Przemysław Palka, MD; Aleksandra Lange, MD; J. Elisabeth Donnelly, MD; Petros Nihoyannopoulos, MD

Differentiation Between Restrictive Cardiomyopathy and Constrictive Pericarditis by Early Diastolic Doppler Myocardial Velocity Gradient at the Posterior Wall Przemysław Palka, MD; Aleksandra Lange, MD; J. Elisabeth Donnelly, MD; Petros Nihoyannopoulos, MD Background The differential diagnosis between restrictive cardiomyopathy (RCM) and constrictive pericarditis (CP) is challenging and, despite combined information from different diagnostic tests, surgical exploration is often necessary. Methods and Results A group of 55 subjects (mean age, 63 11 years; 36 men and 19 women) were enrolled in the study; 15 had RCM, 10 had CP, and 30 were age-matched, normal controls. The diagnosis of RCM was supported by a biopsy; in the CP group, the diagnosis was confirmed either surgically or at autopsy. All patients underwent a transthoracic echocardiogram that included the assessment of Doppler myocardial velocity gradient (MVG), as measured from the left ventricular posterior wall during the predetermined phases of the cardiac cycle. MVG was lower (P 0.01) in RCM patients compared with both CP patients and normal controls during ventricular ejection (2.8 1.2 versus 4.4 1.0 and 4.7 0.8 s 1, respectively) and rapid ventricular filling (1.9 0.8 versus 8.7 1.7 and 3.7 1.4 s 1, respectively). Additionally, during isovolumic relaxation, MVG was positive in RCM patients and negative in both CP patients and normal controls (0.7 0.4 versus 1.0 0.6 and 0.4 0.3 s 1, respectively; P 0.01). During atrial contraction, MVG was similarly low (P 0.01) in both RCM and CP patients compared with normal controls (1.6 1.7 and 1.7 1.8 versus 3.8 0.9 s 1, respectively). Conclusions Doppler myocardial imaging derived MVG, as measured from the left ventricular posterior wall in early diastole during both isovolumic relaxation and rapid ventricular filling, allows for the discrimination of RCM from CP. (Circulation. 2000;102:655-662.) Key Words: cardiomyopathy pericarditis imaging Several echocardiographic parameters have been proposed as ways to differentiate restrictive cardiomyopathy (RCM) from constrictive pericarditis (CP). 1 These parameters are based on conventional M-mode, 2,3 2D images, 4 and Doppler blood-flow patterns. 5 9 The respiratory variation in transmitral velocity blood flow is the most frequently used parameter to differentiate RCM from CP. 5,6 However, respiratory variation can also be observed in patients with chronic obstructive airway disease. 10 Also, a considerable percentage of CP patients do not demonstrate respiratory variation in their blood-flow velocities. 6 Oh et al 11 proposed that in this group of patients, additional echocardiographic tests to reduce preload may help unmask or enhance respiratory variation on transmitral Doppler flow. Nevertheless, in some cases, the diagnosis remains equivocal, and other diagnostic tests and/or surgical exploration are required. 1,12,13 Doppler myocardial imaging (DMI) is an echocardiographic technique that has the potential to enhance the diagnostic information available from Doppler blood-flow indices. 14 19 Pulsed-wave DMI can be used to quantify longitudinal mitral annular motion, which can be useful in the distinction between RCM and CP. 14 Little data exist on the potential role of the myocardial velocity gradient (MVG) in distinguishing RCM from CP. MVG was introduced as a new index of myocardial contraction and relaxation that quantifies the spatial distribution of intramural velocities across the myocardium. 20 24 Recent studies have shown that MVG is relatively independent of the translational motion of the heart 25 and/or preload alterations. 26 In this study, MVG calculation at the left ventricular (LV) posterior wall was used to quantify myocardial contraction and relaxation in RCM and CP patients to establish whether it can be used in defining these groups. Methods A group of 55 subjects (aged 63 11 years; 36 men and 19 women) was enrolled in this study; subjects consisted of 15 RCM patients, 10 CP patients, and 30 age-matched, normal controls (Table 1). Subjects were recruited from the Departments of Cardiology and Rheumatol- Received December 2, 1999; revision received February 18, 2000; accepted March 2, 2000. From the Departments of Cardiology at the Royal Hospital for Sick Children, Edinburgh (P.P., A.L.), and Hammersmith Hospital, DuCane Road, London (J.E.D., P.N.), UK. Correspondence to Dr P. Palka, Department of Echocardiography, The Prince Charles Hospital, Rode Road, Brisbane Q4032, Australia. E-mail ppalka@hotmail.com 2000 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org 655

