International Journal of Cardiology 172 (2014) e39–e42
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Impact of diastolic wall stress on the diagnostic value of visually interpreted dobutamine stress MR imaging☆,☆☆ Jesus G. Mirelis a,b,c,⁎,1, Ingo Paetsch d,1, Cosima Jahnke d,1, Borja Ibañez b,1, Eckart Fleck a,1, Luis A. Alonso-Pulpon d,1, Valentín Fuster b,1, Rolf Gebker a,1 a
German Heart Institute, Berlin, Germany Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Puerta de Hierro Majadahonda University Hospital, Madrid, Spain d Department of Cardiology, University Hospital RWTH Aachen, Aachen, Germany b c
a r t i c l e
i n f o
Article history: Received 24 September 2013 Accepted 21 December 2013 Available online 4 January 2014 Keywords: Dobutamine stress magnetic resonance Myocardial ischemia Left ventricular wall stress
Dobutamine stress magnetic resonance (DSMR) is a valuable tool for the detection of myocardial ischemia in a wide spectrum of patients [1]. However, previous studies indicated that patients with distinct left ventricular (LV) geometries (i.e., concentric hypertrophy or concentric remodeling) exhibited surprisingly low sensitivity regarding the detection of significant coronary artery disease (CAD) [2]. In a subset of patients with such LV geometries, we frequently encountered uncompromised segmental wall motion (normal endocardial inward motion/systolic thickening) during dobutamine stress testing even in the presence of angiographically severe CAD (≥ 70% luminal stenosis). Consistently, high MR image quality in all examinations rendered misinterpretation an unlikely explanation for the observed limited diagnostic value of visually interpreted DSMR. Hence, based on Laplace's law, we hypothesized that the impaired diagnostic accuracy of DSMR in patients with distinct LV geometries may result from lower mean wall stress associated with concentrically thickened LV myocardium [3] (Fig. 1). One hundred fifty-four consecutive patients with suspected or known CAD underwent combined DSMR wall motion and perfusion ☆ Institution from which the work originated: German Heart Institute Berlin, Germany, Augustenburger Platz, 1, 13353 Berlin, Germany. ☆☆ This work was partially supported by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (CARDIOIMAGEN award to J.G.M.). ⁎ Corresponding author at: Melchor Fernandez Almagro, 3, 28029, Madrid, Spain. Tel.: +34 667393212. E-mail address: [email protected] (J.G. Mirelis). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.085
imaging (DSMRP) followed by invasive coronary angiography with invasive pressure measurements. The study was conducted in accordance with the ethical standards defined by local German law. Examinations were performed on a 1.5-T MR system (Philips Achieva, Best, The Netherlands). LV mass was determined from a contiguous stack of short axis cine views. All cardiac standard geometries were acquired at rest and during each dobutamine stress level. At maximum dobutamine infusion level dynamic, contrast-enhanced three-slice perfusion imaging (DSMRP) was additionally performed (0.1 mmol/kg bolus of Gad-DTPA, infusion rate of 4 ml/s followed by a flush of saline solution);
Fig. 1. Top left: thick-wall sphere model of the human heart [3]. EDV, end diastolic volume; EDVM, end diastolic volume mass; EDP, end diastolic pressure; WS, wall stress. Bottom left: detailed force diagram. In this zoomed 3D sector of the model, σ1 and σ2 represent horizontal and vertical stresses. Simplifying to a 2D model, a “short axis view” reference was taken. Although stress vectors (σ1 and σ2) are usually shown in the vertical and horizontal directions, the final vector to be “compensated” by the motion vector could be depicted orthogonal to the surface of the sphere (solid black line). Top right: concentric hypertrophy condition; the wall stress (WS) vector (discontinuous line) is short, indicating low wall stress. This geometry can lead to a false negative outcome of DSMR due to the high threshold for demand ischemia. Bottom right: eccentric hypertrophy condition; this geometry is likely coupled to high wall stress and can lead to a false positive on DSMR due to the low threshold for demand ischemia.
