Anterior aortic plane systolic excursion (AAPSE) was evaluated in the present pilot study as a novel echocardiographic indicator of transplant-free survival in patients with systemic light-chain amyloidosis.
Eighty-nine patients with light-chain amyloidosis were included in the post-hoc analysis. A subgroup of 54 patients with biopsy-proven cardiac amyloid infiltration were compared with 41 healthy individuals to evaluate the discriminative ability of echocardiographic findings. AAPSE is defined as the systolic excursion of the anterior aortic margin. To quantify AAPSE, the M-mode cursor was placed on the aortic valve plane in parasternal long-axis view at end-diastole. Index echocardiography had been performed before chemotherapy. Median follow-up duration was 2.4 years. The primary combined end point was heart transplantation or overall death.
Mean AAPSE was 14 ± 2 mm in healthy individuals (mean age=57 ± 10 years; 56% men; BMI=25 ± 4 kg/m 2 ). AAPSE < 11 mm separated patients from age-, gender-, and BMI–matched control subjects with 93% sensitivity and 97% specificity. Median transplant-free survival of patients with AAPSE < 5 mm was 0.7 versus 4.8 years ( P = .0001). AAPSE was an independent indicator of transplant-free survival in multivariate Cox regression (echocardiographic model: hazard ratio=0.72 [ P = .03]; biomarker model: hazard ratio=0.62 [ P = .0001]). Sequential regression analysis suggested incremental power of AAPSE as a marker of transplant-free survival. An ejection fraction–based model with an overall χ 2 value of 22.8 was improved by the addition of log NT-proBNP (χ 2 = 32.6, P < .005), troponin-T (χ 2 = 39.6, P < .01), and AAPSE (χ 2 = 54.0, P < .0001).
AAPSE is suggested as an indicator of transplant-free survival in patients with systemic light-chain amyloidosis. AAPSE provided significant incremental value to established staging models.
AAPSE is an independent indicator of transplant-free survival in light-chain amyloidosis.
AAPSE offers incremental value to established risk stratification models.
AAPSE provides particular value in daily practice by rapid risk assessment.
Amyloidosis comprises a heterogeneous group of rare disorders with an estimated annual incidence of about five to 12 affected subjects per million. The majority of cases result from systemic light-chain (AL) amyloidosis related to multiple myeloma. The excessive synthesis of immunoglobulin light chains leads to deposition and formation of β pleated sheets caused by changes to secondary protein structure. These extracellular deposits of insoluble fibrillary proteins may cause organ malfunction. Up to 90% of patients with AL amyloidosis experience cardiac involvement during the course of disease. The extent of cardiac impairment determines overall prognosis. The median survival of affected patients with markedly elevated brain natriuretic peptide and cardiac troponin levels is reduced to only 8 months.
Echocardiographic assessment is essential in patients with suspected amyloidosis. The diagnosis of cardiac involvement in systemic amyloidosis requires either positive results on endomyocardial biopsy or an echocardiographic mean wall thickness ≥12 mm, excluding other causes, together with a positive biopsy of noncardiac origin. However, advanced cardiac amyloidosis might even be present in patients with normal interventricular septal thickness.
The value of echocardiography is not limited by its diagnostic abilities, as it also delivers crucial information for further risk stratification in patients with AL. Unlike serum biomarkers, imaging parameters are independent of commonly impaired renal function in patients with AL. Typical morphologic findings include biventricular increased wall thickness, valvular thickening, and myocardial granular sparkling, particularly of the septal wall. Functional contractile impairment commonly precedes these changes and may occur before cardiac symptoms. In this context, diastolic dysfunction and left ventricular longitudinal function provide diagnostic and prognostic information in cardiac amyloidosis.
There is an ongoing need to improve risk stratification and early detection of cardiac involvement in systemic amyloidosis. Noninvasive surrogates ought to be easily assessable in daily practice. Previous studies provided evidence that basal left ventricular segments are most sensitive to functional changes in AL.
Here, we introduce anterior aortic plane systolic excursion (AAPSE), which is defined as the systolic excursion of the anterior margin of the aortic root derived from M-mode echocardiography in the parasternal long-axis view. We hypothesized that AAPSE might provide additional value to established prognosticators in AL, to identify patients at risk for adverse events during follow-up.
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.
