Int J Cardiovasc Imaging (2015) 31:1401–1412 DOI 10.1007/s10554-015-0711-1
ORIGINAL PAPER
Impact of monitoring longitudinal systolic strain changes during serial echocardiography on outcome in patients with AL amyloidosis Kai Hu1,2 • Dan Liu1,2 • Peter Nordbeck1,2 • Maja Cikes3 • Stefan Sto¨rk1,2 Bastian Kramer1,2 • Philipp Daniel Gaudron1,2 • Andreas Schneider1 • Stefan Knop4 • Georg Ertl1,2 • Bart Bijnens5 • Frank Weidemann2,6 • Sebastian Herrmann1,2
•
Received: 22 May 2015 / Accepted: 6 July 2015 / Published online: 16 July 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Relative apical sparing of longitudinal systolic strain (LSsys) with preserved LSsys at apical and significantly reduced LSsys at mid/basal segments is a typical echocardiographic feature in AL amyloidosis patients with cardiac involvement. The present study aims to evaluate the change of this typical feature over time by serial echocardiography and its impact on outcome in AL amyloidosis patients with cardiac involvement. Echocardiography was performed in 24 consecutive patients with biopsy-proven AL amyloidosis (mean age 64 ± 9 years; 50 % male) at baseline and during a median of 257 (quartiles 103–651) days follow-up. Global and segmental LSsys were assessed by two-dimensional speckle-trackingimaging in septal and lateral segments of the left ventricle (LV) from the apical 4-chamber view. Sixteen (67 %) patients died during a median follow-up of 487 days
(quartiles 223–872). LV global and segmental LSsys remained unchanged over time in survivors (all P [ 0.05), while LV global, septal-apical and lateral-apical LSsys significantly decreased in non-survivors. A decrease in lateral-apical LSsys [ 3.0 % independently predicted a fivefold increased all-cause mortality risk after adjustment for age, gender, NYHA class, and treatment strategies. Further, baseline serum NT-proBNP, serum albumin decrease during follow-up, baseline septal apical-to-basal LSsys ratio and lateral-apical LSsys decrease during followup remained independently predictive of increased allcause mortality risk. Serial monitoring of serological and echocardiographic parameters is valuable to predict outcome in AL amyloidosis patients with cardiac involvement. The best follow-up parameter to predict risk for imminent death is a decrease of longitudinal systolic strain at the lateral apical segment. Keywords Systemic amyloidosis Left ventricular strain Speckle tracking Prognosis
Kai Hu and Dan Liu have contributed equally to this work. & Kai Hu [email protected] 1
Department of Internal Medicine I, University Hospital Wu¨rzburg, Wu¨rzburg, Germany
2
Comprehensive Heart Failure Center, Wu¨rzburg, Germany
3
Department for Cardiovascular Diseases, University Hospital Center Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia
4
Department of Internal Medicine II, University Hospital Wu¨rzburg, Wu¨rzburg, Germany
5
ICREA - Universitat Pompeu Fabra, Barcelona, Spain
6
Katharinen-Hospital Unna, Unna, Germany
Introduction Primary light chain amyloidosis (AL) is the most common form of systemic amyloidosis. It is caused by myocardial amyloid deposition leading to cardiomyocyte disarry, tissue stiffening, and decline of vital organ function [1]. Cardiac involvement in AL amyloidosis is the primary cause of death [2–4]. The early diagnosis is essential in order to initiate effective therapy and attenuate organ damage and disease progression [2, 5]. However, early and accurate diagnosis of cardiac impairment in AL amyloidosis still remains a major challenge in daily clinical practice [6].
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Despite improved therapeutic regimens over the past decade, AL cardiac amyloidosis is still associated with a very high mortality [5]. In recent clinical studies, we and others showed that an apical sparing pattern with preserved longitudinal systolic strain (LSsys) at apical segments and significantly reduced LSsys at mid and basal segments is a typical echocardiographic finding in patients with AL cardiac amyloidosis [7–10]. The association between dynamic regional LSsys changes and outcome in these patients has not yet been investigated. The purpose of this study was therefore to observe serial echocardiographic changes of AL amyloidosis patients with cardiac involvement, and to explore the predictive value of changes in global and regional LSsys on outcome in these patients.
Methods Study population and follow-up Consecutive biopsy-proven systemic AL amyloidosis patients with typical echocardiographic features of cardiac involvement [9] referred to the University Hospital of Wu¨rzburg were included into the present study (n = 24). Amyloidosis was histologically confirmed on tissue biopsy stained with Congo red in all patients. At least one biopsy specimen from endomyocardial tissue, bone marrow, rectum, kidney, or subcutaneous fat was positive for amyloid. Amyloid typing was performed by immune histology. Patients with coronary artery disease, moderate to severe cardiac valve disease, and other endocrine or systemic disease were excluded. The median echocardiographic follow-up duration was 257 days (quartiles 103–651) and echocardiography was performed at least twice in all patients (mean 3.8 times). Patients were followed by clinical visit or telephone call for a median of 487 days (quartiles 223–872 days). The primary endpoint was defined as all-cause death. Written informed consent was obtained from all patients or their guardians. The study was approved by the local Ethics Committee at the University of Wu¨rzburg and conducted in accordance to the Declaration of Helsinki. Electrocardiography A standard 12-lead electrocardiography was recorded with a paper speed of 50 mm/s and an amplification of 0.1 mV/ mm. Low QRS voltages were defined as peak to peak QRS amplitudes in each limb lead \0.5, and \1.0 mV in any precordial lead [11]. A pseudoinfarct pattern was defined as
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a QS wave pattern in two contiguous leads in the absence of previous myocardial infarction. Standard echocardiography Left ventricular (LV) end-diastolic and end-systolic dimensions (LVEDD and LVESD), as well as end-diastolic thickness of the posterior wall (LVPWd) and the septum (IVSd) were measured using standard M-mode in the parasternal LV long-axis views at baseline and during follow-up. LV mass, indexed to body surface area, (LVMI) was estimated by LV cavity dimension and wall thickness at end diastole using the following formula [12]: LV mass (g) = 0.8 9 [1.04 9 (LVEDD ? LVPWd ? IVSd)3 - LVEDD3)] ? 0.6. Right ventricular (RV) end-diastolic dimension and RV lateral wall end-diastolic maximal thickness, and end-systolic right atrial (RA) area were measured in an apical 4-chamber view. Left atrial (LA) end-systolic diameter was measured in 2D- mode from a parasternal long-axis view. LA volume was assessed by the biplane area-length method from apical 4- and 2-chamber views. LV ejection fraction (EF) was measured with the biplane Simpson method in apical 4- and 2-chamber views. Mitral annular plane systolic excursion (MAPSE) measured at the septal and lateral sites as well as tricuspid plane annular systolic excursion were obtained by M-mode in an apical 4-chamber view. Systolic pulmonary artery pressure (sPAP) was derived from peak tricuspid regurgitation jet velocity using the simplified Bernoulli equation, in combination with an estimated RA pressure. RA pressure was estimated from inferior vena cava (IVC) diameter and respiratory changes. IVC diameter and inspiratory collapsibility was detected from the subcostal view. Normal RAP of 3 mmHg (range: 0–5 mmHg) was defined as IVC diameter B2.1 cm and inspiratory collapsibility [50 %; 8 mmHg (range: 5–10 mmHg) was defined as IVC diameter B2.1 cm and inspiratory collapsibility \50 %; high RAP of 15 mmHg (range: 10–20 mmHg) was defined as IVC diameter [2.1 cm and inspiratory collapsibility \50 %. Pulsed-wave Doppler was performed in apical 4-chamber views to obtain mitral valve inflow velocities for LV filling pattern evaluation (early filling [E] and late diastolic filling [A] velocities, E/A ratio and deceleration time [DT] of early filling). Tissue Doppler early diastolic mitral annular velocity (E0 ) of the septal annulus was obtained in an apical 4-chamber view. Atrial fibrillation was present in two patients. E, E0 , and DT (averaged from five cardiac circles) were measured in atrial fibrillation patients. The stage of LV diastolic function was diagnosed according to
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the American Society of Echocardiography (ASE) guidelines for the assessment of diastolic function [13]. Speckle tracking imaging Longitudinal segmental strain measurements by 2D speckle tracking imaging (STI) were performed off-line using dedicated software (EchoPAC, GE, Horten, Norway). The 2D grey scale images were recorded with a frame rate of 50–90 frames per second and care was taken to ensure that the entire ventricular wall was clearly visible in all frames. A region of interest (ROI) was created by manually outlining the endocardial border on an apical four-chamber view at the end-systolic frame. The system automatically tracked the tissue within the region and divided the myocardium into standard segments. The tracking was visually checked and, if necessary, adjusted. The trace analysis was automatically displayed after validating the tracking. LV longitudinal peak systolic strain (LSsys) was extracted from the basal, mid, and apical segments of the septal and lateral walls. The ratio between apical LSsys and basal LSsys (LSsysapex/base) in the septum was calculated. Reproducibility Reproducibility of LSsys was assessed by repeated measurements in the same recordings. Intraobserver variation was assessed by repeated analysis of 24 subjects and blinded to the initial results by one investigator (DL). Interobserver variation was done on the same datasets by two observers (DL and KH). Reproducibility was assessed using Bland and Altman analysis. Data analysis Continuous data are presented as mean ± standard deviation (SD) or median (quartiles) and categorical variables as percentages. Skewness, kurtosis, and Q–Q Plots of all continuous variables were applied to explore the normality of distribution. Unpaired Student´s t test and paired Student’s test were conducted for data with normality distribution and data with skewed distribution was tested by non-parametric tests: Mann–Whitney U test comparing survivors and non-survivors; paired sample Wilcoxon signed rank test comparing baseline and follow up. Categorical data were compared using a similar approach employing Chi square test for the overall test and Fisher’s exact for pair-wise group tests, as appropriate. All tests were performed two-sided. The factors predicting all-cause death were sought using Cox proportional-hazards regression models. Hazard ratios (HR) with 95 % confidence intervals (CI) were calculated.