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Table 1 Clinical and hemodynamic data according to the LVDWS quartiles. Q1 (n = 38)
Q2 (n = 39)
Q3 (n = 39)
Q4 (n = 38)
p value
Clinical data Male, n (%) Age (years) BMI (kg/m2) CABG, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Diabetes mellitus, n (%) Smoking, n (%) Family history, n (%) HDL-cholesterol (mg/dl) LDL-Cholesterol (mg/dl) Triglycerides (mg/dl)
31 (82) 63.4 (11.5) 27.3 (3.6) 11 (29) 35 (92) 36 (95) 8 (21) 16 (42) 11 (29) 48.4 (16.4) 106.3 (43.1) 171.4 (108.1)
32 (82) 65.3 (9.6) 28.8(3.7) 11 (28) 36 (92) 32 (82) 19 (49) 14 (36) 7 (18) 43.9 (12.6) 113.3 (29.6) 176.2 (87.7)
28 (72) 65.0 (9.7) 28.5 (4.7) 13 (33) 34 (87) 34 (87) 14 (36) 10 (26) 5 (13) 48.4 (15.0) 114.3 (44.9) 149.0 (77.4)
32 (84) 63.3(7.7) 26.9 (3.3) 11 (29) 38 (100) 36 (95) 16 (42) 11 (29) 12 (32) 47.0 (11.3) 102.5 (28.6) 161.5 (80.1)
0.530 0.699 0.097 0.959 0.094 0.188 0.076 0.423 0.156 0.451 0.453 0.547
Medication β-blocker, n (%) ACEI, n (%) ARB, n (%) Diuretics, n (%) Calcium channel blocker, n (%) Statins, n (%) Nitrates, n (%)
34 (89) 28 (74) 9 (24) 20 (53) 10 (26) 35 (92) 1 (3)
33 (85) 25 (64) 11 (28) 10 (26) 6 (15) 34 (87) 2 (5)
32 (82) 24 (62) 12 (31) 14 (36) 13 (33) 33 (85) 0 (0)
37 (97) 26 (68) 11 (29) 16 (42) 13 (34) 35 (92) 0 (0)
0.167 0.688 0.915 0.102 0.218 0.650 0.297
Hemodynamic data Heart rate at rest (bpm) Peak heart rate (bpm) Systolic blood pressure at rest (mmHg) Peak systolic blood pressure (mmHg) Peak DOUBLE PRODUCT (bpm × mmHg) Submaximal test,a n (%)
72.5 (13.8) 137.9 (8.2) 128.4 (20.8) 138.3 (31.9) 19059 (4441) 5 (13)
73.3 (14.1) 136.3 (11.1) 126.0 (22.0) 137.7 (31.0) 18759 (4321) 5 (13)
71.3 (15.0) 132.4 (12.3) 131.7 (20.7) 143.3 (39.0) 18914 (5185) 9 (23)
68.2 (11.7) 139.6 (8.7) 132.3 (20.6) 145.7 (32.2) 20340 (4604) 4 (11)
0.398 0.017 0.523 0.676 0.428 0.462
LVDWS, left ventricular diastolic wall stress; BMI, body mass index; CABG, coronary artery bypass grafting; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. For all continuous parameters, data are expressed as mean ± standard deviation. P indicates the significance level for differences between geometric groups.aSubmaximal test was defined as the one in which the heart rate achieved was less than 100% of the target heart rate.
immediately after stress perfusion data acquisition, another Gad-DTPA bolus 0.1 mmol/kg was administered as required for optimal late enhancement imaging in all cardiac standard geometries. All image analysis was carried out on a workstation (Extended Workspace®; Philips Medical Systems, Best, The Netherlands). For volume and mass determination following the disk summation method, epi- and endocardial LV contours were defined by a semi-automatic detection algorithm and corrected manually if necessary with papillary muscles being included in the LV blood pool). LV septal and inferolateral wall thickness and LV diameter were measured in a basal end-diastolic short-axis slice. Relative wall thickness (RWT) was calculated as the ratio of septal-
