or "view sharing") was used, which yielded a temporal frame every 40 msec. The acquisition settings were a flip angle of 25°, field of view of 219 x 250 mm, and 126 x 256 matrix. Section thickness was 6 mm with a 4-mm intersection gap, yielding a section distance of 10 mm.
For the Sonata MR system (Siemens Medical Solutions), a steady-state free precession pulse sequence was applied with 11 ky lines per heartbeat and a data acquisition window of 34 msec. Flip angle was 60°, field of view was 228 x 280 mm, and matrix size was 208 x 256. With both MR systems, the field of view could be adapted to the individual patient to obtain optimal images.
The patients who showed a favorable response to nifedipine during the invasive procedure were given another dose after completion of MR imaging. Thirty minutes later, imaging was repeated.
The MR images were processed on a Sun Sparc workstation (Sun Microsystems, Santa Clara, Calif) by using the MASS software package (Department of Radiology, Leiden University Medical Center, and Medis Medical Imaging Solutions, Leiden, the Netherlands). The septal curvature was measured in the short-axis image plane at the most basal level that showed the full myocardial walls around both ventricles and no outflow tracts or valves, as demonstrated in Figure 1. Within this level, the cine image with the most evident deformation of the septum was used for quantification. Septal bowing was quantified by the curvature (defined as 1 divided by the radius of curvature in centimeters), as calculated by entering midwall septal image coordinates into an analytic fitting routine.
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years of experience in cardiac MR image interpretation, whereas observer 2 (T.J.G.) had no previous experience in MR image interpretation in general and received the same instructions as mentioned in the text and in the Appendix. To document in which phase of the LV cycle the curvature was determined, we also measured the time of aortic valve closure. In a subset of 14 patients, we imaged the aortic valves in the three-chamber view with the steady-state free precession cine MR sequence. This cine acquisition (temporal resolution of 35 msec) offers optimal contrast between tissue and blood, and therefore the positioning, opening, and closing of the aortic valves are seen clearly.
Statistical Analysis
To study interobserver variation, we used the Pearson correlation coefficient. A Bland-Altman approach was used to visualize the differences between both observers (9). The relationship between systolic PAP and septal curvature was tested with linear regression analysis. This analysis was performed on the mean values of the curvatures detected by both investigators. Independent-samples t testing was used to test for a significant age difference between men and women. Paired-samples t testing was used to test whether curvature measurement took place after closing of the aortic valves.
A P value less than .05 was considered to indicate a statistically significant difference for all tests. To perform and display the statistics, SPSS 9.0 (SPSS, Chicago, Ill) and GraphPad Prism 4.0 (GraphPad Software, San Diego, Calif) software were used. No power analysis was performed prior to the study.
| RESULTS |
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Ventricular Pressures
The results of the simultaneous measurement of ventricular pressures are shown in Figure 2. In the patient with pulmonary hypertension, the LV pressure exceeded RV pressure until approximately 500 msec after the R wave. From then on, since RV pressure does not decrease as rapidly as LV pressure, RV pressure exceeded LV pressure.
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Systolic PAP and Septal Curvature
The correlation between systolic PAP and septal curvature, as shown in Figure 3, was 0.77 (P < .001, n = 38). The systolic PAP was proportionate to the curvature, with a slope of 114.7 ± 17.5 and a y-intercept of 67.2 ± 3.1. When discarding the data of the two patients without pulmonary hypertension, the correlation between systolic PAP and septal curvature remained significant (r = 0.68, P < .001, n = 36).
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| DISCUSSION |
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A linear relationship between transseptal pressure and septal curvature is indeed expected from application of the Laplace law, because a well-known result from elasticity theory for a thin-walled rotationally symmetric ellipsoid reads as follows:
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P is the transmural pressure difference; RS and RL are the radii of the short and long axes, respectively; PLV and PRV are LV and RV pressures, respectively; and
S and
L are the tangential stresses (10). Rewriting this formula to isolate the RV value (PRV) on the left side and introducing the short-axis curvature CS equal to the reciprocal value of the short axis radius RS yields
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This result can be interpreted as a straight line between RV pressure PRV and curvature of the short-axis CS. The first term in parentheses, h
S, is a negative-valued slope; the second term in parentheses is an intercept. Although this result is obtained by use of a rather simple model of the septum, the formula indicates a linear relationship with a negative slope between curvature and RV pressure, as we observed in our data. Moreover, this slope h
S might be interpreted as the septal wall tension, which is expected to show little interindividual variation in the adapted pulmonary hypertensive subject. In contrast, the intercept may show considerable interindividual variation because the LV pressure PLV, which is dependent on ventricular function and the preload and afterload, is involved. This interindividual variation of the intercept is likely to influence the reported correlation coefficient of 0.77. Finally, this formula indicates that the curvature during LVSB is likely to reach its maximum when the pressure difference in favor of the RV is maximal.