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Variables with P values \0.05 were included in multivariable models, and independent factors were determined using the likelihood ratio test statistic. The cutoff value of lateral-septal LSsys was derived from receiver operating characteristic curve analysis by maximizing the sum of the sensitivity and specificity. A two-tailed probability value \0.05 was considered significant. Statistical analysis was performed using IBM SPSS, version 21 for Windows (SPSS).
Results Treatment strategies and responses Twelve patients received autologous stem cell transplantation with high-dose melphalan and the remaining 12 patients received risk-adapted chemotherapy regimens. Therapy strategies were similar between survivors and nonsurvivors. Hematological response to treatment was defined as a C50 % decrease in the serum and urine monoclonal component; renal response was defined as a 50 % decrease in proteinuria in the absence of a 25 % increase in serum creatinine (Scr), with a minimum of 0.5 mg/dL or a 25 % decrease in glomerular filtration rate or creatinine clearance [14, 15]. The response to treatment was evaluated every 3 months by monitoring serum and urine levels of monoclonal protein. Hematological or renal response to treatment was 25 % in the survivor group and 47 % in the non-survivor group (P [ 0.05). Clinical characteristics at baseline and during follow-up Sixteen out of 24 (67 %) patients died during clinical follow-up. Baseline clinical parameters were similar between survivors and non-survivors (Table 1). Prevalence of systemic hypertension was similar between groups. During follow-up, NYHA functional class was significantly increased and serum albumin level was significantly reduced in non-survivors (all P \ 0.05) while these parameters remained unchanged in survivors. Electrocardiography parameters were similar between survivor and non-survivor groups at baseline (Table 2). NT-proBNP tended to be higher in non-survivors than in survivors at both baseline and during follow-up. Echocardiography characteristics at baseline and during follow-up sPAP at baseline and RA area at both baseline and followup examinations were significantly higher in non-survivors than in survivors. IVSd was significantly increased in non-
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Table 1 Clinical characteristics
Male (n, %)
All n = 24
Survivors n=8
Non-survivors n = 16
P value
12 (50 %)
4 (50 %)
8 (50 %)
1.000 0.709
Age (years)
64 ± 9
65 ± 6
63 ± 10
BMI (kg/m2)
26 ± 5
25 ± 5
26 ± 5
0.744
Heart rate (beats/min)
78 ± 12
75 ± 10
80 ± 13
0.426
Systolic blood pressure (mmHg)
119 ± 23
123 ± 23
116 ± 24
0.526
Diastolic blood pressure (mmHg)
73 ± 14
77 ± 14
70 ± 14
0.290
Systemic hypertension (n, %) Mean NYHA class
12 (50 %)
5 (62.5 %)
7 (43.8 %)
0.667
Baseline
2.2 ± 0.7
1.9 ± 0.7
2.4 ± 0.8
0.185
Follow-up
2.6 ± 0.8*
2.1 ± 0.6
2.9 ± 0.8*
0.029
Baseline
10 (42 %)
2 (25 %)
8 (50 %)
0.388
Follow-up
13 (54 %)
2 (25 %)
11 (69 %)
NYHA class III/IV (n, %)
Light chain type (n, %)
0.082 0.189
j light chain
8 (33 %)
1 (12.5 %)
k light chain
16 (67 %)
7 (87.5 %)
9 (56 %)
1.7 ± 0.8
1.3 ± 0.7
1.9 ± 0.8
0.076
Renal (n, %)
15 (62.5 %)
3 (37.5 %)
12 (75 %)
0.099
Hepatic/gastrointestinal (n, %)
17 (71 %)
5 (62.5 %)
12 (75 %)
0.647
Lung (n, %)
3 (12.5 %)
0 (0 %)
3 (19 %)
0.526
Neuropathic (n, %)
2 (8 %)
1 (12.5 %)
1 (6 %)
1.000
4 (17 %) 12 (50 %)
0 (0 %) 4 (50 %)
4 (25 %) 8 (50 %)
0.262 1.000
Baseline
22 (7–66)
36 (15–58)
20 (3–112)
0.825
Follow-up
36 (14–147)
36 (20–50)
102 (6–312)
0.536
Baseline
39 (18–132)
107 (42–225)
38 (18–96)
0.364
Follow-up
63 (23–103)
63 (26–86)
63 (20–182)
1.000
Number of organ involvements
Soft tissues/bone (n, %) High-dose melphalan plus ASCT (n, %)
7 (44 %)
Serum biomarkers Free j light chain (mg/l)
Free k light chain (mg/l)
j/k ratio Baseline
0.16 (0.10–7.34)
0.51 (0.09–4.10)
0.15 (0.10–8.75)
1.000
Follow-up
0.60 (0.24–1.89)
0.51 (0.44–0.93)
1.51 (0.09–5.04)
0.694
NT-proBNP (pg/ml) Baseline
3097 (915–8967)
2575 (955–8062)
9168 (2217–11,554)
0.126
Follow-up
11,298 (3466–23,963)*
9046 (5866–21,520)
13,550 (9678–14,609)
0.486
1.4 ± 1.0 1.9 ± 1.5*
1.5 ± 1.4 2.5 ± 2.1
1.4 ± 0.7 1.7 ± 0.9
0.811 0.336
Creatinine (mg/ml) Baseline Follow-up eGFR (mL/min/1.73 m2) Baseline
63 ± 29
71 ± 34
60 ± 27
0.421
Follow-up
51 ± 30*
51 ± 40
51 ± 26
0.952
Alkaline phosphatase (U/l) Baseline
136 ± 102
132 ± 65
138 ± 119
0.901
Follow-up
166 ± 141
134 ± 65
181 ± 162
0.446
3.6 ± 0.8
3.4 ± 0.5
3.7 ± 0.9
0.429
Albumin (g/dl) Baseline
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Table 1 continued
Follow-up Clinical Follow-up duration (days)
All n = 24
Survivors n=8
Non-survivors n = 16
P value
3.4 ± 0.7
3.6 ± 0.6
3.3 ± 0.8*
0.341
487 (223–872)
708(160–1070)
388 (223–763)
0.306
BMI body mass index, NYHA New York heart association functional cassification, NT-proBNP N-terminal pro-brain natriuretic peptide, eGFR estimated glomerular filtration rate * P \ 0.05 versus baseline
survivors, LVPWd was significantly higher in both survivor and non-survivor groups during follow-up, compared to baseline level (Table 2). Baseline septal LSsysapex/base ratio was significantly higher in the non-survivor group than in the survivor group (3.70 ± 1.84 vs. 2.35 ± 0.61, P \ 0.05). Compared to baseline, global LSsys was significantly decreased in the non-survivor group (-10 ± 5 % vs. -12 ± 4 %, P \ 0.05) but unchanged in the survivor group (-12 ± 5 % vs. -13 ± 3 %, P [ 0.05) during follow-up. Septal- and lateral-apical LSsys values were significantly decreased during follow-up compared to baseline levels in the non-survivor group (Fig. 1). Figure 2 shows representative longitudinal systolic strain curves derived from 2D STI at baseline and at one-year follow-up in a survived patient (upper panel) and in a non-survivor (lower panel), who died 45 days after this follow-up echocardiographic examination. Spearman correlation showed that reduced global LSsys was correlated with higher NT-proBNP levels at baseline (r = -0.677, P = 0.003). Univariable and independent predictors of all-cause mortality Cox-regression analysis (Table 3) revealed that baseline serum NT-proBNP, serum albumin decrease during followup, baseline septal-mid and septal-basal LSsys, septal LSsysapex/base ratio, and global and lateral-apical LSsys decrease during follow-up were univariable predictors of all-cause mortality risk. Multivariable Cox models (Table 4) were established based on serological data (model 1), baseline echocardiographic variables (model 2), and their changes during follow-up (model 3), respectively, after adjustment for age, gender, NYHA class, and treatment strategies. Baseline serum NT-proBNP (HR 2.75, 95 % CI 1.12–6.78, P = 0.028), serum albumin decrease during follow-up (HR 4.70, 95 % CI 1.20–18.40, P = 0.026), baseline septal LSsysapex/base ratio (HR 1.68, 95 % CI 1.19–2.37, P = 0.003), and lateral-apical LSsys decrease during follow-up (HR 1.39, 95 % CI 1.13–1.70,
P = 0.002) remained independently predictive of increased all-cause mortality. A decrease in lateral-apical LSsys [ 3.0 % predicted a fivefold increased all-cause mortality risk after adjustment for age, gender, NYHA class, and treatment strategies (HR 5.47, 95 % CI 1.58–18.90, P = 0.007). Reproducibility The intra- and inter-observer variability of LSsys was assessed in 144 measured segments at baseline. The intraand inter-observer absolute bias was 0.42 % (95 % limits of agreement -5.4 to 6.2 %) and 0.64 % (95 % limits of agreement -5.0 to 6.3 %), respectively.