plus-inferolateral wall thickness at end-diastole to the LV end-diastolic diameter. Abnormal RWT was defined as ≥0.45; increased LV mass index was defined as N 81 g/m2 and N 62 g/m2 for men and women, respectively [4]. Patients were classified into four groups based on RWT and LV mass index: normal geometry (normal LV mass, normal RWT), concentric remodeling (normal LV mass, increased RWT), concentric hypertrophy (increased LV mass, increased RWT) and eccentric hypertrophy (increased LV mass, normal RWT). Segmental analysis of wall motion or perfusion was performed in consensus by two readers being blinded to all clinical and angiographic data and to the results of the perfusion or wall motion study, respectively. Stress was calculated according to Alter
Table 2 MR data according to the LVDWS quartiles. Q1 (n = 38)
Q2 (n = 39)
Q3 (n = 39)
Q4 (n = 38)
p value
LVEDD (mm) LVEDV (ml) LVESV (ml) LVEF (%) SWT (cm) LWT (cm) LVM (g) LVMI (g/m2)
48.3 (3.9) 136.0 (33.3) 55.5 (17.6) 59.3 (5.6) 11.7 (2.1) 10.0 (1.8) 157.7 (34.3) 81.3 (15.0)
49.7 (3.8) 143.0 (36.9) 63.9 (26.1) 55.9 (9.8) 11.5 (2.5) 9.4 (1.1) 150.6 (37.4) 77.6 (16.1)
49.8 (4.6) 144.6 (35.2) 61.7 (22.4) 58.2 (9.5) 11.0 (2.0) 9.3 (1.4) 149.4 (32.9) 76.4 (14.4)
51.6(3.7) 157.8 (28.9) 69.7 (22.7) 56.5 (7.4) 11.3 (2.2) 9.6 (1.5) 154.9 (42.4) 76.4 (18.7)
0.006 0.043 0.055 0.267 0.528 0.362 0.756 0.503
Geometry Normal, n (%) CR, n (%) CH, n (%) EH, n (%) LVDWS (kPa)
9 (23.7) 10 (26.3) 10 (26.3) 9 (23.7) 2.0 (0.7)
17 (43.6) 6 (15.4) 8 (20.5) 8 (20.5) 2.9 (0.8)
17 (43.6) 5 (12.8) 6 (15.4) 11 (28.2) 3.7 (1.2)
18 (47.4) 1 (2.6) 7 (18.4) 12 (31.6) 4.6 (2.0)
0.139 0.032 0.677 0.698 0.000
LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular systolic volume; LVEF, left ventricular ejection fraction; SWT, septal wall thickness; LWT, lateral wall thickness; LVM, left ventricular mass; LVMI, left ventricular mass index; LVDWS, left ventricular diastolic wall stress; CR, concentric geometry; CH, concentric hypertrophy; EH, eccentric hypertrophy. For all continuous parameters, data are expressed as mean ± standard deviation. P indicates the significance level for differences between LVDWS quartiles.
J.G. Mirelis et al. / International Journal of Cardiology 172 (2014) e39–e42
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Table 3 Diagnostic performance according to LVDWS quartile. Sensitivity
Specificity
Accuracy
Stress quartile
n
DSMR
DSMRP
p value
DSMR
DSMRP
p value
DSMR
DSMRP
p value
Q1 Q2 Q3 Q4
38 39 39 38
17/24 (71) 23/29 (79) 20/24 (83) 23/26 (89)
20/24 (83) 26/29 (90) 21/24 (88) 25/26 (96)
0.508 0.375 1 0.625
12/14 (86) 9/10 (90) 13/15 (87) 10/12 (83)
11/14 (79) 7/10 (70) 10/15 (67) 8/12 (68)
1 0.500 0.453 0.687
29/38 (76) 32/39 (82) 33/39 (85) 33/38 (87)
31/38 (82) 33/39 (85) 31/39 (79) 33/38 (87)
0.774 1 0.774 1
DSMR, Dobutamine stress magnetic resonance; DSMRP, dobutamine stress magnetic resonance perfusion; LVDWS, left ventricular diastolic wall stress. P indicates the significance level for differences between DSMR and DSMRP.
Fig. 2. Diagnostic performance of DSMR and DSMRP according to the LVDWS quartile. The DSMR traces show the inverse relation between sensitivity (solid line) and specificity (broken line): i.e., Q4 patients had the highest levels of sensitivity and the lowest levels of specificity. This inverse relation is also apparent in the DSMRP data, but here Q4 also had the maximal difference between sensitivity and specificity.