A rationale for use of a result derived for a thin-walled ellipsoid, while the thickness of a septum in a hypertrophic heart in pulmonary hypertension is obviously not negligible, comes from observations in modeling studies of the mechanics of the heart. The calculated fiber stress was found to be homogeneous within 10% deviation from the average stress under a wide variation of loading conditions, a finding that was confirmed experimentally (11,12). When postulating homogeneity of fiber stress and strain in the thick wall enclosing a cavity, substantial simplifications can be introduced by leaving out spatial variation of stress in the wall. Under these assumptions, the average stress
equals that assumed in the thin-walled ellipsoid (13). Thus, Laplace law provides a basis for the understanding of the experimentally observed linear relation between RV pressure and curvature of the septum.
At what exact time the curvature is maximal in the cardiac cycle depends on the maximal pressure differences between the two ventricles. LVSB during diastole occurs only when a transseptal pressure gradient (RV pressure LV pressure) is higher than 5 mm Hg, as was shown in an animal study by Beyar et al (3). Both our biventricular pressure measurements and the valve-timing data from the four-chamber cine images, demonstrate that this moment is likely to be shortly after closure of the aortic and pulmonary valve but well before opening of the mitral and tricuspid valvesthus, during the isovolumetric relaxation phase. This implies that correlating systolic RV pressure or PAP with maximum curvature means correlating two variables that were not measured at exactly the same moment in time and thus cannot be explained in simple physiologic terms. Furthermore, the biventricular pressure measurements suggested that there was a slight dissimilarity in ventricular relaxation in patients with RV pressure overload, which caused slightly later pressure decrease in the RV compared with the LV. This asynchrony will result in a moment where RV pressure is still high, whereas LV pressure has already reached its diastolic level.
Because of the earlier decrease, LV pressure is of lesser importance, making curvature a better marker of RV systolic pressure. Although our study focused on the maximal curvature and its moment in the cardiac cycle, it is known from earlier work by Marcus et al (8) that the phenomenon of LVSB can last well into diastole and influence the diastolic filling of the LV.
Atherton et al (14) and Dittrich et al (15) described what happens when a chronically overloaded RV is suddenly unloaded. The RV end-diastolic volume decreases, whereas the LV end-diastolic volume "paradoxically" increases as LV filling improves. This again is a consequence of ventricular interaction. Within the confinement of the pericardium, the unloaded RV takes up less space, leaving more for the LV. The finding in two patients that a decrease in PAP after oral intake of nifedipine is accompanied by a proportional change in septal curvature provides further support for our thesis that the curvature of the interventricular septum can be used to predict PAP. Furthermore, in contrast to an earlier study of Ricciardi et al (4), these two patients showed that severe LVSB does not exclude a favorable response on calcium antagonists.
The finding that LVSB appears in combination with ventricular asynchrony in pulmonary hypertension is not only of interest for the noninvasive prediction of PAP, but it might also give more insight into the pathophysiology of the heart in pulmonary hypertension. Interaction between the two ventricles is known to play an important role in heart failure caused by RV volume or pressure overload. Mahmud et al (16) showed that Doppler-derived indexes of LV filling (the peak transmitral E wave velocity and the E/A ratio) were decreased in patients with RV overload. Specifically, they found a logarithmic negative correlation between the E/A ratio and the mean PAP and cardiac output.
What the effect of a changing heart rate will be on the maximal septal curvature is something we can only speculate about. At this time, we have no reason to assume that the effect will be very large, on the basis of the knowledge that the maximum curvature is observed during the isovolumic ventricular relaxation, a period within the cardiac cycle not subjected to large changes associated with heart rate.
At this moment, we can only speculate about the cause of the ventricular asynchrony that was seen. It is known that patients with pulmonary hypertension often have abnormal electrocardiograms (17), and electrophysiologic phenomena such as a right bundle branch block may play an important role. Altered contractile properties of the hypertrophic myocardium cannot be ruled out, however. Further study of this asynchrony is therefore recommended and should address the electrophysiologic and contractile peculiarities of the ventricles in patients with pulmonary hypertension.
Evaluation of the septum curvature required an accurate dynamic imaging system, as well as a skilled operator, to ensure optimal image quality and reproducible imaging planes. MR imaging offers both high accuracy in the evaluation of cardiac anatomy and good reproducibility in these situations (18). Our calculations of interobserver agreement show that septum curvatures were highly reproducible when using a clear definition of the phase image to be used for curvature measurement. Septal curvature could be determined in 38 of 39 patients; the only patient in which curvature measurement failed experienced both an atrial septum defect and a hypoplastic LV, making interpretation of septal bowing in this context doubtful, anyhow.