Discussion The current study aimed to investigate the utility of changes of clinical and imaging parameters on predicting mortality risk in patients with AL cardiac amyloidosis. The major findings of this study are: (1) Among the established serological biomarkers, higher NT-proBNP at baseline and serum albumin decrease over time were associated with increased all-cause mortality risk in patients with AL cardiac amyloidosis. (2) Among echocardiographic parameters, baseline longitudinal apex-to-base strain gradient served as both a typical feature of cardiac involvement and an indicator of prognosis in these patients. (3) A decrease of longitudinal systolic strain at the lateral-apical segment was a strong predictor of imminent death in AL cardiac amyloidosis patients. Heart and kidney are the predominantly affected vital organs in AL amyloidosis patients [5]. Previous studies suggested that elevated NT-proBNP level was a very good cardiac biomarker for predicting survival in AL amyloidosis patients and was recommended for risk stratification [16, 17]. Consistent with above findings, we showed that elevated NT-proBNP level at baseline was associated with a higher mortality risk in the current cohort. Furthermore,
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Table 2 Electrocardiography and standard echocardiography characteristics All n = 24
Survivors n=8
Non-survivors n = 16
P value
Electrocardiography Unexplained low voltage
46 %
50 %
44 %
0.99
QRS-T wave pseudo-infarct changes
50 %
63 %
44 %
0.667
I/II° atrioventricular block
67 %
71 %
64 %
0.99
Left/right bundle branch block
29 %
25 %
31 %
0.99
257 (103–651)
259 (90–730)
233 (129–526)
0.99
42 %
50 %
37.5 %
0.673
83 %
87.5 %
81 %
1.000
Echocardiography Follow-up duration (days) Pericardial effusion (%) Baseline Sparkling texture (%) Baseline LVEDD (mm) Baseline
43 ± 7
44 ± 8
43 ± 7
0.776
Follow-up
44 ± 7
46 ± 8
43 ± 6
0.292
LVESD (mm) Baseline
31 ± 7
33 ± 10
30 ± 7
0.347
Follow-up
31 ± 7
33 ± 8
31 ± 6
0.448
IVSd (mm) Baseline
14 ± 2
13 ± 2
14 ± 2
0.287
Follow-up
14 ± 2*
13 ± 2
15 ± 2*
0.118
13 ± 2 14 ± 2*
12 ± 2 13 ± 2*
13.8 ± 2 14.4 ± 2*
0.182 0.148
LVPWd (mm) Baseline Follow-up LVMI (g/m2) Baseline
120 ± 28
113 ± 24
125 ± 30
0.342
Follow-up
132 ± 26*
129 ± 23
134 ± 28
0.693
LA diameter (mm) Baseline
41 ± 7
40 ± 8
41 ± 7
0.722
Follow-up
42 ± 6
41 ± 6
43 ± 7
0.493
LA volume (ml) Baseline
65 ± 25
59 ± 24
69 ± 26
0.398
Follow-up
75 ± 26*
69 ± 20
80 ± 31
0.394
RV dimension(mm) Baseline
34 ± 5
31 ± 4
35 ± 5
0.053
Follow-up
36 ± 5*
33 ± 5
38 ± 4
0.053
RA area (cm2) Baseline Follow-up RV free wall thickness (mm)
17 ± 5
13 ± 2
19 ± 5
0.004
19 ± 6*
15 ± 4
21 ± 6
0.019
Baseline
6.2 ± 1.2
6.5 ± 1.2
6.1 ± 1.2
0.418
Follow-up
6.5 ± 1.1
6.7 ± 1.2
6.4 ± 1.1
0.539
Baseline
58 ± 11
58 ± 12
58 ± 11
1.000
Follow-up
57 ± 12
59 ± 14
56 ± 11
0.598
LV EF (%)
Septal MAPSE (mm) Baseline
6±2
7±2
6±2
0.369
Follow-up
6±2
7±1
6±3
0.598
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Table 2 continued All n = 24
Survivors n=8
Non-survivors n = 16
P value
Lateral MAPSE (mm) Baseline
8±3
9±2
8±3
0.626
Follow-up
8±3
9±2
8±4
0.347
Baseline
15 ± 4
15 ± 4
15 ± 4
0.797
Follow-up
15 ± 5
16 ± 4
15 ± 5
0.643
TAPSE (mm)
sPAP (mmHg) Baseline
35 ± 14
25 ± 9
40 ± 13
0.012
Follow-up
36 ± 14
31 ± 11
38 ± 15
0.301
Baseline
85 ± 26
93 ± 31
81 ± 23
0.239
Follow-up
83 ± 21
73 ± 27
87 ± 18
0.146
21 ± 9 19 ± 7
22 ± 10 18 ± 8
20 ± 11 19 ± 7
0.565 0.800
E (cm/s)
E/E’ Baseline Follow-up DT (ms) Baseline
186 ± 46
189 ± 45
185 ± 48
0.846
Follow-up
189 ± 75
230 ± 100
171 ± 55
0.082
48 %
33 %
53 %
0.709
Diastolic pseudonormal or restrictive filling pattern (%)
LVEDD left ventricular end-diastolic dimension, LVESD left ventricular end-systolic dimension, IVSd intervernicular septum at end-diastole, LVPWd Left ventricular posterior wall thickness at end-diastole, LVMI LV mass indexed to body surface area, LA left atrium, RV right ventricle, RA right atrium, EF ejection fraction, MAPSE mitral annular plane systolic excursion, TAPSE tricuspid annular plane systolic excursion, E early diastolic peak filling velocity, E0 tissue Doppler early diastolic septal mitral annular velocity, DT deceleration time of early diastolic peak velocity, sPAP systolic pulmonary artery pressure
in line with finding by Buss et al. [18], we showed that elevated NT-proBNP at baseline was significantly correlated with lower global LSsys at baseline (r = -0.677, P = 0.003), a parameter reflecting LV longitudinal dysfunction in AL amyloidosis patients with cardiac involvement. It is known that lower serum albumin is independently associated with renal progression of AL amyloidosis patients [19, 20]. Consistently, we showed that a decrease of serum albumin levels was related to higher mortality risk in AL cardiac amyloidosis patients.