et al. [5], based on the Laplace theory applied to a thick-wall sphere model using the following formula: σ ¼
P
V lum þV myo 2=3 −1 V lum
;
where σ represents stress, P represents intracavitary pressure, and Vlum and Vmyo represent intraluminal and myocardial volume. For intracavitary pressure, we used the LV end-diastolic pressure derived during catheterization; Vlum and Vmyo were derived from MR measurements. Hence, in the current study, σ constituted left ventricular diastolic wall stress (LVDWS). The study population was divided into four quartiles according to the level of LVDWS, with Q1 representing the lowest level. Within 30 days after MR imaging, all patients underwent left heart catheterization and coronary angiography. Angiograms were evaluated visually by experienced interventionalists blinded to the results of MR imaging. Significant coronary luminal narrowing was defined as ≥70% diameter reduction. Statistical analysis was performed using the IBM SPSS software
(rel. 20.0.0). The authors certify that the manuscript complies with the Principles of Ethical Publishing in the International Journal of Cardiology. Clinical and hemodynamic data from the DSMR analysis are given in Table 1. The stratification of MR data according to LVDWS quartiles is shown in Table 2. Regarding LV geometry, there was a statistically significant difference among quartiles in the concentric remodeling subgroup, with a prevalence of CR = 26.3% in Q1 and 2.6% in Q4, P = 0.032 (LVDWS in Q1 = 2.0 ± 0.7; in Q4 = 4.6 ± 2.0). The diagnostic performance of DSMR and DSMRP is presented in Table 3 and Fig. 2. The sensitivity and accuracy of wall motion and perfusion analysis were significantly lower for patients in the lowest LVDWS quartile (Q1) compared with those in Q4. Conversely, DSMR specificity was higher for patients in Q1 compared with those in Q4 (Table 4). Our study data demonstrated that diastolic wall stress, determined as a surrogate of ventricular geometry and intracavitary pressure, is an important mediator of LV wall motion (probably perfusion either) during pharmacological stress. Therefore, wall stress, calculated on the basis of Laplace's law, could explain the failure to detect the ischemic reaction of a wall motion abnormality by visual assessment of DSMR images. A novel validated method for measuring stress is based exclusively on geometric information and intracavitary pressures (Laplace theory) [5]. Using this approach, Alter et al. [6,7] have determined that wall stress is a relevant factor in several clinical scenarios. Earlier studies assigned the unexpectedly high number of false negatives in dobutamine stress testing to original misdiagnosis. For instance, Secknus et al. showed that the overall sensitivity of DSE was significantly lower for patients with cavity obliteration and claimed that a hyperdynamic response associated with cavity obliteration might obscure wall motion abnormalities [8]. Along the same lines, Smart et al. speculated that the akinetic/hypokinetic segments become visually undetectable due to minimal displacement distance and a “tethering” effect from surrounding hyperkinetic segments in the context of hyperdynamic LV with high “concentricity” [9]. Another study by Yuda et al. [10] demonstrated an influence of wall stress on the diagnostic accuracy of DSE; these authors, however, attributed the low sensitivity of DSE to a decrease in oxygen consumption associated with lower wall stress [10] (and not resulting from misdiagnosis). A linear relation between LV wall stress and myocardial oxygen consumption has in fact been reported in patients with hypertension and dilated cardiomyopathy [11,12]. Mean LV wall stress (LVDWS) is a major determinant of wall motion under stress conditions. In patients with increased LV concentricity, low LV wall stress mediates lower oxygen consumption
Table 4 Diagnostic performance of DSMR and DSMRP according to the lowest and highest LVDWS quartiles.
Sensitivity DSMR Specificity DSMR Accuracy DSMR
Q1
Q4
p value
17/24 (71) 12/14 (86) 29/38 (76)
23/26 (89) 10/12 (83) 33/38 (87)
0.003 0.013 b0.001
Sensitivity DSMRP Specificity DSMRP Accuracy DSMRP
Q1
Q4
p value
20/24 (83) 11/14 (79) 31/38 (82)
25/26 (96) 8/12 (68) 33/38 (87)
0.000 0.118 b0.0001
P indicates the significance level for differences in diagnostic accuracy of DSMR and DSMRP considering only the lowest and highest LVDWS quartiles.
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and thus may explain the relatively high level of false negatives in DSMR analysis.
References [1] Nandalur KR, Dwamena BA, Choudhri AF, Nandalur MR, Carlos RC. Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease: a meta-analysis. J Am Coll Cardiol 2007;50:1343–53. [2] Gebker R, Mirelis JG, Jahnke C, et al. Influence of left ventricular hypertrophy and geometry on diagnostic accuracy of wall motion and perfusion magnetic resonance during dobutamine stress. Circ Cardiovasc Imaging 2010;3:507–14. [3] Mirsky I. Left ventricular stresses in the intact human heart. Biophys J 1969;9:189–208. [4] Salton CJ, Chuang ML, O' Donnell CJ, et al. Gender differences and normal left ventricular anatomy in an adult population free of hypertension. A cardiovascular magnetic resonance study of the Framingham Heart Study Offspring Cohort. J Am Coll Cardiol 2002;39:1055–60. [5] Alter P, Rupp H, Rominger MB, Klose KJ, Maisch B. A new methodological approach to assess cardiac work by pressure-volume and stress-length relations in patients with aortic valve stenosis and dilated cardiomyopathy. Pflugers Arch 2008;455:627–36.