656 Circulation August 8, 2000 TABLE 1. Clinical Characteristics of Study Subjects RCM (n 15) CP (n 10) Normal (n 30) Age, y 54 14 57 14 58 8 Male sex, n (%) 9 (60) 7 (70) 20 (67) Heart rate, beats/min 81 18* 75 14 67 11 Sinus rhythm, n (%) 12 (80) 7 (70) 30 (100) Systolic BP, mm Hg 112 13 109 18 131 8 NYHA class 2.9 0.4 3.1 0.5 Data are presented as mean SD or n (%). BP indicates blood pressure; NYHA, New York Heart Association. *P 0.05 compared with normal subjects; P 0.01 compared with normal subjects (ANOVA). ogy at the following institutions: Victoria Hospital, Kirkcaldy; Western General Hospital and Royal Infirmary, Edinburgh; and Hammersmith Hospital, London, UK. The study group was formed prospectively and in a nonselective manner from all referrals of patients with unexplained right-sided heart failure between January 1994 and December 1998. The diagnosis of RCM or CP was based on clinical assessment and the results of the following diagnostic tests: echocardiogram, cardiac catheterization, MRI, and/or CT scan. All 15 patients with RCM underwent a biopsy, which confirmed amyloidosis in 12 patients. In patients with CP, the diagnosis was confirmed at surgery (n 8) or autopsy (n 2). In 4 patients, CP was described as idiopathic; it was described as postpericardiotomy in 4, as postradiotherapy in 1, and as neoplastic pericardial infiltration in 1. All 15 RCM and 7 of the 10 CP patients had no evidence of coronary artery disease. The remaining 3 CP patients who had previous open heart surgery due to coronary artery disease had not had a myocardial infarction and/or reversible ischemia on the inferoposterior LV wall. Pericardial thickness ( 4 mm) or pericardial calcification was shown in 4 of the 5 CP patients in whom a CT scan and/or an MRI was performed. Protocol Each subject underwent a standard echocardiographic and DMI study of the LV posterior wall using an Acuson ultrasound scanner (XP/10, Aspen). Standard echocardiography consisted of M-mode, 2D, and Doppler blood-flow measurements. The parameters measured at end-diastole were interventricular septum, LV posterior wall, and LV diameter; at end-systole, we measured the left atrium. The M-mode of the LV posterior wall was digitized, and then the normalized peak rates of wall thickening and thinning were analyzed. 27 TABLE 2. Conventional Echocardiographic and Digitized M-Mode Data of Study Subjects LV ejection fraction was measured with a modified, biplane version Simpson s method. Standard methods were used to record pulsed-wave Doppler transmitral velocity, which was used to measure the following: peak E- and A-wave velocities, E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Both transmitral and hepatic venous flow velocities were recorded with simultaneously acquired respiratory tracing using a nasal respiratory probe. 6,11 Good quality pulsed-wave Doppler hepatic vein waveforms were obtained in 13 of the 15 patients with RCM and 9 of the 10 patients with CP. All measurements were averaged over 3 cardiac cycles in patients with sinus rhythm and over 5 cycles for those in atrial fibrillation. Doppler Myocardial Imaging The system used in this study has been previously described. 20,28 M-mode DMI images of the LV posterior wall were obtained at end-expiration and were digitally downloaded to the image capture system for MVG off-line analysis. Peak MVG values were determined in systole during early ventricular ejection (VE), in early diastole during isovolumic relaxation (IR) and rapid ventricular filling (RVF), and in late diastole during atrial contraction (AC). These phases were defined using the combined information derived from M-mode images taken at the tips of mitral valve leaflets with visible valve openings and the simultaneously recorded ECG and phonocardiogram. 