Study Population and Design

In this retrospective observational study, we included a total of 89 patients with systemic light-chain amyloidosis (mean age=59 ± 9 years; 47 men [53%]; mean body mass index [BMI]=25 ± 4 kg/m ² ; mean septal wall thickness = 16 ± 4 mm; mean ejection fraction [EF], 51 ± 11%) to evaluate echocardiographic markers of survival. The discriminative value of these parameters was assessed in the “diagnostic” subgroup of 54 patients with AL amyloidosis with at least one positive left or right ventricular biopsy (mean age=57 ± 8 years; 27 men [50%]; mean BMI=24 ± 4 kg/m ² ; mean septal wall thickness= 19 ± 4 mm; mean EF= 45 ± 12%) compared with 41 sex-, age-, and BMI-matched healthy individuals without medical histories (mean age= 57 ± 10 years; 23 men [56%]; mean BMI=25 ± 4 kg/m ² ; mean septal wall thickness=10 ± 1 mm; mean EF=63 ± 3%). The diagnosis of AL was based on the presence of a monoclonal gammopathy by serum electrophoresis, free light-chain test, immunofixation on serum and urine, confirmed by positive Congo red staining with birefringence under polarized light of any biopsy (periumbilical fat aspiration, rectum, or affected organ), positive results on immunohistology for κ or λ in the biopsy, and on the exclusion of hereditary forms of amyloidosis. The study population was referred to our clinic for echocardiographic routine workup with diagnosed light-chain disorder between February 2006 and August 2008, before chemotherapy. The use of anonymized patient data for research purposes was approved by the institutions ethics committee to the Declaration of Helsinki.

Echocardiographic Examination

Echocardiography was performed at rest with an iE33 (Philips Medical Systems, Andover, MA). Offline analysis of echocardiographic studies was conducted on a commercially available workstation. Heart rate and blood pressure were measured in supine position before echocardiography. Digital images were obtained at optimal frame rates (50–55 frames/sec). Three cardiac cycles were stored in cine loop format for offline analysis. All measurements were acquired by two independent expert examiners who were blinded to the patients’ clinical status according to current recommendations of the American Society of Echocardiography. Accordingly, diastolic dysfunction was classified into three pathologic grades.

Anterior Aortic Plane Systolic Excursion

AAPSE is defined as the systolic excursion of the anterior margin of the aortic root and was assessed from the parasternal long-axis view at passive end-expiration ( Figure 1 ). The M-mode beam was placed on aortic valve plane at end-diastole. The distance from lowest (end-diastole) to highest (end-systole) excursion of the anterior aortic root margin was defined as AAPSE.

Assessment of AAPSE. AAPSE is defined as the excursion of the anterior margin of the aortic root during the cardiac cycle from end-systole (ES) to end-diastole (ED) measured in the parasternal long-axis view by M-mode echocardiography. ( Left ) Normal and ( right ) severely reduced AAPSE.

Mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) were measured from the apical four-chamber view. The systolic excursion of the lateral mitral and tricuspid annulus were measured as previously described. EF was determined using the modified Simpson method for biplane assessment.

Blood samples were drawn on the day of echocardiographic examination. Glomerular filtration rate was estimated using the Modification of Diet in Renal Diseases formula. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and cardiac troponin T (TnT) were measured using a commercially available sandwich immunoassay on a fully automated analyzer (Elecsys; Roche Diagnostics, Mannheim, Germany).

Follow-Up

Follow-up was acquired by review of patients’ electronic records or telephone interviews with patients or their relatives. The primary combined end point was all-cause mortality or heart transplantation.

Reproducibility

The reproducibility of echocardiographic findings was evaluated in a subgroup of 20 randomly selected patients. For intraobserver variability, the same investigator was asked to reassess the parameters of interest 2 weeks after the first measurements had been acquired. For interobserver variability, two different investigators evaluated the echocardiographic studies separately.

Statistical Methods

Data were analyzed using SPSS version 23.0.0.2 (IBM, Armonk, NY). Continuous variables are expressed as mean ± SD. Group differences for continuous variables were tested using the independent t test and for ordinal variables using the Mann-Whitney U test, and differences between nominal variables were assessed using the Fisher exact test. Correlation analyses were performed using the Spearman coefficient. Correlation coefficients were classified as weak ( r > 0 to r < 0.2), mild ( r ≥ 0.2 to r < 0.4), moderate ( r ≥ 0.4 to r < 0.6), moderately strong ( r ≥ 0.6 to r < 0.8), and strong ( r ≥ 0.8 to r ≤ 1.0). Kaplan-Meier curves were used to estimate the distribution of survival as a function of follow-up duration. The association of clinical, echocardiographic, and serologic parameters with outcomes was evaluated using multivariate Cox proportional hazards regression models. Receiver operating characteristic curves were used to define optimal cutoff values using the Youden J statistic. Coefficients of variation and intraclass correlation coefficients (ICC) (with 95% CI) were calculated to assess inter- and intraobserver variability. For ICC, an α two-way random model with absolute agreement analysis was used. Differences were considered statistically significant at P < .05.