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.
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 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.
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.
Data were analyzed using SPSS version 188.8.131.52 (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.
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 ).
|Parameter||Cardiac biopsy–positive AL ( n = 54)||Healthy control ( n = 41)||P|
|Age (y)||57 ± 8||57 ± 10||NS|
|Men||27 (50%)||23 (56%)||NS|
|BMI (kg/m 2 )||24 ± 4||25 ± 4||NS|
|Heart rate (beats/min)||83 ± 13||74 ± 8||.004|
|SBP (mm Hg)||106 ± 18||128 ± 15||.0001|
|DBP (mm Hg)||72 ± 13||80 ± 9||.005|
|NYHA class ≥ III||19 (72%)||0 (0%)||.0001|
|AAPSE (mm)||5 ± 2||14 ± 2||.0001|
|MAPSE (mm)||7 ± 4||19 ± 3||.0001|
|TAPSE (mm)||13 ± 7||23 ± 4||.0001|
|Septal wall thickness (mm)||19 ± 4||10 ± 1||.0001|
|LV mass (g)||327 ± 119||128 ± 30||.0001|
|LA volume (mL)||67 ± 17||42 ± 12||.0001|
|EF (%)||45 ± 12||63 ± 3||.0001|
|Fractional shortening (%)||29 ± 1||38 ± 5||.0001|
|E/e′ septal ratio||22 ± 10||6 ± 2||.0001|
|Grade of diastolic dysfunction||2 (1–2)||0 (0–0)||.0001|
|sPAP (mm Hg)||35 (30–40)||25 (20–25)||.0001|
|Pericardial effusion (%)||21 (81)||0 (0)||.0001|
|Cutoff||AUC||Sensitivity (%)||Specificity (%)||P|
|Grade of diastolic dysfunction||−0.612||.0001|
|Pericardial effusion present||−0.522||.0001|
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).
|Heart transplantation or death ( n = 36)||Transplant-free survivors ( n = 53)||P|
|Age (y)||58 ± 9||59 ± 8||NS|
|Men||19 (53%)||28 (53%)||NS|
|BMI (kg/m 2 )||24 ± 3||25 ± 4||NS|
|Heart rate (beats/min)||85 ± 16||81 ± 15||NS|
|SBP (mm Hg)||101 ± 21||119 ± 22||.0001|
|DBP (mm Hg)||69 ± 13||79 ± 10||.0001|
|NYHA class ≥ III||24 (67%)||15 (29%)||.001|
|eGFR (mL/min/1.73 m 2 )||64 ± 26||70 ± 31||NS|
|NT-proBNP (pg/mL)||6,125 (3,342–10,395)||1,116 (241–3,486)||.0001|
|TnT (μg/L)||0.06 (0.03–0.18)||0.005 (0.005–0.025)||.0001|
|FLC difference (mg/dL)||425 (169–832)||124 (59–305)||.0001|
|Mayo Clinic score||3 (2–3)||2 (1–2)||.001|
|Amyloid organs involved||3 (2–3)||3 (2–3)||NS|
|AAPSE (cm)||0.5 ± 0.3||0.9 ± 0.3||.0001|
|MAPSE (cm)||0.6 ± 0.3||1.1 ± 0.4||.0001|
|TAPSE (cm)||1.2 ± 0.7||1.8 ± 0.5||.0001|
|Septal wall thickness (mm)||18 ± 3||15 ± 3||.0001|
|LV mass (gr)||316 ± 109||244 ± 79||.001|
|LA volume (mL)||71 ± 26||56 ± 20||.004|
|EF (%)||45 ± 12||56 ± 7||.0001|
|Fractional shortening (%)||28 ± 9||34 ± 8||.003|
|Grade of diastolic dysfunction||2 (2–2)||1 (0–1)||.001|
|E/e′ septal ratio||22 ± 10||13 ± 9||.0001|
|sPAP (mm Hg)||38 ± 9||29 ± 7||.0001|
|Pericardial effusion||28 (78%)||25 (47%)||.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 ).
|TnT (>0.03μg/l) ∗||6.63||3.17–13.86||.0001|
|Log NT-proBNP (pg/ml)||5.60||2.87–10.93||.0001|
|Log FLC difference (mg/dl)||4.54||2.21–9.32||.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|
|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|