17,20,28 To obtain M-mode DMI images, the echocardiographic examination was extended by 2 to 3 minutes. Another 5 to 10 minutes were used for off-line analysis of images. None of the patients was excluded from the study on the basis of DMI image quality. Doppler MVG was defined as the slope of linear regression of the myocardial velocity estimates along each M-mode scan line throughout the thickness of the myocardium. 20 26,28 Myocardial velocity estimates were calculated automatically in each pixel of each M-mode scan. Positive or negative MVG indicated a faster motion of either a subendocardial or a subepicardial layer, respectively. To calculate peak MVG in the predefined phases of the cardiac cycle, a plot graph of MVG changes over time was drawn using computer software. Interobserver and intraobserver variability for MVG were assessed in our previous work. 20,28 Both interobserver and intraobserver variability were low, at 0.1 0.2 and 0.2 0.2 s 1, respectively. Statistics Data are expressed as mean SD. ANOVA with Scheffe s F adjustment for multiple comparisons was used to assess the differences between each group. The degree of respiratory variation in peak E-wave velocity was calculated as follows: {[(peak E-wave in expiration) (peak E-wave in inspiration)]/(peak E-wave in expiration)} 100%. 11 Multivariate regression analysis was performed to RCM CP Normal LV wall thickness, cm 1.3 0.3 1.0 0.2 0.9 0.1 LV diameter, cm 4.3 0.5* 4.5 0.5 4.8 0.6 Left atrial diameter, cm 4.1 0.7 4.2 0.4 3.2 0.4 Peak rate of posterior wall thickening, s 1 4.5 1.8 4.8 1.8 5.6 1.5 Peak rate of posterior wall thinning, s 1 5.4 2.3* 7.6 2.5 7.8 2.0 Peak E-wave, m/s 1.03 0.25 0.96 0.27 0.59 0.10 Peak A-wave, m/s 0.55 0.21 0.42 0.22 0.58 0.10 E/A ratio 2.21 0.82 2.61 1.20 1.05 0.23 E-wave deceleration time, ms 111 13 114 11 195 14 IR time, ms 54 12 48 13 90 8 Ejection fraction, % 58 7 56 7 59 4 *P 0.05; P 0.01 compared with normal subjects (by ANOVA).

Palka et al Myocardial Velocity Gradient in RCM 657 TABLE 3. Doppler MVG Measurements in the Study Groups RCM (n 15) CP (n 10) Normal (n 30) VE-MVG, s 1 2.8 1.2* 4.4 1.0 4.7 0.8 IR-MVG, s 1 0.7 0.4* 1.0 0.6 0.4 0.3 RVF-MVG, s 1 1.9 0.8* 8.7 1.7 3.7 1.4 AC-MVG, s 1 1.6 1.7 1.7 1.8 3.8 0.9 *P 0.01 compared with CP patients or normal subjects; P 0.01 compared with normal subjects (ANOVA). Analysis was of subjects in sinus rhythm only; patients with atrial fibrillation were rejected. VE-MVG in RCM patients (n 13) was lower compared with CP patients (n 7) and normal subjects (3.0 1.2 vs 4.8 0.9 and 4.7 0.8 s 1, respectively; P 0.01). IR-MVG was positive in RCM patients compared with CP patients and normal subjects (0.8 0.4 vs 1.0 0.6 and 0.4 0.3 s 1, respectively; P 0.01). RVF-MVG was lower in RCM patients compared with CP patients and normal subjects (2.1 0.7 vs 8.2 1.6 and 3.7 1.4 s 1, respectively; P 0.01). evaluate the relation between the MVG and other echocardiographic variables. Linear regression analysis was performed to present the relationship between VE-MVG and LV posterior wall thickness in RCM patients. P 0.05 was considered significant. Results Standard Echocardiography The RCM group had a greater LV wall thickness (44%) and a smaller LV diameter ( 10%) compared with age-matched normal controls (Table 2). The pericardium was calcified/ thickened in 6 CP patients, and interventricular septal motion with a respiratory bounce was seen in 8 CP patients. When compared with normal subjects, RCM and CP patients had greater left atrial diameters (28% and 31%, respectively), higher peak E-waves (75% and 63%), higher E/A ratios (110% and 149%), shorter E-wave decelerations ( 46% and 44%), and shorter isovolumetric relaxation times ( 40% and 47%). In the CP group, the mean peak E-wave was 0.96 0.27 m/s in expiration and 0.69 0.18 m/s in inspiration; the mean respiratory variation in this group was 38 17% (range, 10% to 68%). In 8 of the 10 CP patients, respiratory variations were 25%, and the peak E-wave decreased from 1.06 0.20 m/s (range, 0.77 to 1.41 m/s) in expiration to 0.74 0.16 m/s (range, 0.50 to 1.00 m/s) in inspiration. In the remaining 2 CP patients, respiratory variations in the peak E-wave were 25% (10% and 15%). In hepatic venous flow by pulsed-wave Doppler, a constriction pattern with a 25% decrease in diastolic forward flow and/or