[6] Alter P, Rupp H, Adams P, et al. Occurrence of late gadolinium enhancement is associated with increased left ventricular wall stress and mass in patients with non-ischaemic dilated cardiomyopathy. Eur J Heart Fail 2011;13:937–44. [7] Alter P, Rupp H, Stoll F, et al. Increased enddiastolic wall stress precedes left ventricular hypertrophy in dilative heart failure-use of the volume-based wall stress index. Int J Cardiol 2012;157:233–8. [8] Secknus MA, Niedermaier ON, Lauer MS, Marwick TH. Diagnostic and prognostic implications of left ventricular cavity obliteration response to dobutamine echocardiography. Am J Cardiol 1998;81:1318–22. [9] Smart SC, Knickelbine T, Malik F, Sagar KB. Dobutamine-atropine stress echocardiography for the detection of coronary artery disease in patients with left ventricular hypertrophy. Importance of chamber size and systolic wall stress. Circulation 2000;101:258–63. [10] Yuda S, Khoury V, Marwick TH. Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 2002;40:1311–9. [11] Cholley BP, Shroff SG, Sandelski J, et al. Differential effects of chronic oral antihypertensive therapies on systemic arterial circulation and ventricular energetics in African-American patients. Circulation 1995;91:1052–62. [12] Hasenfuss G, Holubarsch C, Heiss HW, et al. Myocardial energetics in patients with dilated cardiomyopathy. Influence of nitroprusside and enoximone. Circulation 1989;80:51–64.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Impact of diastolic wall stress on the diagnostic value of visually interpreted dobutamine stress MR imaging☆,☆☆ Jesus G. Mirelis a,b,c,⁎,1, Ingo Paetsch d,1, Cosima Jahnke d,1, Borja Ibañez b,1, Eckart Fleck a,1, Luis A. Alonso-Pulpon d,1, Valentín Fuster b,1, Rolf Gebker a,1 a
German Heart Institute, Berlin, Germany Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain Puerta de Hierro Majadahonda University Hospital, Madrid, Spain d Department of Cardiology, University Hospital RWTH Aachen, Aachen, Germany b c
a r t i c l e
i n f o
Article history: Received 24 September 2013 Accepted 21 December 2013 Available online 4 January 2014 Keywords: Dobutamine stress magnetic resonance Myocardial ischemia Left ventricular wall stress
Dobutamine stress magnetic resonance (DSMR) is a valuable tool for the detection of myocardial ischemia in a wide spectrum of patients [1]. However, previous studies indicated that patients with distinct left ventricular (LV) geometries (i.e., concentric hypertrophy or concentric remodeling) exhibited surprisingly low sensitivity regarding the detection of significant coronary artery disease (CAD) [2]. In a subset of patients with such LV geometries, we frequently encountered uncompromised segmental wall motion (normal endocardial inward motion/systolic thickening) during dobutamine stress testing even in the presence of angiographically severe CAD (≥ 70% luminal stenosis). Consistently, high MR image quality in all examinations rendered misinterpretation an unlikely explanation for the observed limited diagnostic value of visually interpreted DSMR. Hence, based on Laplace's law, we hypothesized that the impaired diagnostic accuracy of DSMR in patients with distinct LV geometries may result from lower mean wall stress associated with concentrically thickened LV myocardium [3] (Fig. 1). One hundred fifty-four consecutive patients with suspected or known CAD underwent combined DSMR wall motion and perfusion ☆ Institution from which the work originated: German Heart Institute Berlin, Germany, Augustenburger Platz, 1, 13353 Berlin, Germany. ☆☆ This work was partially supported by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (CARDIOIMAGEN award to J.G.M.). ⁎ Corresponding author at: Melchor Fernandez Almagro, 3, 28029, Madrid, Spain. Tel.: +34 667393212. E-mail address: [email protected] (J.G. Mirelis). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.085
imaging (DSMRP) followed by invasive coronary angiography with invasive pressure measurements. The study was conducted in accordance with the ethical standards defined by local German law. Examinations were performed on a 1.5-T MR system (Philips Achieva, Best, The Netherlands). LV mass was determined from a contiguous stack of short axis cine views. All cardiac standard geometries were acquired at rest and during each dobutamine stress level. At maximum dobutamine infusion level dynamic, contrast-enhanced three-slice perfusion imaging (DSMRP) was additionally performed (0.1 mmol/kg bolus of Gad-DTPA, infusion rate of 4 ml/s followed by a flush of saline solution);
Fig. 1. Top left: thick-wall sphere model of the human heart [3]. EDV, end diastolic volume; EDVM, end diastolic volume mass; EDP, end diastolic pressure; WS, wall stress. Bottom left: detailed force diagram. In this zoomed 3D sector of the model, σ1 and σ2 represent horizontal and vertical stresses. Simplifying to a 2D model, a “short axis view” reference was taken. Although stress vectors (σ1 and σ2) are usually shown in the vertical and horizontal directions, the final vector to be “compensated” by the motion vector could be depicted orthogonal to the surface of the sphere (solid black line). Top right: concentric hypertrophy condition; the wall stress (WS) vector (discontinuous line) is short, indicating low wall stress. This geometry can lead to a false negative outcome of DSMR due to the high threshold for demand ischemia. Bottom right: eccentric hypertrophy condition; this geometry is likely coupled to high wall stress and can lead to a false positive on DSMR due to the low threshold for demand ischemia.