The cardiomyopathy in CA patients Myocardial strain echocardiography is a sensitive tool for evaluating LV function in AL cardiac amyloidosis patients. The advantage of strain echocardiography is multiple: First, the measured reduction of longitudinal strain is a very typical feature in these patients. Second, cardiac involvement can be detected much earlier by quantification of longitudinal strain than by established conventional
echocardiographic parameters like global LV ejection fraction. Third, a staging of cardiac involvement with clinical impact on prognosis is possible by measuring the intra-wall strain gradient [9]. The prognostic value of LSsys measurement in AL cardiac amyloidosis patients has been previously demonstrated by our group and others [9, 10]. In a large cohort of patients with AL amyloidosis, Buss et al. demonstrated that LV longitudinal function assessed by LSsys could serve as an independent predictor of survival, thus provided incremental information beyond standard clinical and biomarkers [18]. The current study also confirmed the prognostic value of assessing baseline LSsys in AL cardiac amyloidosis patients as shown by a reduced septal LSsysapex/base in non-survivors compared to survivors. Thus, this strain gradient seems to predict the general prognosis as it is related to the stage of the disease. Although this strain gradient might be helpful during a unique evaluation to predict the long term progression of the disease, it is not meaningful for the evaluation of imminent events. In this context, monitoring the change of longitudinal strain during serial examinations is a superior option for predicting the imminent risk of death in AL
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Int J Cardiovasc Imaging (2015) 31:1401–1412 b Fig. 1 Apical, mid and basal longitudinal systolic strain (LSsys) of
septal and lateral left ventricular walls at baseline (BS, open bar) and follow-up (FU, solid bar) in survivors and non-survivors of AL cardiac amyloidosis patients
cardiac amyloidosis patients. Our study reports for the first time that the dynamic change in LSsys during serial echocardiography is an independent predictor of imminent risk of death in cardiac amyloidosis patients. A decrease in lateral-apical LSsys [ 3.0 % independently predicted a fivefold increased all-cause mortality risk after adjustment for age, gender and NYHA class. Thus, serial monitoring of segmental LSsys is of clinical importance to define AL cardiac amyloidosis patients at increased risk of imminent death. The pathophysiological mechanisms inducing reduced longitudinal strain and consequently leading to cardiac
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death in AL cardiac amyloidosis patients remain elusive. It is of note that LVEF was preserved in both survivors and non-survivors at baseline and during follow-up, suggesting that reduced longitudinal function, but not radial function, is the prominent outcome determinant in AL cardiac amyloidosis patients. The potential reason for the reduction of longitudinal function in AL cardiac amyloidosis patients was speculated to be related to a dominant deposition of amyloid protein at the subendocardium as evidenced by a cardiovascular magnetic resonance study [21]. It is known that there is an intra-wall longitudinal deformation gradient with preserved LSsys at the apical segments and significantly reduced LSsys at the mid and basal segments in AL cardiac amyloidosis patients [7–10] and this apical sparing phenomenon could be used to differentiate cardiac amyloidosis patients from other causes of concentric myocardial hypertrophy [22, 23]. Extending these previous
Fig. 2 Representative longitudinal strain curves at baseline (left) and one-year follow-up (right) in patients with AL cardiac amyloidosis. Patient 1: survivor. Patient 2: dying 45 days after the last echocardiography examination
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Table 3 Univariable predictors of mortality risk (Cox proportional-hazards regression analysis) Hazard ratio (95 % CI) Baseline
Wald
P value
Hazard ratio (95 % CI) Change during follow-up
Wald
P value
Age
0.99 (0.92–1.07)
0.05
0.824
–
–
–
Gender
1.62 (0.60–4.35)
0.90
0.342
–
–
–
NYHA class
1.86 (0.90–3.85)
2.79
0.095
1.26 (0.66–2.37)
0.49
0.482
High-dose melphalan plus ASCT
1.40 (0.50–3.87)
0.41
0.521
–
–
Systemic hypertension
1.46 (0.51–4.17)
0.51
0.475
–
–
Serum NT-proBNP (pg/ml)
2.14 (1.10–4.16)
5.01
0.025
1.18 (0.57–2.46)
0.20
0.657
Serum creatinine (mg/ml) Serum albumin (g/dL)
0.79 (0.43–1.46) 1.08 (0.48–2.44)
0.55 0.03
0.459 0.854
0.31 (0.09–1.01) 0.32 (0.13–0.83)
3.74 5.48
0.053 0.019
LVMI (g/m2)
1.01 (0.99–1.03)
1.76
0.185
0.98 (0.95–1.01)
2.68
0.102
EF (%)
0.98 (0.94–1.03)
0.43
0.511
0.99 (0.93–1.05)
0.18
0.671
RAA (cm2)
1.06 (0.98–1.14)
2.17
0.140
1.05 (0.89–1.24)
0.34
0.562
sPAP (mmHg)
1.04 (1.00–1.09)
3.54
0.060
0.97 (0.93–1.02)
1.06
0.303
Septal-basal LSsys (%)
1.35 (1.09–1.68)
7.27
0.007
0.99 (0.83–1.20)
0.00
0.958
Septal-mid LSsys (%)
1.28 (1.07–1.53)
7.16
0.007
1.07 (0.93–1.24)
0.87
0.350
Septal-apical LSsys (%)
1.05 (0.93–1.18)
0.69
0.406
1.09 (1.00–1.18)
3.67
0.055
Lateral-basal LSsys (%)
1.05 (0.89–1.24)
0.34
0.560
1.06 (0.96–1.18)
1.46
0.228
Lateral-mid LSsys (%)
1.03 (0.91–1.15)
0.18
0.671
1.13 (1.00–1.28)
3.59
0.058
– –
Lateral-apical LSsys (%)
1.00 (0.90–1.11)
0.00
0.989
1.14 (1.05–1.25)
9.15
0.002
Global LSsys (%)
1.11 (0.92–1.35)
1.21
0.271
1.17 (1.02–1.35)
5.02
0.025
Septal LSsysapex/base
1.67 (1.20–2.33)
9.17
0.002
1.05 (0.90–1.23)
0.37
0.541
NYHA New York heart association functional classification, LVMI LV mass indexed to body surface area, EF ejection fraction, sPAP systolic pulmonary artery pressure, LSsys longitudinal peak systolic strain, LSsysapex/base septal apical to basal longitudinal systolic strain ratio
Table 4 Multivariable predictors of mortality risk (Cox proportional hazards regression) Hazard ratio* (95 % CI)
Wald
P value
Baseline serum NT-proBNP (pg/ml)
2.75 (1.12–6.78)
4.85
0.028
Serum albumin decrease during follow-up (g/dL)
4.70 (1.20–18.40)
4.94
0.026
Model 1: clinical data*
Model 2: baseline echocardiographic data* Septal-basal LSsys (%)
0.80 (0.45–1.42)
0.60
0.438
Septal-mid LSsys (%)
1.10 (0.88–1.38)
0.77
0.382
Septal LSsysapex/base
1.68 (1.19–2.37)
8.77
0.003
Model 3: change of echocardiographic data during follow-up* Global LSsys decrease (%)
0.98 (0.67–1.45)
0.01
0.928
Septal-apical LSsys decrease (%)
0.85 (0.71–1.01)
3.40
0.065
Lateral-apical LSsys decrease (%)
1.39 (1.13–1.70)
9.83
0.002
Lateral-apical LSsys decrease [3.0 versus B3.0 % during follow-up*
5.47 (1.58–18.90)
7.22
0.007
* Adjustment for age, gender, NYHA class, and high-dose melphalan plus ASCT with backward stepwise (likelihood ratio). For abbreviation, see Table 3
findings, we demonstrated that reduced lateral-apical LSsys during follow-up is an independent mortality predictor for AL cardiac amyloidosis patients. Thus, it seems that the final echocardiographic progression marker before death is
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the deformation change in the apical segment. Interestingly, a fall in apical LV systolic strain was also observed in 10 out of 11 senile cardiac amyloidosis patients by Falk and Quarta [24] during a mean of 11.9 months follow-up.
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Although the underlying mechanisms between the reduction of apical strain and end-stage disease progression of AL cardiac amyloidosis remain unclear, our results suggest that serial assessment of longitudinal systolic strain, especially the apical strain changes, is helpful to define AL cardiac amyloidosis patients at increased risk of death.
Limitations The patient cohort is relatively small as only patients were included in whom serial echocardiographic examinations were available. Thus, studies with larger patient numbers are warranted to verify the outcome results. In addition, because of the small patient cohort, it was not possible to investigate the responses to various therapy regimens by the dynamic change of LSsys.