prominent late diastolic flow reversal after the onset of expiration was observed in 8 CP patients (7 of 8 with a concomitant characteristic pattern of transmitral inflow and one with an inconclusive pattern of transmitral inflow). The diagnosis of CP as based on combined information from all Doppler blood-flow recordings was inconclusive in 1 of the 10 CP patients studied. Digitized M-Mode No differences existed between the RCM and CP groups in the measurement of the peak rate of systolic wall thickening and diastolic wall thinning. However, the peak rate of wall Figure 1. Comparison of Doppler MVG measurements between the study groups. MVG was taken (A) during VE, (B) during IR and RVF, and (C) during AC. F indicates patients with sinus rhythm; E, patients with atrial fibrillation. *P 0.01 compared with CP or normal subjects; P 0.01 compared with normal subjects, by ANOVA. thinning was lower in the RCM group than in normal subjects ( 31%). MVG VE-MVG was lower in the RCM group when compared with both the CP group ( 36%) and normal controls ( 40%). In all groups, VE-MVG was positive, indicating that during the LV posterior wall thickening, the subendocardium was mov-

658 Circulation August 8, 2000 Figure 2. Examples of Doppler myocardial M-mode imaging of the LV posterior wall (top) with calculated MVG (middle) and corresponding transmitral pulsed-wave Doppler blood flow (bottom). A, RCM patient; B, CP patient with marked ( 25%) E-wave reduction in inspiration; C, CP patient with nondiagnostic ( 15%) E-wave reduction in inspiration. Arrows (middle) indicate peak values of the MVG in the predetermined phases of the cardiac cycle. Note that the *RVF-MVG was 3 times higher in both CP patients (B, C) compared with RCM patient (A) and that the #IR-MVG was positive in RCM patient and negative in both CP patients. ing faster than the subepicardium (Table 3 and Figure 1). For all groups, the IR-MVG was relatively low compared with either the VE-MVG or RVF-MVG. IR-MVG differed between the RCM group and both the CP group and normal controls. The absolute value of IR-MVG was 75% higher for RCM patients and 150% higher for CP patients than in normal controls. During the IR, the analyzed myocardium was coded as blue, indicating that the movement was away from the center of the LV. In the RCM group, IR-MVG was positive, indicating that the subendocardium was moving faster than the subepicardium. Conversely, in both CP patients and normal controls, the IR-MVG was negative, indicating that outward movement was mainly due to subepicardial motion. The RVF-MVG was lower in RCM patients compared with both CP patients ( 78%) and normal controls ( 49%); RVF-MVG was higher in CP patients than in normal controls (135%). In all groups, RVF-MVG was positive, indicating that the LV posterior wall was thinning and the subendocardium was moving faster than the subepicardium. AC-MVG was lower in both the RCM and CP groups compared with normal controls ( 68% and 55%, respectively); AC-MVG was positive, indicating that the LV posterior wall was thinning due to a faster motion of the subendocardium rather than the subepicardium. Examples of MVG analysis in RCM and CP patients (with and without marked respiratory variation on transmitral Doppler blood flow) are shown in Figure 2. Figure 3 shows the differences in early diastolic MVG changes in the study groups. Multivariate Regression Analysis of MVG Systole In RCM patients, VE-MVG was dependent on LV posterior wall thickness but was independent of other echocardiographic and clinical variables. Figure 4A shows a correlation between LV posterior wall thickness and VE-MVG (for RCM group, r 0.75; P 0.001). Diastole All diastolic MVGs (IR-MVG, RVF-MVG, and AC-MVG) were independent of other echocardiographic variables, including transmitral Doppler blood-flow indices, LV dimension, and the degree of LV posterior wall thickness (Figures 4B through 4D). Also, IR-MVG and RVF-MVG were inde-