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Table 1 Clinical and hemodynamic data according to the LVDWS quartiles. Q1 (n = 38)
Q2 (n = 39)
Q3 (n = 39)
Q4 (n = 38)
p value
Clinical data Male, n (%) Age (years) BMI (kg/m2) CABG, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Diabetes mellitus, n (%) Smoking, n (%) Family history, n (%) HDL-cholesterol (mg/dl) LDL-Cholesterol (mg/dl) Triglycerides (mg/dl)
31 (82) 63.4 (11.5) 27.3 (3.6) 11 (29) 35 (92) 36 (95) 8 (21) 16 (42) 11 (29) 48.4 (16.4) 106.3 (43.1) 171.4 (108.1)
32 (82) 65.3 (9.6) 28.8(3.7) 11 (28) 36 (92) 32 (82) 19 (49) 14 (36) 7 (18) 43.9 (12.6) 113.3 (29.6) 176.2 (87.7)
28 (72) 65.0 (9.7) 28.5 (4.7) 13 (33) 34 (87) 34 (87) 14 (36) 10 (26) 5 (13) 48.4 (15.0) 114.3 (44.9) 149.0 (77.4)
32 (84) 63.3(7.7) 26.9 (3.3) 11 (29) 38 (100) 36 (95) 16 (42) 11 (29) 12 (32) 47.0 (11.3) 102.5 (28.6) 161.5 (80.1)
0.530 0.699 0.097 0.959 0.094 0.188 0.076 0.423 0.156 0.451 0.453 0.547
Medication β-blocker, n (%) ACEI, n (%) ARB, n (%) Diuretics, n (%) Calcium channel blocker, n (%) Statins, n (%) Nitrates, n (%)
34 (89) 28 (74) 9 (24) 20 (53) 10 (26) 35 (92) 1 (3)
33 (85) 25 (64) 11 (28) 10 (26) 6 (15) 34 (87) 2 (5)
32 (82) 24 (62) 12 (31) 14 (36) 13 (33) 33 (85) 0 (0)
37 (97) 26 (68) 11 (29) 16 (42) 13 (34) 35 (92) 0 (0)
0.167 0.688 0.915 0.102 0.218 0.650 0.297
Hemodynamic data Heart rate at rest (bpm) Peak heart rate (bpm) Systolic blood pressure at rest (mmHg) Peak systolic blood pressure (mmHg) Peak DOUBLE PRODUCT (bpm × mmHg) Submaximal test,a n (%)
72.5 (13.8) 137.9 (8.2) 128.4 (20.8) 138.3 (31.9) 19059 (4441) 5 (13)
73.3 (14.1) 136.3 (11.1) 126.0 (22.0) 137.7 (31.0) 18759 (4321) 5 (13)
71.3 (15.0) 132.4 (12.3) 131.7 (20.7) 143.3 (39.0) 18914 (5185) 9 (23)
68.2 (11.7) 139.6 (8.7) 132.3 (20.6) 145.7 (32.2) 20340 (4604) 4 (11)
0.398 0.017 0.523 0.676 0.428 0.462
LVDWS, left ventricular diastolic wall stress; BMI, body mass index; CABG, coronary artery bypass grafting; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. For all continuous parameters, data are expressed as mean ± standard deviation. P indicates the significance level for differences between geometric groups.aSubmaximal test was defined as the one in which the heart rate achieved was less than 100% of the target heart rate.