Conclusions Serial monitoring of serological and conventional and speckle tracking imaging echocardiographic parameters is valuable to predict outcome in AL amyloidosis patients with cardiac involvement. The intra-wall strain gradient is not only a typical feature for AL cardiac amyloidosis patients but also an independent predictor of all-cause mortality risk in AL cardiac amyloidosis patients. In particular, the decrease in longitudinal systolic strain at the lateral-apical segment is an ominous sign of imminent death in these patients. Acknowledgments This work was supported by Grants from the Bundesministerium fu¨r Bildung und Forschung (BMBF01 EO1004). Compliance with Ethical Standards Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
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1411 6. Banypersad SM, Moon JC, Whelan C, Hawkins PN, Wechalekar AD (2012) Updates in cardiac amyloidosis: a review. J Am Heart Assoc 1(2):e000364 7. Bostan C, Sinan UY, Canbolat P, Kucukoglu S (2014) Cardiac amyloidosis cases with relative apical sparing of longitudinal strain. Echocardiography 31(2):241–244 8. Phelan D, Collier P, Thavendiranathan P, Popovic ZB, Hanna M, Plana JC, Marwick TH, Thomas JD (2012) Relative apical sparing of longitudinal strain using two-dimensional speckletracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart 98(19):1442–1448 9. Liu D, Hu K, Niemann M, Herrmann S, Cikes M, Stork S, Beer M, Gaudron PD, Morbach C, Knop S, Geissinger E, Ertl G, Bijnens B, Weidemann F (2013) Impact of regional left ventricular function on outcome for patients with Al amyloidosis. PLoS One 8(3):e56923 10. Koyama J, Falk RH (2010) Prognostic significance of strain Doppler imaging in light-chain amyloidosis. J Am Coll Cardiol Img 3(4):333–342 11. Kadish AH, Buxton AE, Kennedy HL, Knight BP, Mason JW, Schuger CD, Tracy CM, Winters WL Jr, Boone AW, Elnicki M, Hirshfeld JW Jr, Lorell BH, Rodgers GP, Weitz HH (2001) ACC/ AHA clinical competence statement on electrocardiography and ambulatory electrocardiography: a report of the ACC/AHA/ACPASIM task force on clinical competence (ACC/AHA Committee to develop a clinical competence statement on electrocardiography and ambulatory electrocardiography) endorsed by the International Society for Holter and noninvasive electrocardiology. Circulation 104(25):3169–3178 12. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ (2005) Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18(12):1440–1463 13. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A (2009) Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 22(2):107–133 14. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM (1997) A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336(17): 1202–1207 15. Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O’Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG (2004) High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 140(2):85–93 16. Palladini G, Campana C, Klersy C, Balduini A, Vadacca G, Perfetti V, Perlini S, Obici L, Ascari E, d’Eril GM, Moratti R, Merlini G (2003) Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation 107(19):2440–2445 17. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, McConnell JP, Litzow MR, Gastineau DA, Tefferi A, Inwards DJ, Micallef IN, Ansell SM, Porrata LF, Elliott MA, Hogan WJ, Rajkumar SV, Fonseca R, Greipp PR, Witzig TE, Lust JA, Zeldenrust SR, Snow DS, Hayman SR, McGregor CG, Jaffe AS (2004) Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients
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ORIGINAL PAPER
Impact of monitoring longitudinal systolic strain changes during serial echocardiography on outcome in patients with AL amyloidosis Kai Hu1,2 • Dan Liu1,2 • Peter Nordbeck1,2 • Maja Cikes3 • Stefan Sto¨rk1,2 Bastian Kramer1,2 • Philipp Daniel Gaudron1,2 • Andreas Schneider1 • Stefan Knop4 • Georg Ertl1,2 • Bart Bijnens5 • Frank Weidemann2,6 • Sebastian Herrmann1,2
•
Received: 22 May 2015 / Accepted: 6 July 2015 / Published online: 16 July 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Relative apical sparing of longitudinal systolic strain (LSsys) with preserved LSsys at apical and significantly reduced LSsys at mid/basal segments is a typical echocardiographic feature in AL amyloidosis patients with cardiac involvement. The present study aims to evaluate the change of this typical feature over time by serial echocardiography and its impact on outcome in AL amyloidosis patients with cardiac involvement. Echocardiography was performed in 24 consecutive patients with biopsy-proven AL amyloidosis (mean age 64 ± 9 years; 50 % male) at baseline and during a median of 257 (quartiles 103–651) days follow-up. Global and segmental LSsys were assessed by two-dimensional speckle-trackingimaging in septal and lateral segments of the left ventricle (LV) from the apical 4-chamber view. Sixteen (67 %) patients died during a median follow-up of 487 days
(quartiles 223–872). LV global and segmental LSsys remained unchanged over time in survivors (all P [ 0.05), while LV global, septal-apical and lateral-apical LSsys significantly decreased in non-survivors. A decrease in lateral-apical LSsys [ 3.0 % independently predicted a fivefold increased all-cause mortality risk after adjustment for age, gender, NYHA class, and treatment strategies. Further, baseline serum NT-proBNP, serum albumin decrease during follow-up, baseline septal apical-to-basal LSsys ratio and lateral-apical LSsys decrease during followup remained independently predictive of increased allcause mortality risk. Serial monitoring of serological and echocardiographic parameters is valuable to predict outcome in AL amyloidosis patients with cardiac involvement. The best follow-up parameter to predict risk for imminent death is a decrease of longitudinal systolic strain at the lateral apical segment. Keywords Systemic amyloidosis Left ventricular strain Speckle tracking Prognosis
Kai Hu and Dan Liu have contributed equally to this work. & Kai Hu [email protected] 1
Department of Internal Medicine I, University Hospital Wu¨rzburg, Wu¨rzburg, Germany
2
Comprehensive Heart Failure Center, Wu¨rzburg, Germany
3
Department for Cardiovascular Diseases, University Hospital Center Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia
4
Department of Internal Medicine II, University Hospital Wu¨rzburg, Wu¨rzburg, Germany
5
ICREA - Universitat Pompeu Fabra, Barcelona, Spain
6
Katharinen-Hospital Unna, Unna, Germany
Introduction Primary light chain amyloidosis (AL) is the most common form of systemic amyloidosis. It is caused by myocardial amyloid deposition leading to cardiomyocyte disarry, tissue stiffening, and decline of vital organ function [1]. Cardiac involvement in AL amyloidosis is the primary cause of death [2–4]. The early diagnosis is essential in order to initiate effective therapy and attenuate organ damage and disease progression [2, 5]. However, early and accurate diagnosis of cardiac impairment in AL amyloidosis still remains a major challenge in daily clinical practice [6].
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Despite improved therapeutic regimens over the past decade, AL cardiac amyloidosis is still associated with a very high mortality [5]. In recent clinical studies, we and others showed that an apical sparing pattern with preserved longitudinal systolic strain (LSsys) at apical segments and significantly reduced LSsys at mid and basal segments is a typical echocardiographic finding in patients with AL cardiac amyloidosis [7–10]. The association between dynamic regional LSsys changes and outcome in these patients has not yet been investigated. The purpose of this study was therefore to observe serial echocardiographic changes of AL amyloidosis patients with cardiac involvement, and to explore the predictive value of changes in global and regional LSsys on outcome in these patients.
Methods Study population and follow-up Consecutive biopsy-proven systemic AL amyloidosis patients with typical echocardiographic features of cardiac involvement [9] referred to the University Hospital of Wu¨rzburg were included into the present study (n = 24). Amyloidosis was histologically confirmed on tissue biopsy stained with Congo red in all patients. At least one biopsy specimen from endomyocardial tissue, bone marrow, rectum, kidney, or subcutaneous fat was positive for amyloid. Amyloid typing was performed by immune histology. Patients with coronary artery disease, moderate to severe cardiac valve disease, and other endocrine or systemic disease were excluded. The median echocardiographic follow-up duration was 257 days (quartiles 103–651) and echocardiography was performed at least twice in all patients (mean 3.8 times). Patients were followed by clinical visit or telephone call for a median of 487 days (quartiles 223–872 days). The primary endpoint was defined as all-cause death. Written informed consent was obtained from all patients or their guardians. The study was approved by the local Ethics Committee at the University of Wu¨rzburg and conducted in accordance to the Declaration of Helsinki. Electrocardiography A standard 12-lead electrocardiography was recorded with a paper speed of 50 mm/s and an amplification of 0.1 mV/ mm. Low QRS voltages were defined as peak to peak QRS amplitudes in each limb lead \0.5, and \1.0 mV in any precordial lead [11]. A pseudoinfarct pattern was defined as
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a QS wave pattern in two contiguous leads in the absence of previous myocardial infarction. Standard echocardiography Left ventricular (LV) end-diastolic and end-systolic dimensions (LVEDD and LVESD), as well as end-diastolic thickness of the posterior wall (LVPWd) and the septum (IVSd) were measured using standard M-mode in the parasternal LV long-axis views at baseline and during follow-up. LV mass, indexed to body surface area, (LVMI) was estimated by LV cavity dimension and wall thickness at end diastole using the following formula [12]: LV mass (g) = 0.8 9 [1.04 9 (LVEDD ? LVPWd ? IVSd)3 - LVEDD3)] ? 0.6. Right ventricular (RV) end-diastolic dimension and RV lateral wall end-diastolic maximal thickness, and end-systolic right atrial (RA) area were measured in an apical 4-chamber view. Left atrial (LA) end-systolic diameter was measured in 2D- mode from a parasternal long-axis view. LA volume was assessed by the biplane area-length method from apical 4- and 2-chamber views. LV ejection fraction (EF) was measured with the biplane Simpson method in apical 4- and 2-chamber views. Mitral annular plane systolic excursion (MAPSE) measured at the septal and lateral sites as well as tricuspid plane annular systolic excursion were obtained by M-mode in an apical 4-chamber view. Systolic pulmonary artery pressure (sPAP) was derived from peak tricuspid regurgitation jet velocity using the simplified Bernoulli equation, in combination with an estimated RA pressure. RA pressure was estimated from inferior vena cava (IVC) diameter and respiratory changes. IVC diameter and inspiratory collapsibility was detected from the subcostal view. Normal RAP of 3 mmHg (range: 0–5 mmHg) was defined as IVC diameter B2.1 cm and inspiratory collapsibility [50 %; 8 mmHg (range: 5–10 mmHg) was defined as IVC diameter B2.1 cm and inspiratory collapsibility \50 %; high RAP of 15 mmHg (range: 10–20 mmHg) was defined as IVC diameter [2.1 cm and inspiratory collapsibility \50 %. Pulsed-wave Doppler was performed in apical 4-chamber views to obtain mitral valve inflow velocities for LV filling pattern evaluation (early filling [E] and late diastolic filling [A] velocities, E/A ratio and deceleration time [DT] of early filling). Tissue Doppler early diastolic mitral annular velocity (E0 ) of the septal annulus was obtained in an apical 4-chamber view. Atrial fibrillation was present in two patients. E, E0 , and DT (averaged from five cardiac circles) were measured in atrial fibrillation patients. The stage of LV diastolic function was diagnosed according to
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the American Society of Echocardiography (ASE) guidelines for the assessment of diastolic function [13]. Speckle tracking imaging Longitudinal segmental strain measurements by 2D speckle tracking imaging (STI) were performed off-line using dedicated software (EchoPAC, GE, Horten, Norway). The 2D grey scale images were recorded with a frame rate of 50–90 frames per second and care was taken to ensure that the entire ventricular wall was clearly visible in all frames. A region of interest (ROI) was created by manually outlining the endocardial border on an apical four-chamber view at the end-systolic frame. The system automatically tracked the tissue within the region and divided the myocardium into standard segments. The tracking was visually checked and, if necessary, adjusted. The trace analysis was automatically displayed after validating the tracking. LV longitudinal peak systolic strain (LSsys) was extracted from the basal, mid, and apical segments of the septal and lateral walls. The ratio between apical LSsys and basal LSsys (LSsysapex/base) in the septum was calculated. Reproducibility Reproducibility of LSsys was assessed by repeated measurements in the same recordings. Intraobserver variation was assessed by repeated analysis of 24 subjects and blinded to the initial results by one investigator (DL). Interobserver variation was done on the same datasets by two observers (DL and KH). Reproducibility was assessed using Bland and Altman analysis. Data analysis Continuous data are presented as mean ± standard deviation (SD) or median (quartiles) and categorical variables as percentages. Skewness, kurtosis, and Q–Q Plots of all continuous variables were applied to explore the normality of distribution. Unpaired Student´s t test and paired Student’s test were conducted for data with normality distribution and data with skewed distribution was tested by non-parametric tests: Mann–Whitney U test comparing survivors and non-survivors; paired sample Wilcoxon signed rank test comparing baseline and follow up. Categorical data were compared using a similar approach employing Chi square test for the overall test and Fisher’s exact for pair-wise group tests, as appropriate. All tests were performed two-sided. The factors predicting all-cause death were sought using Cox proportional-hazards regression models. Hazard ratios (HR) with 95 % confidence intervals (CI) were calculated.