Palka et al Myocardial Velocity Gradient in RCM 659 Figure 3. Schematic diagram of early diastolic pattern of MVG in RCM patients, CP patients, and normal subjects. Both phases IR and RVF consist of outward motions with negative velocities. The sign of the MVG depends on the relative fastness of subendocardial or subepicardial velocities; it is positive if subendocardial velocities move faster and negative in the opposite scenario. pendent of age, heart rate, and systolic blood pressure. Figure 5 shows a relation between the transmitral peak E-wave, E-wave deceleration time, and RVF-MVG. Discussion The results of this study indicate that the assessment of myocardial contraction and relaxation using Doppler MVG at the LV posterior wall may be helpful in distinguishing RCM from CP. Although in CP patients there is an increase in ventricular interaction 29 and a dissociation of intrathoracic-intracardiac pressure changes with respiration, 5,6,30 both CP and RCM may have similar clinical manifestations, which are related to decreased LV compliance. 31 However, the mechanism leading to the decrease in chamber compliance is different. In CP, decreased ventricular compliance is due to an increase in pericardial restraint, which is related to the pathological process of pericardial scarring and/or calcification. 32 Conversely, in RCM, the LV wall is resistant to stretch due to myocardial or endocardial disease. 33 In this study, Doppler MVG was used to quantify structural/functional myocardial status by following the hypothesis that DMI has the potential to quantify changes in the intrinsic mechanical elastic properties of the myocardium. 19 Garcia et al 14 conducted the first pulsed-wave DMI study to measure mitral annulus longitudinal velocities to differentiate RCM from CP. Although pulsed-wave DMI records myocardial motion as reflected by annulus motion, it has some important limitations, including the angulation of the ultrasound beam and the potential effect of LV contractile function and cavity size/shape on mitral annulus velocities. 14 A different approach was undertaken to quantify color DMI images by our group and others. 16 26,28 Findings Conventional echocardiographic assessment allowed us to establish the correct diagnosis in all RCM and CP patients. 1 6 The evaluation of respiratory variations of Doppler bloodflow velocities alone were inconclusive in 2 patients for transmitral velocity pattern and in 2 patients for hepatic vein flow. For the entire study group, the information from both transmitral and hepatic vein Doppler blood flow assisted the diagnosis of CP in all but one patient. This is in agreement with Oh et al, 6 who found that characteristic respiratory variations of Doppler blood-flow velocities are present in 88% of CP patients. Our results from digitized M-mode images are in agreement with previously published data. 2 Although the peak rate of wall thinning was reduced in RCM patients compared with normal subjects, the data did not allow for a clear distinction between RCM and CP. Both VE-MVG and RVF-MVG were reduced in RCM patients compared with both CP patients and normal subjects. Although VE-MVG was reduced by 36% in RCM patients compared with CP patients, an overlap in MVG measurements still occurred; this overlap did not allow for a clear-cut distinction between RCM and CP. In addition, this reduction of VE-MVG in RCM was dependent on LV hypertrophy. The most striking difference between RCM patients and both CP patients and normal controls was observed during RVF; at this time, no overlap between the study groups occurred. In RCM patients, the RVF-MVG was 78% lower than that measured in CP patients and 50% lower than that in normal controls. Also, IR-MVG differed between RCM patients and both CP patients and normal subjects. The absolute value of IR-MVG was 75% higher in RCM patients and 150% higher in CP patients compared with normal subjects. Both IR-MVG and RVF-MVG were independent of the degree of LV hypertrophy. Thus, even in the absence of LV hypertrophy in RCM patients, RVF-MVG was lower in the RCM group than in the CP group. Low VE-MVG and RVF-MVG in the RCM group indicate a pathological uniform distribution of transmyocardial velocities between the endocardium and epicardium. We believe that the observed clear reduction in both VE-MVG and RVF-MVG in the RCM group results from fibrotic and/or infiltrative processes involving the subendocardium and/or myocardium. 