immediately after stress perfusion data acquisition, another Gad-DTPA bolus 0.1 mmol/kg was administered as required for optimal late enhancement imaging in all cardiac standard geometries. All image analysis was carried out on a workstation (Extended Workspace®; Philips Medical Systems, Best, The Netherlands). For volume and mass determination following the disk summation method, epi- and endocardial LV contours were defined by a semi-automatic detection algorithm and corrected manually if necessary with papillary muscles being included in the LV blood pool). LV septal and inferolateral wall thickness and LV diameter were measured in a basal end-diastolic short-axis slice. Relative wall thickness (RWT) was calculated as the ratio of septal-
plus-inferolateral wall thickness at end-diastole to the LV end-diastolic diameter. Abnormal RWT was defined as ≥0.45; increased LV mass index was defined as N 81 g/m2 and N 62 g/m2 for men and women, respectively [4]. Patients were classified into four groups based on RWT and LV mass index: normal geometry (normal LV mass, normal RWT), concentric remodeling (normal LV mass, increased RWT), concentric hypertrophy (increased LV mass, increased RWT) and eccentric hypertrophy (increased LV mass, normal RWT). Segmental analysis of wall motion or perfusion was performed in consensus by two readers being blinded to all clinical and angiographic data and to the results of the perfusion or wall motion study, respectively. Stress was calculated according to Alter
Table 2 MR data according to the LVDWS quartiles. Q1 (n = 38)
Q2 (n = 39)
Q3 (n = 39)
Q4 (n = 38)
p value
LVEDD (mm) LVEDV (ml) LVESV (ml) LVEF (%) SWT (cm) LWT (cm) LVM (g) LVMI (g/m2)
48.3 (3.9) 136.0 (33.3) 55.5 (17.6) 59.3 (5.6) 11.7 (2.1) 10.0 (1.8) 157.7 (34.3) 81.3 (15.0)
49.7 (3.8) 143.0 (36.9) 63.9 (26.1) 55.9 (9.8) 11.5 (2.5) 9.4 (1.1) 150.6 (37.4) 77.6 (16.1)
49.8 (4.6) 144.6 (35.2) 61.7 (22.4) 58.2 (9.5) 11.0 (2.0) 9.3 (1.4) 149.4 (32.9) 76.4 (14.4)
51.6(3.7) 157.8 (28.9) 69.7 (22.7) 56.5 (7.4) 11.3 (2.2) 9.6 (1.5) 154.9 (42.4) 76.4 (18.7)
0.006 0.043 0.055 0.267 0.528 0.362 0.756 0.503
Geometry Normal, n (%) CR, n (%) CH, n (%) EH, n (%) LVDWS (kPa)
9 (23.7) 10 (26.3) 10 (26.3) 9 (23.7) 2.0 (0.7)
17 (43.6) 6 (15.4) 8 (20.5) 8 (20.5) 2.9 (0.8)
17 (43.6) 5 (12.8) 6 (15.4) 11 (28.2) 3.7 (1.2)
18 (47.4) 1 (2.6) 7 (18.4) 12 (31.6) 4.6 (2.0)
0.139 0.032 0.677 0.698 0.000
LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular systolic volume; LVEF, left ventricular ejection fraction; SWT, septal wall thickness; LWT, lateral wall thickness; LVM, left ventricular mass; LVMI, left ventricular mass index; LVDWS, left ventricular diastolic wall stress; CR, concentric geometry; CH, concentric hypertrophy; EH, eccentric hypertrophy. For all continuous parameters, data are expressed as mean ± standard deviation. P indicates the significance level for differences between LVDWS quartiles.
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Table 3 Diagnostic performance according to LVDWS quartile. Sensitivity
Specificity
Accuracy
Stress quartile
n
DSMR
DSMRP
p value
DSMR
DSMRP
p value
DSMR
DSMRP
p value
Q1 Q2 Q3 Q4
38 39 39 38
17/24 (71) 23/29 (79) 20/24 (83) 23/26 (89)
20/24 (83) 26/29 (90) 21/24 (88) 25/26 (96)
0.508 0.375 1 0.625
12/14 (86) 9/10 (90) 13/15 (87) 10/12 (83)
11/14 (79) 7/10 (70) 10/15 (67) 8/12 (68)
1 0.500 0.453 0.687
29/38 (76) 32/39 (82) 33/39 (85) 33/38 (87)
31/38 (82) 33/39 (85) 31/39 (79) 33/38 (87)
0.774 1 0.774 1
DSMR, Dobutamine stress magnetic resonance; DSMRP, dobutamine stress magnetic resonance perfusion; LVDWS, left ventricular diastolic wall stress. P indicates the significance level for differences between DSMR and DSMRP.