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Variables with P values \0.05 were included in multivariable models, and independent factors were determined using the likelihood ratio test statistic. The cutoff value of lateral-septal LSsys was derived from receiver operating characteristic curve analysis by maximizing the sum of the sensitivity and specificity. A two-tailed probability value \0.05 was considered significant. Statistical analysis was performed using IBM SPSS, version 21 for Windows (SPSS).
Results Treatment strategies and responses Twelve patients received autologous stem cell transplantation with high-dose melphalan and the remaining 12 patients received risk-adapted chemotherapy regimens. Therapy strategies were similar between survivors and nonsurvivors. Hematological response to treatment was defined as a C50 % decrease in the serum and urine monoclonal component; renal response was defined as a 50 % decrease in proteinuria in the absence of a 25 % increase in serum creatinine (Scr), with a minimum of 0.5 mg/dL or a 25 % decrease in glomerular filtration rate or creatinine clearance [14, 15]. The response to treatment was evaluated every 3 months by monitoring serum and urine levels of monoclonal protein. Hematological or renal response to treatment was 25 % in the survivor group and 47 % in the non-survivor group (P [ 0.05). Clinical characteristics at baseline and during follow-up Sixteen out of 24 (67 %) patients died during clinical follow-up. Baseline clinical parameters were similar between survivors and non-survivors (Table 1). Prevalence of systemic hypertension was similar between groups. During follow-up, NYHA functional class was significantly increased and serum albumin level was significantly reduced in non-survivors (all P \ 0.05) while these parameters remained unchanged in survivors. Electrocardiography parameters were similar between survivor and non-survivor groups at baseline (Table 2). NT-proBNP tended to be higher in non-survivors than in survivors at both baseline and during follow-up. Echocardiography characteristics at baseline and during follow-up sPAP at baseline and RA area at both baseline and followup examinations were significantly higher in non-survivors than in survivors. IVSd was significantly increased in non-
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Table 1 Clinical characteristics
Male (n, %)
All n = 24
Survivors n=8
Non-survivors n = 16
P value
12 (50 %)
4 (50 %)
8 (50 %)
1.000 0.709
Age (years)
64 ± 9
65 ± 6
63 ± 10
BMI (kg/m2)
26 ± 5
25 ± 5
26 ± 5
0.744
Heart rate (beats/min)
78 ± 12
75 ± 10
80 ± 13
0.426
Systolic blood pressure (mmHg)
119 ± 23
123 ± 23
116 ± 24
0.526
Diastolic blood pressure (mmHg)
73 ± 14
77 ± 14
70 ± 14
0.290
Systemic hypertension (n, %) Mean NYHA class
12 (50 %)
5 (62.5 %)
7 (43.8 %)
0.667
Baseline
2.2 ± 0.7
1.9 ± 0.7
2.4 ± 0.8
0.185
Follow-up
2.6 ± 0.8*
2.1 ± 0.6
2.9 ± 0.8*
0.029
Baseline
10 (42 %)
2 (25 %)
8 (50 %)
0.388
Follow-up
13 (54 %)
2 (25 %)
11 (69 %)
NYHA class III/IV (n, %)
Light chain type (n, %)
0.082 0.189
j light chain
8 (33 %)
1 (12.5 %)
k light chain
16 (67 %)
7 (87.5 %)
9 (56 %)
1.7 ± 0.8
1.3 ± 0.7
1.9 ± 0.8
0.076
Renal (n, %)
15 (62.5 %)
3 (37.5 %)
12 (75 %)
0.099
Hepatic/gastrointestinal (n, %)
17 (71 %)
5 (62.5 %)
12 (75 %)
0.647
Lung (n, %)
3 (12.5 %)
0 (0 %)
3 (19 %)
0.526
Neuropathic (n, %)
2 (8 %)
1 (12.5 %)
1 (6 %)
1.000
4 (17 %) 12 (50 %)
0 (0 %) 4 (50 %)
4 (25 %) 8 (50 %)
0.262 1.000
Baseline
22 (7–66)
36 (15–58)
20 (3–112)
0.825
Follow-up
36 (14–147)
36 (20–50)
102 (6–312)
0.536
Baseline
39 (18–132)
107 (42–225)
38 (18–96)
0.364
Follow-up
63 (23–103)
63 (26–86)
63 (20–182)
1.000
Number of organ involvements
Soft tissues/bone (n, %) High-dose melphalan plus ASCT (n, %)
7 (44 %)
Serum biomarkers Free j light chain (mg/l)
Free k light chain (mg/l)
j/k ratio Baseline
0.16 (0.10–7.34)
0.51 (0.09–4.10)
0.15 (0.10–8.75)
1.000
Follow-up
0.60 (0.24–1.89)
0.51 (0.44–0.93)
1.51 (0.09–5.04)
0.694
NT-proBNP (pg/ml) Baseline
3097 (915–8967)
2575 (955–8062)
9168 (2217–11,554)
0.126
Follow-up
11,298 (3466–23,963)*
9046 (5866–21,520)
13,550 (9678–14,609)
0.486
1.4 ± 1.0 1.9 ± 1.5*
1.5 ± 1.4 2.5 ± 2.1
1.4 ± 0.7 1.7 ± 0.9
0.811 0.336
Creatinine (mg/ml) Baseline Follow-up eGFR (mL/min/1.73 m2) Baseline
63 ± 29
71 ± 34
60 ± 27
0.421
Follow-up
51 ± 30*
51 ± 40
51 ± 26
0.952
Alkaline phosphatase (U/l) Baseline
136 ± 102
132 ± 65
138 ± 119
0.901
Follow-up
166 ± 141
134 ± 65
181 ± 162
0.446
3.6 ± 0.8
3.4 ± 0.5
3.7 ± 0.9
0.429
Albumin (g/dl) Baseline
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Table 1 continued
Follow-up Clinical Follow-up duration (days)
All n = 24
Survivors n=8
Non-survivors n = 16
P value
3.4 ± 0.7
3.6 ± 0.6
3.3 ± 0.8*
0.341
487 (223–872)
708(160–1070)
388 (223–763)
0.306
BMI body mass index, NYHA New York heart association functional cassification, NT-proBNP N-terminal pro-brain natriuretic peptide, eGFR estimated glomerular filtration rate * P \ 0.05 versus baseline
survivors, LVPWd was significantly higher in both survivor and non-survivor groups during follow-up, compared to baseline level (Table 2). Baseline septal LSsysapex/base ratio was significantly higher in the non-survivor group than in the survivor group (3.70 ± 1.84 vs. 2.35 ± 0.61, P \ 0.05). Compared to baseline, global LSsys was significantly decreased in the non-survivor group (-10 ± 5 % vs. -12 ± 4 %, P \ 0.05) but unchanged in the survivor group (-12 ± 5 % vs. -13 ± 3 %, P [ 0.05) during follow-up. Septal- and lateral-apical LSsys values were significantly decreased during follow-up compared to baseline levels in the non-survivor group (Fig. 1). Figure 2 shows representative longitudinal systolic strain curves derived from 2D STI at baseline and at one-year follow-up in a survived patient (upper panel) and in a non-survivor (lower panel), who died 45 days after this follow-up echocardiographic examination. Spearman correlation showed that reduced global LSsys was correlated with higher NT-proBNP levels at baseline (r = -0.677, P = 0.003). Univariable and independent predictors of all-cause mortality Cox-regression analysis (Table 3) revealed that baseline serum NT-proBNP, serum albumin decrease during followup, baseline septal-mid and septal-basal LSsys, septal LSsysapex/base ratio, and global and lateral-apical LSsys decrease during follow-up were univariable predictors of all-cause mortality risk. Multivariable Cox models (Table 4) were established based on serological data (model 1), baseline echocardiographic variables (model 2), and their changes during follow-up (model 3), respectively, after adjustment for age, gender, NYHA class, and treatment strategies. Baseline serum NT-proBNP (HR 2.75, 95 % CI 1.12–6.78, P = 0.028), serum albumin decrease during follow-up (HR 4.70, 95 % CI 1.20–18.40, P = 0.026), baseline septal LSsysapex/base ratio (HR 1.68, 95 % CI 1.19–2.37, P = 0.003), and lateral-apical LSsys decrease during follow-up (HR 1.39, 95 % CI 1.13–1.70,
P = 0.002) remained independently predictive of increased all-cause mortality. A decrease in lateral-apical LSsys [ 3.0 % predicted a fivefold increased all-cause mortality risk after adjustment for age, gender, NYHA class, and treatment strategies (HR 5.47, 95 % CI 1.58–18.90, P = 0.007). Reproducibility The intra- and inter-observer variability of LSsys was assessed in 144 measured segments at baseline. The intraand inter-observer absolute bias was 0.42 % (95 % limits of agreement -5.4 to 6.2 %) and 0.64 % (95 % limits of agreement -5.0 to 6.3 %), respectively.