33,34 This process of structural and functional myocardial changes is typical for RCM rather than CP. High IR-MVG and RVF-MVG in CP patients may be explained by the increased dissociation of intrathoracicintracardiac pressure changes during end-respiration. In all study subjects, the LV posterior wall was thickening during VE and thinning during RVF; in both these time periods, wall thickening and thinning was generated by a faster movement of the subendocardial layer. The situation was different in early diastole during IR. In all study groups, the IR period was coded blue, indicating that the wall movement was away from the center of the LV. We found that during this time period, MVG was positive in RCM patients, indicating that the LV posterior wall was thinning due to faster subendocardial velocities. In both CP patients and normal subjects, the IR period was also coded blue, but the MVG was negative, which indicates a faster movement of the subepicardial layer, causing wall thickening. Although this was observed in all study patients, the magnitude of IR-MVG was relatively low compared with other analyzed

660 Circulation August 8, 2000 Figure 5. The relationship between RVF-MVG and (A) peak E-wave and (B) E-wave deceleration time. periods; therefore, a study in a larger patient population is needed to fully investigate this observation. AC-MVG was reduced by 50% in both the RCM group and CP group. Thus, the analysis of MVG in late diastole was not helpful in differentiating RCM from CP. We speculate that the increase in LV end-diastolic pressure, which is well documented in both RCM and CP, 29,34 reduces late diastolic blood inflow to the LV, 35 which will reduce AC-MVG. Table 4 summarizes our results in light of already published data on the role of MVG in the differentiation of myocardial/pericardial disorders. Limitations In this study, we do not have a patient in whom the diagnosis of CP or RCM was not made by standard echocardiography alone. However, a standard echocardiographic study is technically demanding and involves complex measurements taken from several acoustic windows. No single conventional echocardiographic parameter could have been used to make the diagnosis. The measurement of MVG, taken as a single diagnostic index, allowed for the differentiation of CP from RCM in all patients. The DMI study was technically simple, and it was not time consuming. We did not routinely perform Figure 4. The relationship between LV posterior wall thickness and MVG as measured during (A) VE, (B) IR, (C) RVF, and (D) AC. A shows a linear regression analysis for the RCM group (r 0.75; P 0.001). Dotted lines indicate the 95% predictive interval.

Palka et al Myocardial Velocity Gradient in RCM 661 TABLE 4. The Role of Doppler MVG in Distinguishing Different Myocardial/Pericardial Disease Doppler MVG VE( ) IR( / ) RVF( ) AC( ) Ischemic cardiomyopathy 22,24,26 2 No data 2 No data Dilated cardiomyopathy 24,26,28 22 N 1/2 2 Young hypertrophic cardiomyopathy 20 2 No data 22 N Old hypertrophic cardiomyopathy 20 2 No data 2 2 RCM 2 1 ( ) 2 2 CP N 1 ( ) 11 2 N indicates normal; 2, decrease in MVG compared with normals; 1, increase in MVG compared with normals; ( ), positive MVG; ( ), negative MVG; Old, 46 70 years; and Young, 18 45 years. preload reduction to unmask Doppler respiratory variation. 10 However, a recent study by Shimizu et at 26 showed that MVG is relatively independent of loading conditions. Therefore, we can assume that MVG measurements should be similar to those obtained with preload reduction. Our study group consisted of 6 subjects (24%) in atrial fibrillation, and the influence of missing atrial function might be an important underscoring factor for blood-flow recordings or MVG calculation. However, MVG did not differ between patients in sinus rhythm and those in atrial fibrillation. Therefore, we assume that MVG can be of clinical value in the differentiation of CP from RCM in patients in both sinus rhythm and atrial fibrillation. RCM patients had a lower New York Heart Association class than CP patients, which suggests that the latter group had a higher left atrial pressure. This could lead to an earlier mitral valve opening and/or an increase in RVF-MVG in CP patients. However, in this study, invasive measurements of LV diastolic function were not performed to verify this hypothesis. 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