Use of MR imaging for curvature measurement alone is hardly realistic, considering costs and the existence of other noninvasive techniques. However, the four-chamber cine images and the stack of short-axis images also yield important anatomic information and can be used to calculate ventricular volumes and masses to assess RV and LV function (8). Furthermore, our data showed that flattening of the interventricular septum is a certain sign of pulmonary hypertension and that a negative curvature can only be noticed at systolic pressures higher than 67 mm Hg, thus enabling the imager a direct visible diagnosis of pulmonary hypertension while reviewing cardiac cine MR images.
Echocardiography is undoubtedly the best-known imaging modality for estimation of (systolic) PAP by means of measuring the velocity of the tricuspid regurgitation jet. The reliability of this method is questionable, however (19). Earlier studies by Shimada et al (20) and Reisner et al (21) indicate that echocardiography can also be used to evaluate septal curvature and estimate RV or pulmonary pressure. The relative simplicity and low costs of echocardiography are certainly important arguments in favor of this modality. Whether the same accuracy and reproducibility can be achieved in comparison with MR imaging is unknown. Short-axis septal curvature evaluation by means of echocardiography and comparison with MR images for estimation of systolic PAP in patients with pulmonary hypertension should therefore be the subject of future study.
Study Limitations
As is the case in many single-center studies on the evaluation of pulmonary hypertension, ours too has to deal with a relatively small group of subjects to be studied. In past years, this group has been growing steadily, and it is expected that the study can continue in a larger group of patients. However, it is not expected that a larger group will lead to a significantly different outcome.
Unfortunately, we were not able to perform simultaneous pressure measurement and septal curvature estimation, as MR imagingcompatible pressure measurement equipment was not available to us. To minimize the effect of asynchronous measurement, the patients were kept in stable clinical condition in the period between MR imaging and catheterization. To minimize the time delay, we made use of two MR imagers, depending on availability, but this resulted in two types of imaging sequences. Furthermore, care was taken to obtain the MR images at approximately the same heart rate as during catheterization.
Finally, the small number of biventricular pressure measurements forms a weak point in our study. The original study protocol did not mention such measurements, and therefore the LV pressure measurements could only be performed after the protocol was amended or in patients in whom LV pressure measurement was requested because of possible clinical relevance. The ideal situation for performance of LV and RV pressure measurement and MR imaging curvature evaluation at the same time should be the next step along this line of investigation.
In conclusion, short-axis curvature of the maximal leftward displacement of the interventricular septum in patients with pulmonary hypertension may be used as a marker of PAP, as there is a significant correlation between these two parameters. The cause of this leftward septum displacement appears to be a pressure excess of the RV relative to the LV. Our data in 39 subjects showed that a systolic PAP higher than 67 mm Hg might be expected if LVSB is seen.
| APPENDIX |
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In solving Equations (A2) and (A3) for xm and ym, it is convenient to define the following intermediate variables: D = xb2 + yb2 xa2 ya2, E = xb2 yb2 + xc2 + yc2, F = 2(xb xa), G = 2(yb ya), H = 2(xc xb), and I = 2(yc yb).
Then, it follows from linear algebra that xm = (DI GE)/(IF GH) and ym = (EF HD)/(IF GH).
Finally, substitute (xm, ym) in Equation (A1) to find Ra. R equals Ra. If xa and ya, xb and yb, and xc and yc were given in pixel numbers, then R needs to be multiplied by the pixel size in centimeters. The curvature equals R1. This procedure for calculating the curvature is easily programmed in Excel (Microsoft, Redmond, Wash), Matlab (release 13, version 6.5; MathWorks, Natick, Mass), or any programming language.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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See Materials and Methods for conflict of interest information.
Author contributions: Guarantor of integrity of entire study, R.J.R.; study concepts, R.J.R., J.T.M., T.J.C.F., P.E.P., A.V.N.; study design, all authors; literature research, R.J.R., T.J.C.F., A.V.N.; clinical studies, R.J.R., J.T.M., T.J.G., A.B., A.V.N.; data acquisition, R.J.R., J.T.M., A.B., A.V.N.; data analysis/interpretation, R.J.R., J.T.M., T.J.G., T.J.C.F., P.E.P., A.V.N.; statistical analysis, R.J.R., T.J.G., T.J.C.F., A.V.N.; manuscript preparation, R.J.R., J.T.M., T.J.C.F., A.V.N.; manuscript definition of intellectual content, all authors; manuscript editing, R.J.R.; manuscript revision/review and final version approval, all authors
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