Discriminative Ability

Fifty-four patients with AL and biopsy-proven cardiac involvement were compared with 41 age-, gender-, and BMI-matched healthy individuals to define the discriminative value of echocardiographic findings. The clinical and echocardiographic baseline characteristics of the study populations are presented in Table 1A . Mean AAPSE was 13.9 ± 2 mm in healthy control subjects. Discriminative performance of AAPSE and other common parameters is shown in Table 2 . AAPSE < 11 mm separated patients from control subjects with 93% sensitivity and 97% specificity ( Table 1B ).

Correlations to Structural and Functional Alterations

AAPSE was moderately associated with exercise intolerance according to NYHA functional class ( r = −0.47, P = .0001). Moderately strong to strong correlations were found for structural or functional changes of MAPSE ( r = 0.84, P = .0001), TAPSE ( r = 0.70, P = .0001), EF ( r = 0.68, P ≤ .0001), diastolic dysfunction ( r = −0.61, P = .0001), and septal wall thickness ( r = −0.58, P = .0001). Furthermore, AAPSE was more closely associated with NT-proBNP ( r = −0.71, P = .0001) than with TnT ( r = −0.51, P = .0001) or serum free light-chain difference ( r = −0.33, P = .002) ( Table 2 ).

Indicator of Transplant-Free Survival

Survival analysis was performed in a total of 89 patients with AL of whom 54 had biopsy-proven cardiac involvement (mean age=57 ± 8 years; 27 men [50%]; mean BMI=24 ± 4 kg/m ² ; mean septal wall thickness= 19 ± 4 mm; mean EF= 45 ± 12%) and another 35 (mean age= 62 ± 10 years; 20 men [57%]; mean BMI= 27 ± 4 kg/m ² ; mean septal wall thickness= 11 ± 4 mm; mean EF= 60 ± 5%) in whom a myocardial biopsy had not been performed. The median follow-up duration was 2.4 years (interquartile range, 0.4–4.6 years). Echocardiography was performed before chemotherapy in all patients.

The median time to death or transplantation was 0.7 years (interquartile range, 0.2–1.7 years). Thirty-six patients (40.4%) died or underwent transplantation after 12 months of follow-up. Baseline characteristics of patients after 12 months of follow-up who reached the primary combined end point versus transplant-free survivors are shown in Table 3 . Subjects who died or underwent transplantation during follow-up had lower blood pressure ( P = .0001) and worse NYHA functional class ( P = .001). Regarding biomarkers, patients who reached the primary combined end point had elevated levels of NT-proBNP ( P = .0001), TnT ( P = .0001), and free serum light-chain difference ( P = .0001). Parameters describing systolic function, such as AAPSE ( P = .0001), MAPSE ( P = .0001), TAPSE ( P = .0001), and EF ( P = .0001) were significantly reduced in patients who died or underwent transplantation during follow-up. Beyond this, patients who reached the primary combined end point had increased wall thickness ( P = .0001) and left ventricular mass ( P = .001), and pericardial effusion was more frequent ( P = .004).

In univariate hazard analysis, AAPSE (hazard ratio [HR]= 0.66; P = .0001), MAPSE (HR=0.74; P = .0001), diastolic dysfunction (HR= 6.86; P = .0001), log NT-proBNP (HR= 5.6; P = .0001), TnT (HR= 6.63, P = .0001) and log free light-chain difference (HR= 4.54; P = .0001) were indicators of overall death or heart transplantation ( Table 4 ).

Table 4

Univariate hazards analysis for overall survival or heart transplantation ( n = 89)

Variable	HR	95% CI	P
Age (y)	0.98	0.95–1.02	NS
Male ∗	0.96	0.50–1.85	NS
NYHA class	1.80	1.23–2.63	.002
Laboratory data
TnT (>0.03μg/l) ∗	6.63	3.17–13.86	.0001
Log NT-proBNP (pg/ml)	5.60	2.87–10.93	.0001
eGFR (ml/min/1.73m2)	0.99	0.98–1.01	NS
Log FLC difference (mg/dl)	4.54	2.21–9.32	.0001
Echocardiographic data
AAPSE (mm)	0.66	0.56–0.77	.0001
MAPSE (mm)	0.74	0.67–0.82	.0001
TAPSE (mm)	0.87	0.82–0.92	.0001
Septal wall thickness (mm)	1.14	1.01–1.21	.0001
LV mass (per 100 g)	1.68	1.27–2.21	.0001
LA volume (per 10 ml)	1.26	1.11–1.43	.0001
EF (%)	0.92	0.89–0.95	.0001
Grade of diastolic dysfunction	6.86	3.33–14.14	.0001
E/e′ septal ratio	1.06	1.03–1.08	.0001
sPAP (per 5mmHg)	1.57	1.37–1.86	.0001
Pericardial effusion present ∗	2.95	1.34–6.49	.007

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