Discussion The current study aimed to investigate the utility of changes of clinical and imaging parameters on predicting mortality risk in patients with AL cardiac amyloidosis. The major findings of this study are: (1) Among the established serological biomarkers, higher NT-proBNP at baseline and serum albumin decrease over time were associated with increased all-cause mortality risk in patients with AL cardiac amyloidosis. (2) Among echocardiographic parameters, baseline longitudinal apex-to-base strain gradient served as both a typical feature of cardiac involvement and an indicator of prognosis in these patients. (3) A decrease of longitudinal systolic strain at the lateral-apical segment was a strong predictor of imminent death in AL cardiac amyloidosis patients. Heart and kidney are the predominantly affected vital organs in AL amyloidosis patients [5]. Previous studies suggested that elevated NT-proBNP level was a very good cardiac biomarker for predicting survival in AL amyloidosis patients and was recommended for risk stratification [16, 17]. Consistent with above findings, we showed that elevated NT-proBNP level at baseline was associated with a higher mortality risk in the current cohort. Furthermore,
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Table 2 Electrocardiography and standard echocardiography characteristics All n = 24
Survivors n=8
Non-survivors n = 16
P value
Electrocardiography Unexplained low voltage
46 %
50 %
44 %
0.99
QRS-T wave pseudo-infarct changes
50 %
63 %
44 %
0.667
I/II° atrioventricular block
67 %
71 %
64 %
0.99
Left/right bundle branch block
29 %
25 %
31 %
0.99
257 (103–651)
259 (90–730)
233 (129–526)
0.99
42 %
50 %
37.5 %
0.673
83 %
87.5 %
81 %
1.000
Echocardiography Follow-up duration (days) Pericardial effusion (%) Baseline Sparkling texture (%) Baseline LVEDD (mm) Baseline
43 ± 7
44 ± 8
43 ± 7
0.776
Follow-up
44 ± 7
46 ± 8
43 ± 6
0.292
LVESD (mm) Baseline
31 ± 7
33 ± 10
30 ± 7
0.347
Follow-up
31 ± 7
33 ± 8
31 ± 6
0.448
IVSd (mm) Baseline
14 ± 2
13 ± 2
14 ± 2
0.287
Follow-up
14 ± 2*
13 ± 2
15 ± 2*
0.118
13 ± 2 14 ± 2*
12 ± 2 13 ± 2*
13.8 ± 2 14.4 ± 2*
0.182 0.148
LVPWd (mm) Baseline Follow-up LVMI (g/m2) Baseline
120 ± 28
113 ± 24
125 ± 30
0.342
Follow-up
132 ± 26*
129 ± 23
134 ± 28
0.693
LA diameter (mm) Baseline
41 ± 7
40 ± 8
41 ± 7
0.722
Follow-up
42 ± 6
41 ± 6
43 ± 7
0.493
LA volume (ml) Baseline
65 ± 25
59 ± 24
69 ± 26
0.398
Follow-up
75 ± 26*
69 ± 20
80 ± 31
0.394
RV dimension(mm) Baseline
34 ± 5
31 ± 4
35 ± 5
0.053
Follow-up
36 ± 5*
33 ± 5
38 ± 4
0.053
RA area (cm2) Baseline Follow-up RV free wall thickness (mm)
17 ± 5
13 ± 2
19 ± 5
0.004
19 ± 6*
15 ± 4
21 ± 6
0.019
Baseline
6.2 ± 1.2
6.5 ± 1.2
6.1 ± 1.2
0.418
Follow-up
6.5 ± 1.1
6.7 ± 1.2
6.4 ± 1.1
0.539
Baseline
58 ± 11
58 ± 12
58 ± 11
1.000
Follow-up
57 ± 12
59 ± 14
56 ± 11
0.598
LV EF (%)
Septal MAPSE (mm) Baseline
6±2
7±2
6±2
0.369
Follow-up
6±2
7±1
6±3
0.598
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Table 2 continued All n = 24
Survivors n=8
Non-survivors n = 16
P value
Lateral MAPSE (mm) Baseline
8±3
9±2
8±3
0.626
Follow-up
8±3
9±2
8±4
0.347
Baseline
15 ± 4
15 ± 4
15 ± 4
0.797
Follow-up
15 ± 5
16 ± 4
15 ± 5
0.643
TAPSE (mm)
sPAP (mmHg) Baseline
35 ± 14
25 ± 9
40 ± 13
0.012
Follow-up
36 ± 14
31 ± 11
38 ± 15
0.301
Baseline
85 ± 26
93 ± 31
81 ± 23
0.239
Follow-up
83 ± 21
73 ± 27
87 ± 18
0.146
21 ± 9 19 ± 7
22 ± 10 18 ± 8
20 ± 11 19 ± 7
0.565 0.800
E (cm/s)
E/E’ Baseline Follow-up DT (ms) Baseline
186 ± 46
189 ± 45
185 ± 48
0.846
Follow-up
189 ± 75
230 ± 100
171 ± 55
0.082
48 %
33 %
53 %
0.709
Diastolic pseudonormal or restrictive filling pattern (%)
LVEDD left ventricular end-diastolic dimension, LVESD left ventricular end-systolic dimension, IVSd intervernicular septum at end-diastole, LVPWd Left ventricular posterior wall thickness at end-diastole, LVMI LV mass indexed to body surface area, LA left atrium, RV right ventricle, RA right atrium, EF ejection fraction, MAPSE mitral annular plane systolic excursion, TAPSE tricuspid annular plane systolic excursion, E early diastolic peak filling velocity, E0 tissue Doppler early diastolic septal mitral annular velocity, DT deceleration time of early diastolic peak velocity, sPAP systolic pulmonary artery pressure
in line with finding by Buss et al. [18], we showed that elevated NT-proBNP at baseline was significantly correlated with lower global LSsys at baseline (r = -0.677, P = 0.003), a parameter reflecting LV longitudinal dysfunction in AL amyloidosis patients with cardiac involvement. It is known that lower serum albumin is independently associated with renal progression of AL amyloidosis patients [19, 20]. Consistently, we showed that a decrease of serum albumin levels was related to higher mortality risk in AL cardiac amyloidosis patients.
