Left Ventricular Myocardial Work to Differentiate Cardiac Amyloidosis From Hypertrophic Cardiomyopathy

Cardiac amyloidosis (CA) is a progressive disorder with a reported median survival of 2.5 to 3.5 years after diagnosis.1Grogan M. Scott C.G. Kyle R.A. Zeldenrust S.R. Gertz M.A. Lin G. et al.Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system.J Am Coll Cardiol. 2016; 68: 1014-1020Crossref PubMed Scopus (393) Google Scholar Novel treatment options are emerging that could improve prognosis but seem most efficient when started at an early stage of the disease, underscoring the importance of early diagnosis. Echocardiography is the first-line imaging technique for the assessment of cardiac structure and function and might raise suspicion of CA. Although “relative apical sparing” of speckle-tracking-derived left ventricular (LV) longitudinal strain (LS) measurements was suggested to help diagnose CA,2Phelan D. Collier P. Thavendiranathan P. Popovic Z.B. Hanna M. Plana J.C. et al.Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis.Heart. 2012; 98: 1442-1448Crossref PubMed Scopus (608) Google Scholar differentiating CA from other causes of LV hypertrophy remains difficult. Assessment of LV myocardial work (MW) is a novel, noninvasive method to characterize LV systolic function, taking into consideration LV afterload. The aim of the current study was to assess the added value of LV MW measurements (and in particular of constructive work [CW]), to distinguish CA from hypertrophic cardiomyopathy (HCM), when evaluating patients presenting with LV hypertrophy. Eighty-three CA and 83 HCM (excluding apical HCM) patients, diagnosed between 2003 and 2019 and matched for age (59 ± 12 years) and septal thickness (17 ± 3 mm), were included. Disease diagnosis was made according to current guidelines.3Kittleson M.M. Maurer M.S. Ambardekar A.V. Bullock-Palmer R.P. Chang P.P. Eisen H.J. et al.Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association.Circulation. 2020; 142: e7-e22Crossref PubMed Scopus (258) Google Scholar,4Elliott P.M. Anastasakis A. Borger M.A. Borggrefe M. Cecchi F. Charron P. et al.2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Eur Heart J. 2014; 35: 2733-2779Crossref PubMed Scopus (38) Google Scholar The study was approved by the institutional review boards. Left ventricular LS was measured using automated function imaging (EchoPAC, ver. 202, GE Medical Systems, Horten, Norway). The LV MW calculation has been described elsewhere.5Russell K. Eriksen M. Aaberge L. Wilhelmsen N. Skulstad H. Remme E.W. et al.A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work.Eur Heart J. 2012; 33: 724-733Crossref PubMed Scopus (408) Google Scholar Briefly, LV LS measurements and noninvasive brachial blood pressure measures were combined, and the software created a noninvasive LV pressure-strain curve for the entire cardiac cycle. Left ventricular CW was defined as the work that results by shortening during systole and lengthening during isovolumic relaxation. Left ventricular global LS and LV global CW were averaged from 17 LV segments. Relative apical LS was calculated as average apical LS/(average basal LS + average mid LS). A relative apical LS value ≥ 1 (“apical sparing”) has previously been proposed for diagnosing CA.2Phelan D. Collier P. Thavendiranathan P. Popovic Z.B. Hanna M. Plana J.C. et al.Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis.Heart. 2012; 98: 1442-1448Crossref PubMed Scopus (608) Google Scholar Relative apical CW was not calculated, because this ratio does not adjust for LV afterload (having the blood pressure in both the numerator and denominator) and is therefore not different from relative apical LS. Receiver operating characteristics curves and binary regression analysis were performed, using CA as the outcome variable, to investigate whether relative apical LS and LV global LS or LV global CW had an independent diagnostic value for detection of CA, in addition to standard echocardiographic measures. Symptoms (defined as New York Heart Association class III-IV) were more prevalent in CA than in HCM patients (33% vs 4%, P < .001), although diuretic use was not different between groups (25% vs 29%, P = .600). Prevalence of LV hypertrophy on electrocardiogram was higher in patients with HCM (22% vs 5%, P < .001). Left ventricular diastolic dysfunction was more pronounced in CA patients, with larger left atrial volume index (45 ± 16 vs 36 ± 14 mL/m2, P < .001), higher E/e’ (17 [12-24] vs 12 [9-18], P < .001), and higher pulmonary artery pressures (38 ± 14 vs 27 ± 9 mm Hg, P < .001). In addition, septal to posterior wall thickness ratio was higher in HCM than in CA patients (1.4 vs 1.2, P < .001). Left ventricular systolic function parameters, assessed with LV ejection fraction (53% ± 13% vs 63% ± 13%), LV global LS (12% ± 5% vs 14% ± 5%), and LV global CW (1,022 ± 542 vs 1,793 ± 603 mm Hg%) were all significantly more impaired in CA patients (P < .001 for all). Relative apical LV LS ≥ 1 was able to detect CA in only 31/83 (37%) cases but had a larger area under the curve (AUC; 0.755) than LV global LS (AUC = 0.681). However, when looking at LV function global measurements, LV global CW (AUC = 0.820) discriminated CA from HCM better than LV global LS (AUC = 0.681), relative apical LV LS (AUC = 0.755), LV ejection fraction (0.729), septal to posterior wall thickness ratio (AUC = 0.775), left atrial volume index (AUC = 0.657), or E/e’ (AUC = 0.659; Figure 1). Receiver operating characteristics analysis showed an optimal LV global CW cutoff value of 1,541 mm Hg% to differentiate CA from HCM (sensitivity = 86%, specificity = 70%). Left ventricular global CW < 1,541 mm Hg% was able to detect CA in 43/52 (83%) patients having a relative apical LV LS < 1. On binary logistic regression analysis (adjusting for LV hypertrophy on electrocardiogram, New York Heart Association functional class III-IV, left atrial volume index, and E/e’), relative apical LV LS (β = 4.760; 95% CI, 1.306-17.356, P = .018) was independently associated with the diagnosis of CA. Importantly, whereas LV global CW (β = 0.998; 95% CI, 0.997-0.999; P < .001) was independently associated with the diagnosis of CA, LV global LS (β = 1.115; 95% CI, 0.987-1.260; P = .081) was not. These findings suggest the importance of adjusting the measures of LV systolic function for afterload in patients with CA, who often present with low blood pressure and possibly therefore an overestimation of LV systolic function according to other measures such as LV ejection fraction and LV LS. In addition, the combination of global and regional MW measurements may better reflect the complex alterations occurring at the myocardial level in CA and therefore have additional value to identify CA patients. Particularly, in patients with a relative apical LV LS (or relative apical LV CW) < 1, lower values of LV global CW should still raise the suspicion of CA and prompt the physician to further investigate the presence of CA.