Fig. 2. Diagnostic performance of DSMR and DSMRP according to the LVDWS quartile. The DSMR traces show the inverse relation between sensitivity (solid line) and specificity (broken line): i.e., Q4 patients had the highest levels of sensitivity and the lowest levels of specificity. This inverse relation is also apparent in the DSMRP data, but here Q4 also had the maximal difference between sensitivity and specificity.
et al. [5], based on the Laplace theory applied to a thick-wall sphere model using the following formula: σ ¼
P
V lum þV myo 2=3 −1 V lum
;
where σ represents stress, P represents intracavitary pressure, and Vlum and Vmyo represent intraluminal and myocardial volume. For intracavitary pressure, we used the LV end-diastolic pressure derived during catheterization; Vlum and Vmyo were derived from MR measurements. Hence, in the current study, σ constituted left ventricular diastolic wall stress (LVDWS). The study population was divided into four quartiles according to the level of LVDWS, with Q1 representing the lowest level. Within 30 days after MR imaging, all patients underwent left heart catheterization and coronary angiography. Angiograms were evaluated visually by experienced interventionalists blinded to the results of MR imaging. Significant coronary luminal narrowing was defined as ≥70% diameter reduction. Statistical analysis was performed using the IBM SPSS software
(rel. 20.0.0). The authors certify that the manuscript complies with the Principles of Ethical Publishing in the International Journal of Cardiology. Clinical and hemodynamic data from the DSMR analysis are given in Table 1. The stratification of MR data according to LVDWS quartiles is shown in Table 2. Regarding LV geometry, there was a statistically significant difference among quartiles in the concentric remodeling subgroup, with a prevalence of CR = 26.3% in Q1 and 2.6% in Q4, P = 0.032 (LVDWS in Q1 = 2.0 ± 0.7; in Q4 = 4.6 ± 2.0). The diagnostic performance of DSMR and DSMRP is presented in Table 3 and Fig. 2. The sensitivity and accuracy of wall motion and perfusion analysis were significantly lower for patients in the lowest LVDWS quartile (Q1) compared with those in Q4. Conversely, DSMR specificity was higher for patients in Q1 compared with those in Q4 (Table 4). Our study data demonstrated that diastolic wall stress, determined as a surrogate of ventricular geometry and intracavitary pressure, is an important mediator of LV wall motion (probably perfusion either) during pharmacological stress. Therefore, wall stress, calculated on the basis of Laplace's law, could explain the failure to detect the ischemic reaction of a wall motion abnormality by visual assessment of DSMR images. A novel validated method for measuring stress is based exclusively on geometric information and intracavitary pressures (Laplace theory) [5]. Using this approach, Alter et al. [6,7] have determined that wall stress is a relevant factor in several clinical scenarios. Earlier studies assigned the unexpectedly high number of false negatives in dobutamine stress testing to original misdiagnosis. For instance, Secknus et al. showed that the overall sensitivity of DSE was significantly lower for patients with cavity obliteration and claimed that a hyperdynamic response associated with cavity obliteration might obscure wall motion abnormalities [8]. Along the same lines, Smart et al. speculated that the akinetic/hypokinetic segments become visually undetectable due to minimal displacement distance and a “tethering” effect from surrounding hyperkinetic segments in the context of hyperdynamic LV with high “concentricity” [9]. Another study by Yuda et al. [10] demonstrated an influence of wall stress on the diagnostic accuracy of DSE; these authors, however, attributed the low sensitivity of DSE to a decrease in oxygen consumption associated with lower wall stress [10] (and not resulting from misdiagnosis). A linear relation between LV wall stress and myocardial oxygen consumption has in fact been reported in patients with hypertension and dilated cardiomyopathy [11,12]. Mean LV wall stress (LVDWS) is a major determinant of wall motion under stress conditions. In patients with increased LV concentricity, low LV wall stress mediates lower oxygen consumption
Table 4 Diagnostic performance of DSMR and DSMRP according to the lowest and highest LVDWS quartiles.
Sensitivity DSMR Specificity DSMR Accuracy DSMR
Q1
Q4
p value
17/24 (71) 12/14 (86) 29/38 (76)
23/26 (89) 10/12 (83) 33/38 (87)
0.003 0.013 b0.001
Sensitivity DSMRP Specificity DSMRP Accuracy DSMRP
Q1
Q4
p value
20/24 (83) 11/14 (79) 31/38 (82)
25/26 (96) 8/12 (68) 33/38 (87)
0.000 0.118 b0.0001
P indicates the significance level for differences in diagnostic accuracy of DSMR and DSMRP considering only the lowest and highest LVDWS quartiles.
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and thus may explain the relatively high level of false negatives in DSMR analysis.
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