Longitudinal Strain Predicts Survival and Response in AL Amyloidosis
- In systemic AL (light-chain immunoglobulin) amyloidosis, cardiac involvement is seen in more than two thirds of cases and is a major determinant of prognosis.
- Baseline longitudinal strain correlates with worsened cardiac involvement and predicts survival independent of patient characteristics, comorbidities and other measures of cardiac dysfunction.
- Absolute improvement of longitudinal strain is a useful additional measure of response to therapy.
In patients with cardiac involvement of systemic AL (light-chain immunoglobulin) amyloidosis, what is the impact of longitudinal strain (LS) on overall survival (OS) and the impact of changes in LS following treatment on outcomes?
All patients seen at the UK National Amyloidosis Center between 2010–2017 were included. Diagnosis was confirmed by central histology review and subtype identified by immunohistochemistry with specific antibodies. Baseline assessment included comprehensive echocardiography including strain measurements with subsequent reassessment at 12 and 24 months. Peak LS was generated from regional data from six segments in the apical four-chamber view to calculate an average value (a more negative score being better), using GE Vivid E9 ultrasound machines. All patients received bortezomib as first-line treatment.
Patients were stratified according to a European modification of the 2004 Mayo staging criteria: Mayo stage I, Mayo stage II, Mayo stage IIIa (N-terminal pro–B-type natriuretic peptide [NT-proBNP] <8500 ng/L), and IIIb (NT-proBNP >8500 ng/L). Hematologic complete response (CR) was defined by the absence of detectable monoclonal protein and normalization of free light chain ratio.
Of the 915 patients included in the study, 628 (69%) had cardiac involvement. Mean baseline LS worsened with advancing cardiac Mayo stage (stage I: -21.1%, stage II: -17.1%, stage IIIa: 12.9%, and stage IIIb: -12.1%; p < 0.0001). Similarly, median OS (the number of months until 50% of patients died) decreased with worsening baseline LS quartiles: ≤-16.2%: 80 months, -16.1 to -12.2%: 36 months, -12.1 to -9.1%: 22 months, and ≥-9.1%: 5 months (p < 0.0001). On multivariable analysis, baseline LS was a predictor of survival independent of multiple patient characteristics (age, sex, renal function) and comorbidities (atrial fibrillation, diabetes, hypertension, ischemic heart disease, valvular dysfunction). Furthermore, the two lowest LS quartiles were predictive of survival independent of modified cardiac Mayo staging, systolic blood pressure, ejection fraction, and left ventricular (LV) wall thickness (hazard ratios of 1.6 and 2.24, respectively).
In 342 patients in whom LS could be assessed at baseline and 12 months (225 patients died before 12 months and 49 patients had missing or uninterpretable data), >2% improvement in LS was associated with greater median OS (p < 0.0001). Improvement in LS and NT-proBNP was associated with improved median OS as compared to biomarker improvement alone (p < 0.0001). Change in LS also correlated with hematologic response, with improved LS in patients achieving CR and worsened LS in patients with incomplete response. Patients with both CR and improvement in LS had greater median OS than those with CR alone (p = 0.009).
In patients with systemic AL amyloidosis, baseline LS correlates with worsened cardiac involvement and survival. As a predictor of survival, baseline LS was found to be independent of patient characteristics, comorbidities, traditional markers of cardiac dysfunction (e.g., ejection fraction, LV wall thickness), and even the biomarker-based modified Mayo staging system.
The change in LS on serial measurement may also have prognostic value, as it correlated with both survival and hematologic response in patients who survived to 12 months. Multivariable analysis was not performed, however, so its value as an independent predictor of outcome remains unclear.
This is the first report of a large cohort of prospectively followed patients with AL amyloidosis, of whom 69% had cardiac involvement. Multivariable analysis showed that poor baseline LS remained a predictor of poor outcome independent of multiple patient characteristics, comorbidities, and notably the standard biomarker-based system used for defining prognosis in these patients. If these results are validated in future studies, baseline LS may be incorporated into future clinical practice guidelines.
Despite the size of the cohort, one notable limitation was the single-center design of the study. Likewise, strain analysis was performed using only six segments from the four-chamber apical view, as opposed to the more widely used “global longitudinal strain,” which incorporates strain from apical two-, three-, and four-chamber views. While the simpler analysis was chosen to minimize exclusion of patients due to missing or poor-quality data, the findings may need to be validated using the more established global strain model.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Hypertension
Keywords: Amyloidosis, Atrial Fibrillation, Biomarkers, Blood Pressure, Bortezomib, Cardiomyopathies, Cardiotoxicity, Diabetes Mellitus, Diagnostic Imaging, Echocardiography, Heart Failure, Hypertension, Immunoglobulin Light-chain Amyloidosis, Myocardial Ischemia, Natriuretic Peptide, Brain, Peptide Fragments, Stroke Volume, Ultrasonography
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