The cardiomyopathy in CA patients Myocardial strain echocardiography is a sensitive tool for evaluating LV function in AL cardiac amyloidosis patients. The advantage of strain echocardiography is multiple: First, the measured reduction of longitudinal strain is a very typical feature in these patients. Second, cardiac involvement can be detected much earlier by quantification of longitudinal strain than by established conventional
echocardiographic parameters like global LV ejection fraction. Third, a staging of cardiac involvement with clinical impact on prognosis is possible by measuring the intra-wall strain gradient [9]. The prognostic value of LSsys measurement in AL cardiac amyloidosis patients has been previously demonstrated by our group and others [9, 10]. In a large cohort of patients with AL amyloidosis, Buss et al. demonstrated that LV longitudinal function assessed by LSsys could serve as an independent predictor of survival, thus provided incremental information beyond standard clinical and biomarkers [18]. The current study also confirmed the prognostic value of assessing baseline LSsys in AL cardiac amyloidosis patients as shown by a reduced septal LSsysapex/base in non-survivors compared to survivors. Thus, this strain gradient seems to predict the general prognosis as it is related to the stage of the disease. Although this strain gradient might be helpful during a unique evaluation to predict the long term progression of the disease, it is not meaningful for the evaluation of imminent events. In this context, monitoring the change of longitudinal strain during serial examinations is a superior option for predicting the imminent risk of death in AL
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Int J Cardiovasc Imaging (2015) 31:1401–1412 b Fig. 1 Apical, mid and basal longitudinal systolic strain (LSsys) of
septal and lateral left ventricular walls at baseline (BS, open bar) and follow-up (FU, solid bar) in survivors and non-survivors of AL cardiac amyloidosis patients
cardiac amyloidosis patients. Our study reports for the first time that the dynamic change in LSsys during serial echocardiography is an independent predictor of imminent risk of death in cardiac amyloidosis patients. A decrease in lateral-apical LSsys [ 3.0 % independently predicted a fivefold increased all-cause mortality risk after adjustment for age, gender and NYHA class. Thus, serial monitoring of segmental LSsys is of clinical importance to define AL cardiac amyloidosis patients at increased risk of imminent death. The pathophysiological mechanisms inducing reduced longitudinal strain and consequently leading to cardiac
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death in AL cardiac amyloidosis patients remain elusive. It is of note that LVEF was preserved in both survivors and non-survivors at baseline and during follow-up, suggesting that reduced longitudinal function, but not radial function, is the prominent outcome determinant in AL cardiac amyloidosis patients. The potential reason for the reduction of longitudinal function in AL cardiac amyloidosis patients was speculated to be related to a dominant deposition of amyloid protein at the subendocardium as evidenced by a cardiovascular magnetic resonance study [21]. It is known that there is an intra-wall longitudinal deformation gradient with preserved LSsys at the apical segments and significantly reduced LSsys at the mid and basal segments in AL cardiac amyloidosis patients [7–10] and this apical sparing phenomenon could be used to differentiate cardiac amyloidosis patients from other causes of concentric myocardial hypertrophy [22, 23]. Extending these previous
Fig. 2 Representative longitudinal strain curves at baseline (left) and one-year follow-up (right) in patients with AL cardiac amyloidosis. Patient 1: survivor. Patient 2: dying 45 days after the last echocardiography examination
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Table 3 Univariable predictors of mortality risk (Cox proportional-hazards regression analysis) Hazard ratio (95 % CI) Baseline
Wald
P value
Hazard ratio (95 % CI) Change during follow-up
Wald
P value
Age
0.99 (0.92–1.07)
0.05
0.824
–
–
–
Gender
1.62 (0.60–4.35)
0.90
0.342
–
–
–
NYHA class
1.86 (0.90–3.85)
2.79
0.095
1.26 (0.66–2.37)
0.49
0.482
High-dose melphalan plus ASCT
1.40 (0.50–3.87)
0.41
0.521
–
–
Systemic hypertension
1.46 (0.51–4.17)
0.51
0.475
–
–
Serum NT-proBNP (pg/ml)
2.14 (1.10–4.16)
5.01
0.025
1.18 (0.57–2.46)
0.20
0.657
Serum creatinine (mg/ml) Serum albumin (g/dL)
0.79 (0.43–1.46) 1.08 (0.48–2.44)
0.55 0.03
0.459 0.854
0.31 (0.09–1.01) 0.32 (0.13–0.83)
3.74 5.48
0.053 0.019
LVMI (g/m2)
1.01 (0.99–1.03)
1.76
0.185
0.98 (0.95–1.01)
2.68
0.102
EF (%)
0.98 (0.94–1.03)
0.43
0.511
0.99 (0.93–1.05)
0.18
0.671
RAA (cm2)
1.06 (0.98–1.14)
2.17
0.140
1.05 (0.89–1.24)
0.34
0.562
sPAP (mmHg)
1.04 (1.00–1.09)
3.54
0.060
0.97 (0.93–1.02)
1.06
0.303
Septal-basal LSsys (%)
1.35 (1.09–1.68)
7.27
0.007
0.99 (0.83–1.20)
0.00
0.958
Septal-mid LSsys (%)
1.28 (1.07–1.53)
7.16
0.007
1.07 (0.93–1.24)
0.87
0.350
Septal-apical LSsys (%)
1.05 (0.93–1.18)
0.69
0.406
1.09 (1.00–1.18)
3.67
0.055
Lateral-basal LSsys (%)
1.05 (0.89–1.24)
0.34
0.560
1.06 (0.96–1.18)
1.46
0.228
Lateral-mid LSsys (%)
1.03 (0.91–1.15)
0.18
0.671
1.13 (1.00–1.28)
3.59
0.058
– –
Lateral-apical LSsys (%)
1.00 (0.90–1.11)
0.00
0.989
1.14 (1.05–1.25)
9.15
0.002
Global LSsys (%)
1.11 (0.92–1.35)
1.21
0.271
1.17 (1.02–1.35)
5.02
0.025
Septal LSsysapex/base
1.67 (1.20–2.33)
9.17
0.002
1.05 (0.90–1.23)
0.37
0.541
NYHA New York heart association functional classification, LVMI LV mass indexed to body surface area, EF ejection fraction, sPAP systolic pulmonary artery pressure, LSsys longitudinal peak systolic strain, LSsysapex/base septal apical to basal longitudinal systolic strain ratio
Table 4 Multivariable predictors of mortality risk (Cox proportional hazards regression) Hazard ratio* (95 % CI)
Wald
P value
Baseline serum NT-proBNP (pg/ml)
2.75 (1.12–6.78)
4.85
0.028
Serum albumin decrease during follow-up (g/dL)
4.70 (1.20–18.40)
4.94
0.026
Model 1: clinical data*
Model 2: baseline echocardiographic data* Septal-basal LSsys (%)
0.80 (0.45–1.42)
0.60
0.438
Septal-mid LSsys (%)
1.10 (0.88–1.38)
0.77
0.382
Septal LSsysapex/base
1.68 (1.19–2.37)
8.77
0.003
Model 3: change of echocardiographic data during follow-up* Global LSsys decrease (%)
0.98 (0.67–1.45)
0.01
0.928
Septal-apical LSsys decrease (%)
0.85 (0.71–1.01)
3.40
0.065
Lateral-apical LSsys decrease (%)
1.39 (1.13–1.70)
9.83
0.002
Lateral-apical LSsys decrease [3.0 versus B3.0 % during follow-up*
5.47 (1.58–18.90)
7.22
0.007
* Adjustment for age, gender, NYHA class, and high-dose melphalan plus ASCT with backward stepwise (likelihood ratio). For abbreviation, see Table 3
findings, we demonstrated that reduced lateral-apical LSsys during follow-up is an independent mortality predictor for AL cardiac amyloidosis patients. Thus, it seems that the final echocardiographic progression marker before death is
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the deformation change in the apical segment. Interestingly, a fall in apical LV systolic strain was also observed in 10 out of 11 senile cardiac amyloidosis patients by Falk and Quarta [24] during a mean of 11.9 months follow-up.
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Although the underlying mechanisms between the reduction of apical strain and end-stage disease progression of AL cardiac amyloidosis remain unclear, our results suggest that serial assessment of longitudinal systolic strain, especially the apical strain changes, is helpful to define AL cardiac amyloidosis patients at increased risk of death.
Limitations The patient cohort is relatively small as only patients were included in whom serial echocardiographic examinations were available. Thus, studies with larger patient numbers are warranted to verify the outcome results. In addition, because of the small patient cohort, it was not possible to investigate the responses to various therapy regimens by the dynamic change of LSsys.
Conclusions Serial monitoring of serological and conventional and speckle tracking imaging echocardiographic parameters is valuable to predict outcome in AL amyloidosis patients with cardiac involvement. The intra-wall strain gradient is not only a typical feature for AL cardiac amyloidosis patients but also an independent predictor of all-cause mortality risk in AL cardiac amyloidosis patients. In particular, the decrease in longitudinal systolic strain at the lateral-apical segment is an ominous sign of imminent death in these patients. Acknowledgments This work was supported by Grants from the Bundesministerium fu¨r Bildung und Forschung (BMBF01 EO1004). Compliance with Ethical Standards Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
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